CHAPTER 24: PATHOPHYSIOLOGY OF HYPERTENSION

More than 1 billion individuals worldwide, including at least 70 million Americans, have high blood pressure (BP) warranting some form of treatment.^1,2,3,4 Higher-than-optimal BP is the largest contributor to global mortality, and approximately 9.4 million deaths per year are attributed to uncontrolled hypertension.^2,3,4 As life expectancy continues to increase, hypertension will become an even more important medical and public health issue because BP typically increases with aging in most industrialized countries. In the United States, 50% of people 60 to 69 years of age and approximately 75% of people 70 years or older have hypertension.³ In some nonindustrialized populations, however, BP does not rise with increasing age, and only a small fraction of the population develops hypertension. This suggests that predisposing environmental factors play a major role in causing hypertension and that an increase in BP with aging is not inevitable when these factors are absent.

A direct positive relationship between BP and cardiovascular disease (CVD) risk has been observed in men and women of all ages, races, ethnic groups, and countries, regardless of other risk factors for CVD.¹ Observational studies indicate that death from CVD increases progressively and linearly as BP increases above 115 mm Hg systolic and 75 mm Hg diastolic.¹ For every 20 mm Hg increase in systolic BP or 10 mm Hg increase in diastolic BP, there is a doubling of mortality from both ischemic heart disease and stroke in all age groups from 40 to 89 years of age.⁵

Despite major advances in our understanding of its pathophysiology and the availability of many drugs that can effectively reduce BP in most hypertensive subjects, hypertension continues to be the most important modifiable risk factor for CVD.

BP is a variable, quantitative trait with a nearly normal distribution. In industrialized societies, where there is typically higher dietary sodium and increasing body weight with age, the BP distribution is skewed slightly to the right.

BP classification is determined through analysis of observational and experimental data (clinical trials) regarding the relationship of BP and cardiovascular risk. Several organizations provide BP or hypertension classifications based largely on measurements obtained in a single encounter (“office” BPs). Classifications based on home BP monitoring and 24-hour ambulatory BP monitoring will likely be common in the future.⁶

The cutoff points for BP classification are generally driven by evidence from clinical trials and represent recommended levels for initiation of pharmacological therapy, goal BP, and recommended levels for initiation of nonpharmacological therapy. The levels for initiation of drug therapy and goal BP have traditionally been the same BP level.

The most commonly cited and used BP classifications are the 2003 Seventh Report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)⁷ (Table 24–1) and the 2013 European Society of Cardiology/European Society of Hypertension Guidelines for the Management of Hypertension⁸ (Table 24–2). The JNC guidelines will, in the future, be replaced by guidelines from the American College of Cardiology/American Heart Association.⁹

Results of the Systolic Blood Pressure Intervention Trial (SPRINT)^10,11 will have an impact on upcoming guidelines, including the classification of BP. The SPRINT protocol called for treating participants over age 50 years with systolic BP of 130 to 180 mm Hg and high cardiovascular risk to goal systolic BP of 140 or 120 mm Hg. Based on a clear benefit for the systolic BP goal of 120 mm Hg, we anticipate that the threshold for initiation of pharmacological therapy and the goal systolic BP may be reduced compared to previous guidelines.

Primary (Essential) Hypertension

Primary (essential) hypertension accounts for about 95% of all cases of hypertension and has been traditionally defined as high BP for which an obvious secondary cause (eg, renovascular disease, aldosteronism, pheochromocytoma, or gene mutations) cannot be determined.

Although primary hypertension is heterogeneous, some of the main causes of high BP are known. For example, overweight and obesity may account for 65% to 75% of the risk for primary hypertension, as discussed later in this chapter. Sedentary lifestyle, excess intake of alcohol or salt, and low potassium intake are also known to increase BP in some patients. Thus, identified causes can be often found in patients classified as having primary hypertension.¹²

This chapter discusses basic concepts of circulatory regulation, the physiologic mechanisms involved in short- and long-term BP control, and the pathophysiologic changes that can lead to secondary hypertension as well as primary hypertension. We also review interactions of genetic and environmental factors that influence intermediate phenotypes such as activity of the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), endothelial factors, oxidative stress, and natriuretic hormones. These, in turn, influence vascular resistance, cardiac output, renal excretion of salt and water, and therefore BP.

Relationship of Tissue Blood Flow and Cardiac Output Regulation

Discussion of cardiac output (CO) regulation often begins with the well-known formula cardiac output = stroke volume × heart rate. This equation describes mathematically the determinants of cardiac pumping but does not elucidate another major factor that normally controls CO—the venous return (total tissue blood flow), which is the amount of blood available for the heart to pump.

Figure 24–1 illustrates the relationship between CO and tissue blood flows; it is obvious that CO, in the steady state, is equal to the sum of the blood flows in the body’s tissues and organs. Removing one kidney, for example, decreases venous return to the heart by approximately 10% (assuming that total flow to both kidneys is approximately 20% of the CO). Decreased CO would also occur with amputation of an arm or a leg, or removal of any other tissue from the body. Conversely, increased CO occurs when additional tissue is added to the body during normal growth, weight gain, or pregnancy. These examples illustrate that CO is determined not only by the pumping ability of the heart but also by the peripheral circulation. Except when the heart is severely weakened and unable to adequately pump the venous return, CO (total tissue blood flow) is determined mainly by the metabolic needs and other special requirements of the body’s tissues and organs; the heart plays a permissive role is controlling CO and intrinsic and neurohumoral mechanisms normally allow the heart to effectively accommodate large changes in venous return.

This conceptual framework helps to explain changes in CO during exercise (when metabolic activity and skeletal muscle blood flow are increased), after eating a large meal (which increases metabolic activity and gastrointestinal blood flow), and in pathophysiologic conditions such as hypertension, in which CO and tissue blood flows are usually normal unless metabolic demands of the tissues are altered.

The importance of tissue blood flow regulation in determining CO can also be illustrated by considering the chronic effects of vasodilators and vasoconstrictors. In most cases, CO changes very little even when there are high levels of circulating vasoconstrictors (eg, angiotensin II [Ang II]) or vasodilators (eg, calcium channel blockers). If CO regulation is the sum of all local blood flow regulations, why is CO not significantly altered in these conditions?

To answer this question, consider one of the most fundamental principles of circulatory function—the ability of each tissue to autoregulate its own blood flow according to the metabolic needs and other functions of the tissue.^13,14,15 Administration of a powerful vasoconstrictor, such as Ang II, may cause a transient decrease in tissue blood flow and CO but usually has little long-term effect if tissue metabolic rate is unchanged. Likewise, vasodilators cause only short-term changes in tissue blood flow and CO if they do not alter tissue metabolism.

Therefore, consideration of tissue blood flow control is important for understanding CO regulation. Local tissue blood flow regulation involves short- and long-term mechanisms. Acute control occurs within seconds or minutes as a result of constriction or dilatation of the vasculature. After administration of a vasoconstrictor that does not alter tissue metabolic rate, there is a transient decrease in tissue supply of nutrients and oxygen and accumulation of metabolic waste products. This, in turn, causes vasodilation and return of tissue blood flow toward normal. In tissues where blood flow regulation is not determined mainly by metabolic needs, such as the kidney, some vasoconstrictors, such as Ang II, may cause small, sustained decreases in blood flow that barely reduce CO. Other short-term controls, such as the myogenic response, also alter vascular resistance in response to changes in BP and help to autoregulate tissue blood flow.¹⁶

Long-term blood flow regulation takes place over days or weeks and involves structural changes in the blood vessels, such as thickening of vessel walls and decreased numbers of capillaries (rarefaction) in some tissues when BP is chronically elevated. When tissues grow, additional blood vessels are generated (angiogenesis or vasculogenesis) to provide the required blood flow and metabolic substrates for the tissues. Together, the short- and long-term mechanisms maintain the required levels of blood flow in each tissue to ensure normal function. Thus, in most physiologic conditions, excluding those associated with impaired cardiac pumping ability, CO reflects mainly the combined actions of multiple control mechanisms for blood flows in the body’s tissues and organs.

In conditions such as heart failure, or when large increases in cardiac output are needed to meet the metabolic demands of the body’s tissues, such as exercise, various factors that alter cardiac pumping also play a major role in regulating cardiac output.

Blood Flow Regulation in Hypertension

The main function of the circulation is to provide adequate blood flow to each tissue to meet its requirements. This is achieved by a combination of local tissue controls that regulate vascular tone as well as overall adjustments of the circulation that influence cardiac pumping and vascular tone.^13,17 For example, during intense exercise, local conditions (eg, accumulation of metabolites or decreased levels of oxygen and nutrients) in skeletal muscles cause intense vasodilation that permits adequate blood flow to match the increased metabolic requirements of the muscles. Although decreased peripheral vascular resistance tends to decrease BP, this is usually offset by multiple neurohumoral changes (eg, sympathetic stimulation) that tend to elevate BP.

If decreased vascular resistance continues for several days, such as occurs with anemia or with opening a large arteriovenous fistula, additional adjustments take place that cause salt and water retention by the kidneys and increased blood volume or even hypertrophy of the heart if the stimulus lasts for several weeks. Thus, multiple factors that control the circulation, including those that influence CO, BP, blood volume, and others, normally work in concert to provide adequate tissue blood flow.

These same mechanisms also operate in hypertension. However, one of the important characteristics of many, but not all, hypertensive patients is that they have increased total peripheral vascular resistance (TPR). In most instances, however, tissue blood flows are approximately the same in normotensive and hypertensive subjects and are regulated at a level that is adequate for the tissue needs.¹⁸ The elevated TPR observed in many patients with hypertension appears to be an autoregulatory response that helps to maintain normal tissue blood flow despite increased BP rather than a primary cause of the hypertension. Thus, the hemodynamic pattern often (but not always) observed in nonobese subjects with primary hypertension is normal blood flow, normal oxygen consumption, and elevated vascular resistance.¹⁸

Cerebral blood flow, for example, shows a normal value of about 50 mL/min/100 g per tissue weight in primary hypertension. Coronary blood flow is elevated in essential hypertension in proportion to the increase in myocardial hypertrophy. Blood flow per unit weight of heart muscle is usually normal, however, with a value of about 80 mL/min/100 g per tissue weight. Splanchnic blood flow is slightly reduced in essential hypertension, having a typical value of about 750 mL/min/m² of surface area compared with about 800 mL/min/m² in normotensive subjects. Skin blood flow is also normal in individuals with primary hypertension.

Renal blood flow may be increased, normal, or decreased in primary hypertension. These seemingly disparate observations, however, should be interpreted with regard to the special functional needs of the kidney and the conditions under which renal blood flow is studied. For example, increased dietary protein, high sodium intake, and excess weight gain all are associated with increased renal blood flow. Nephron loss, which may occur with prolonged, uncontrolled hypertension and diabetes, leads to reduction in renal blood flow. Impaired renal blood flow is also related to the cause of hypertension in some individuals.

Although resting skeletal muscle blood flow is usually normal in primary hypertension, several differences in blood flow regulation have been noted. For example, the ability of skeletal muscle blood vessels to dilate in some patients with primary hypertension is impaired. This reduced blood flow “reserve” in hypertension is probably a result of structural limitations imposed by blood vessel hypertrophy and of endothelial dysfunction and impaired release of nitric oxide (NO).

In general, the maximal level of exercise, as quantified by oxygen uptake, is depressed in proportion to the severity of hypertension. BP is high before exercising and increases even further during exercise. In the presence of impaired vasodilation, elevated BP boosts blood flow through the skeletal muscle but it also increases cardiac afterload, which limits CO and exercise performance. At each level of exercise below maximum, however, CO and skeletal muscle blood flow are generally identical to flows seen in normotensive subjects.¹⁸ These flows are achieved at higher vascular resistances and higher BPs; the resistance and BP effects cancel each other to yield a normal blood flow in most tissues.

In obese hypertensive patients, resting skeletal muscle blood flow per gram of tissue weight may be elevated compared with lean individuals. However, increased muscle blood flow during exercise is attenuated and forearm-reactive hyperemia after temporary occlusion of the brachial artery is less in obese than in lean normotensive subjects.¹⁹ Thus, although obesity-associated hypertension may be associated with increased resting blood flow, flow reserve is often reduced.

In older hypertensive individuals, total tissue blood flow (ie, CO) may be reduced compared with flow in younger individuals. This is perhaps not surprising if one considers that lean muscle mass usually decreases with aging. Because CO represents total tissue blood flow, decreased muscle mass and decreased physical activity characteristic of older hypertensive patients also are associated with reduced CO and decreased total body oxygen consumption.

Arterial Pressure and Regional Blood Flow Regulation

Adequate tissue blood flow in response to normal daily activities requires adequate BP. When a person with normal autonomic reflexes begins to exercise, skeletal muscle vascular resistance is reduced, but muscle blood flow and CO increase markedly and BP remains relatively constant. In persons with autonomic dysfunction, exercise also decreases skeletal muscle vascular resistance, but BP decreases and muscle blood flow and CO increase only modestly because of impaired autonomic reflexes. Therefore, exercise is not well tolerated and syncope may occur.

When CO is inadequate to meet normal tissue needs, as in heart failure or severe hypovolemia, strong activation of the SNS, the RAAS, and other hormonal factors produce vasoconstriction that may override normal flow regulation in some organs, such as skeletal muscle and skin. This keeps BP from falling too low and provides adequate blood flow to the vital organs, especially the brain and the heart.

Basic Principles of Blood Pressure Regulation

The major function of BP is to provide the driving force that moves blood through the vascular system to supply the needs of the tissues. Consequently, BP regulation is a complex physiologic function that depends on integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems.

BP varies throughout the day, depending on the activity of the body, environmental influences, and the responses of multiple BP control systems. Hypertension is usually considered to be a disorder of the average level at which BP is regulated during resting conditions, although there is increasing interest in other measures of BP, including peak arterial pressure, lability of BP, nighttime and daytime BP, responses of BP to stress, and so forth.²⁰ Many of the cardiovascular derangements associated with hypertension, such as cardiac and vascular hypertrophy, arise as compensatory mechanisms for hypertension, and reducing BP can largely reverse these changes if they have not progressed too far.

The multiple local, hormonal, neural, and renal systems that regulate BP are often discussed in terms of how they influence cardiac pumping or vascular resistance because of the well-known formula mean arterial pressure = CO × TPR. This mathematical description of BP (with addition of factors that influence vascular capacity and transcapillary exchange) adequately explains short-term BP regulation but is inadequate when discussing abnormalities of long-term BP regulation, such as hypertension.

To illustrate this point, consider the changes in BP, CO, and extracellular fluid volume after a 25% increase in TPR caused by closure of a large arteriovenous (AV) fistula. In this case, cardiac pumping ability is not directly altered and TPR is chronically increased by 25%. One might assume that BP would also rise because of increased TPR. However, there are no detectable changes in mean arterial pressure a few days after AV fistula closure despite a sustained increase of TPR.²¹ Likewise, increasing TPR by amputation of a limb or hypothyroidism (which reduces metabolic rate of the tissues and increases vascular resistance) or decreasing TPR by creating an AV fistula, anemia, or hyperthyroidism fails to have a significant long-term effect on mean arterial pressure (Fig. 24–2).²¹ To explain BP regulation in these circumstances, we introduce two other concepts: (1) time dependency of BP control mechanisms and (2) the necessity of maintaining balance between intake and output of water and electrolytes and the role of BP in maintaining this balance.

Feedback Control Systems for Blood Pressure Are Time Dependent

The effectiveness of BP control systems can be expressed in terms of feedback gain, which is defined as the amount of “correction” by the control system divided by the remaining “error” after a perturbation. For example, if a disturbance initially increases BP from 100 to 150 mm Hg and a control system returns BP to 125 mm Hg, the correction would be -25 mm Hg, and the remaining error would be +25 mm Hg. Therefore, the feedback gain would be -25/+25, or -1.0, indicating a negative feedback that corrects one half of the initial disturbance. The higher the feedback gain, the more powerful the control system.

BP control systems are often considered as if they were static, and time dependency is usually not discussed. Short-term mechanisms are often emphasized to a greater degree than long-term controls, probably because they have been studied much more extensively and are easier to explain, even though most cardiovascular disorders, including hypertension, involve abnormalities of long-term regulation.

If we examine the maximal feedback gains of several BP controllers, it is obvious that their quantitative importance is highly time dependent. Figure 24–3 shows the response of some of the major control systems after a sudden change in BP, as might occur with rapid blood loss. Three important neural control systems begin to function powerfully within seconds: (1) the arterial baroreceptors, which detect changes in BP and send appropriate autonomic reflex signals back to the heart and blood vessels to return the BP toward normal; (2) the chemoreceptors, which detect changes in oxygen or carbon dioxide in the blood and initiate autonomic feedback responses that influence BP; and (3) the central nervous system (CNS), which responds within a few seconds to ischemia of the vasomotor centers in the medulla, especially when BP falls below about 50 mm Hg. Each of these nervous control mechanisms works rapidly and can have potent effects on BP. Also note, however, that the feedback gains of these systems decreases with time, as a disturbance of BP is maintained.

Within a few minutes or hours after a BP disturbance, additional controls react, including (1) a shift of fluid from the interstitial spaces into the blood in response to decreased BP (or a shift of fluid out of the blood into the interstitial spaces in response to increased BP); (2) the RAAS, which is activated when BP falls too low and suppressed when BP increases above normal; and (3) multiple vasodilators systems (not shown in the figure) that are suppressed when BP decreases and stimulated when BP increases above normal.

Most of the BP regulators are proportional control systems. This means that they can partly correct a BP abnormality. The arterial baroreceptor reflex system, for example, has a proportional feedback gain of approximately 2.0 during acute changes in BP and therefore buffers about two-thirds of a sudden change in the BP.

There is one BP control system, the renal–body fluid feedback system, with near infinite feedback gain if it is given enough time to operate.^21,22 Thus, the renal–body fluid feedback control mechanism does not stop functioning until the BP returns nearly all the way back to its original control level, as discussed below.

Long-Term Blood Pressure Regulation by Renal–Body Fluid Feedback

Figure 24–4 shows the conceptual framework for understanding long-term control of BP by the renal–body fluid feedback. Extracellular fluid volume is determined by the balance between intake and excretion of salt and water by the kidneys. Even temporary imbalances between intake and output can lead to changes in extracellular volume and potentially changes in BP. During steady-state conditions, there must be balance between intake and output of salt and water; otherwise, there would be continued accumulation or loss of fluid leading to circulatory collapse.

A key mechanism for regulating salt and water balance is pressure natriuresis and diuresis, the effect of increased BP to raise sodium and water excretion.^21,23 Under most conditions, this mechanism stabilizes BP and body fluid volumes. For example, when BP increases above the renal set point, because of increased TPR or increased cardiac pumping, this also increases sodium and water excretion via pressure natriuresis. As long as fluid excretion exceeds fluid intake, extracellular fluid volume continues to decrease, reducing venous return and CO until BP returns to normal and fluid balance is reestablished.

An important feature of pressure natriuresis is that hormonal and neural control systems can amplify or attenuate the basic effects of BP on sodium and water excretion.¹² For example, during chronic increases in sodium intake, only small changes in BP occur in most people. One reason for this insensitivity of BP to changes in salt intake is decreased formation of antinatriuretic hormones such as Ang II and aldosterone, which enhance the effectiveness of pressure natriuresis and allow sodium balance to be maintained with little or no increase in BP. On the other hand, overactivation of these antinatriuretic systems can reduce the effectiveness of pressure natriuresis, thereby necessitating greater increases in BP to maintain sodium balance.¹²

Another important feature of pressure natriuresis is that it continues to operate until BP returns to nearly the original set point. In other words, it acts as part of a near infinite gain feedback control system.²² As far as we know, it is the only feedback system for BP regulation that displays near infinite feedback gain, and this property makes it a dominant long-term BP controller.

Figure 24–5 illustrates the near infinite gain characteristic of the renal–body fluid feedback system. In this case, BP is increased without a change in pressure natriuresis, as would occur with increased TPR because of closure of an AV fistula, coarctation of the aorta below the kidneys (aortic coarctation above the kidneys causes hypertension), or other changes that increase TPR without influencing renal vascular resistance. The peripheral constriction initially increases BP from point A to point B, but the rise in BP cannot be sustained; as long as pressure natriuresis is unaltered, sodium excretion will increase above intake, thereby reducing extracellular fluid volume and CO until BP eventually returns to normal. In fact, normal BP is the only point at which sodium and water balance can be maintained if pressure natriuresis is unaltered. Likewise, disturbances that decrease TPR or alter cardiac function without influencing renal pressure natriuresis have no long-term effect on BP.^21,22

In all types of human or experimental hypertension studied thus far, there is a shift of pressure natriuresis that appears to sustain the hypertension. In some cases, abnormal pressure natriuresis is caused by intrarenal disturbances that alter renal hemodynamics or increased tubular reabsorption. In other cases, altered kidney function is caused by extrarenal disturbances, such as increased SNS activity or excessive formation of antinatriuretic hormones that reduce the kidney’s ability to excrete sodium and water and eventually increase BP. Consequently, effective treatment of patients with hypertension requires interventions that reset pressure natriuresis toward normal BP either by directly increasing renal excretory capability (eg, with diuretics), or by reducing antinatriuretic influences (eg, with RAAS blockers) on the kidneys.

Severe kidney disease has long been recognized as a cause as well as a consequence of hypertension. However, the importance of more subtle renal dysfunction in the pathogenesis of essential hypertension has not been widely appreciated, partly because there are no obvious renal defects in many patients with primary hypertension. Measurements commonly used to evaluate kidney function, such as glomerular filtration rate (GFR), renal blood flow, serum creatinine, and sodium excretion are often within the normal range in the early stages of hypertension before kidney damage occurs. On the other hand, TPR is often increased in hypertensive subjects, leading many to conclude that vasoconstriction is the cause of increased BP. However, as discussed previously, increased TPR may be an autoregulatory response to increased BP in many hypertensive subjects and in the absence of altered kidney function does not cause sustained hypertension.

An observation that points toward abnormal kidney function as a key factor in hypertension is that most models of experimental hypertension and monogenic forms of human hypertension are caused by obvious insults to the kidneys that alter renal hemodynamics or tubular reabsorption. For example, constriction of the renal arteries (eg, Goldblatt hypertension), compression of the kidneys (eg, perinephritic hypertension), or administration of sodium-retaining hormones (eg, mineralocorticoids or Ang II) are all associated with initial reductions in GFR or increases in renal tubular reabsorption prior to development of hypertension. Likewise, in monogenic human hypertension, the common pathway to hypertension appears to be increased renal sodium reabsorption caused by mutations that directly increase renal electrolyte transport or the synthesis/activity of antinatriuretic hormones. As BP increases, the initial renal changes are often obscured by compensations that restore kidney function toward normal. Increased BP then initiates a cascade of cardiovascular changes that may be more striking than the initial disturbance of kidney function. For this reason, the importance of renal dysfunction in causing hypertension has often been underestimated. However, one aspect of kidney function that is abnormal in all types of experimental and clinical hypertension is renal pressure natriuresis.^12,21

The general types of renal abnormalities that can alter pressure natriuresis and cause chronic hypertension include increased preglomerular resistance, decreased glomerular capillary filtration coefficient, reduced numbers of functional nephrons, and increased tubular reabsorption (Table 24–3). Some of these kidney abnormalities increase salt sensitivity of BP, whereas others cause salt-insensitive hypertension.

Increased Preglomerular Resistance

Generalized Increases in Preglomerular Resistance Cause Salt-Insensitive Hypertension

Examples of generalized increases in preglomerular resistance are those caused by suprarenal aortic coarctation or constriction of one of the renal arteries and removal of the contralateral kidney (eg, one-kidney, one-clip Goldblatt hypertension). Immediately after constriction of the renal artery or aortic coarctation, renal blood flow decreases, renin secretion increases, and sodium excretion transiently decreases. Within a few days, sodium excretion returns to normal, and sodium balance is reestablished (Fig. 24–6). If sodium intake is normal, renin secretion also returns to normal in the established phase of hypertension. At this point, most indices of renal function are nearly normal, including BP distal to the stenosis if the constriction is not too severe. The rate at which renal function returns to normal and the time course for development of hypertension depend on the severity of the stenosis, sodium intake, and the rate of Ang II formation.^21,24

How do these experimental models relate to human hypertension, other than the obvious conditions of aortic coarctation or renal artery stenosis? Presumably, functional or pathologic increases in preglomerular resistance at other sites besides the main renal arteries, such as the interlobular arteries or afferent arterioles, could increase BP through the same mechanisms as activated by clipping the renal artery. For example, widespread structural increases in afferent arteriolar resistance (eg, nephrosclerosis) or functional increases in resistance caused by excessive activation of the SNS or high levels of catecholamines (eg, pheochromocytoma) would also cause hypertension through the same mechanisms as constriction of the main renal artery.

Some patients with primary hypertension have nearly the same characteristics seen in the one-kidney, one-clip Goldblatt model of hypertension, including nearly normal GFR and plasma renin activity, a parallel shift of pressure natriuresis to higher BP, and a relatively salt-insensitive form of hypertension.^21,24 Thus, primary hypertension in some patients may be caused by functional or pathologic increases in preglomerular resistance. This is almost certainly the case in patients who have severe atherosclerotic lesions in the renal blood vessels.

Patchy Increases in Preglomerular Resistance Cause Salt-Sensitive Hypertension

In the two-kidney, one-clip Goldblatt model of hypertension and in patients with a stenosis in only one renal artery, there is a nonhomogeneous increase in preglomerular resistance with ischemia occurring in nephrons of the clipped or stenotic kidney; nephrons in the contralateral nonclipped or nonstenotic kidney have normal or increased single-nephron blood flow and GFR. Whereas the underperfused clipped kidney secretes large amounts of renin, the untouched kidney secretes very little renin.¹²

An important distinction between a generalized increase in preglomerular resistance and patchy, nonhomogeneous increases in preglomerular resistance is the evolution of renal injury associated with hypertension. When there is a generalized, homogeneous increase in preglomerular resistance, the glomeruli are protected from the damaging effects of increased BP. In the two-kidney, one-clip model, however, the glomeruli of the untouched kidney are subjected to the effects of increased BP. With prolonged hypertension, pathologic changes in the untouched kidney add to the impairment of overall renal excretory capability. At this stage, removal of the clipped kidney only partially restores BP to normal. However, removal of the contralateral untouched kidney and unclipping the stenotic kidney usually normalizes BP. Thus, chronic exposure to high BP in the untouched kidney causes structural changes as well as functional changes that contribute to the progression of hypertension.

The relevance of experimental models of nonhomogeneous increases in preglomerular resistance to human hypertension is obvious when there is stenosis of only one renal artery with the contralateral kidney being initially unaffected. Also, some patients with primary hypertension may have patchy nephrosclerosis within each kidney. In these instances, the ischemic nephrons secrete large amounts of renin, and the nonischemic nephrons may initially have increased single-nephron GFR. The combined effects of hypertension and hyperfiltration, however, may eventually damage the nephrons that were not initially ischemic, leading to progressive nephron loss.

Decreased Glomerular Capillary Filtration Coefficient

Reducing the glomerular capillary filtration coefficient (K_f) initially lowers GFR and sodium excretion while stimulating renin release and causing dilation of afferent arterioles via a macula densa feedback.^12,21 The sodium retention and increased Ang II formation increase BP, which then helps to restore GFR and renin release toward normal. After these compensations, the main persistent abnormalities of kidney function are reduced filtration fraction, increased glomerular hydrostatic pressure, and increased renal blood flow. BP is often salt sensitive when reductions in K_f are severe.

Compensatory increases in BP and glomerular hydrostatic pressure, which offset a decrease in K_f and restore sodium excretion to normal, may also lead to additional renal dysfunction over a period of years by causing further glomerular injury; the gradual injury and loss of glomeruli further reduce K_f and elicit additional increases in BP to maintain normal water and electrolyte balances. Such a sequence may initiate progressive kidney damage, worsening of hypertension, and greater salt sensitivity of BP.

The clinical counterparts of this sequence may be found in hypertension caused by glomerulonephritis or by other conditions that cause thickening and damage to the glomerular capillary membranes, such as chronic diabetes mellitus.¹²

Nephron Loss

A factor that contributes to BP salt sensitivity in some hypertensive patients is loss of functional nephrons. Complete loss of nephrons (eg, surgical reduction of kidney mass or unilateral nephrectomy) in the absence of other abnormalities may not lead to significant hypertension.¹² In contrast, loss of functional nephrons because of ischemia or infarction of renal tissue usually induces hypertension that initially is caused by increased renin secretion and Ang II formation and then is eventually mediated by additional abnormalities, such as immunologic and renal injury, in the established phase of the hypertension.²⁵

Reductions in nephron number might be expected to impair renal excretory capability and cause hypertension regardless of whether the loss was associated with renal ischemia. Yet, experimental studies show that surgical removal of large amounts of the kidney, to the point that uremia occurs, rarely causes severe hypertension as long as sodium intake is normal.^21,26 Figure 24–7 shows the effect of surgically reducing kidney mass on salt sensitivity in dogs. As long as sodium intake was normal, surgical reduction of kidney mass by 25%, or even as much as 70%, did not markedly alter BP.²⁶ However, after loss of kidney mass, BP became exquisitely sensitive to changes in sodium intake, and with high sodium intake, BP increased by approximately 40 mm Hg.

The reason hypertension often does not develop with nephron loss is that glomerular filtration and tubular reabsorption capability are proportionally reduced so that balance between filtration and reabsorption can be maintained without major adaptive changes in BP.

Reducing the number of functional nephrons, however, makes the kidneys susceptible to additional insults that impair their function or to additional challenges of sodium homeostasis. Thus, hypertension associated with excess mineralocorticoids is much more severe after reducing kidney mass. Likewise, the kidney’s ability to increase sodium excretion in response to the additional challenge of high sodium intake is accompanied by much larger increases in BP when kidney mass is reduced.^12,21

After loss of entire nephrons, the surviving nephrons must excrete greater amounts of sodium and water to maintain balance. This is achieved by increasing GFR and decreasing reabsorption in the remaining nephrons, resulting in increased sodium chloride delivery to the macula densa and suppression of renin release. This, in turn, impairs the kidney’s ability to further decrease renin secretion during high sodium intake, and BP becomes salt sensitive.

Nephron loss may also initiate compensatory changes that damage surviving nephrons. For example, over long periods of time, renal vasodilation and increased single-nephron GFR may lead to glomerulosclerosis and reductions in K_f. These pathologic changes, in addition to the loss of functional nephrons, may eventually impair pressure natriuresis sufficiently to cause substantial hypertension.

With normal aging, especially after age 40 to 50 years, there is gradual nephron loss that is accelerated by renal diseases, such as glomerulonephritis, diabetes mellitus, or long-standing hypertension. Thus, even though hypertension may not begin with nephron loss, chronic elevations in glomerular pressure and other metabolic abnormalities that are often associated with hypertension may eventually cause progressive nephron loss that amplifies the hypertension and makes BP more salt sensitive.

Nephron Loss by Partial Renal Infarction Causes Salt-Sensitive Hypertension

The experimental model of surgical reduction of kidney mass discussed above should not be confused with the model of partial renal infarction hypertension produced by tying off branches of the renal artery, the so-called 5/6 ablation model. This model is usually produced by removing one kidney and obstructing two of the three branches of the renal artery of the remaining kidney. In the infarction model, hypertension develops even without a high sodium intake because of ischemia of surviving nephrons, activation of the RAAS, and immune-mediated injury of the kidney.²⁵ The 5/6 renal ablation hypertension is a model of severe patchy renal ischemia with characteristics similar to that described for the two-kidney, one-clip Goldblatt model or nonhomogeneous patchy glomerulosclerosis. The clinical counterpart of this model occurs with partial renal infarction caused by septic emboli, thrombus, or trauma, or sometimes after corrective surgery for renal artery stenosis.

Increased Renal Tubular Sodium Reabsorption

Factors that increase renal tubular sodium reabsorption, such as excessive levels of mineralocorticoids or Ang II, can also cause hypertension. The severity of hypertension depends on the degree to which tubular reabsorption is stimulated and on other factors, such as the functional kidney mass and sodium intake.^12,21 With nephron loss or high sodium intake, the hypertensive potency of mineralocorticoids or Ang II is greatly enhanced.

Excessive Distal and Collecting Tubule Reabsorption Causes Salt-Sensitive Hypertension

One feature of hypertension caused by increased distal or collecting tubular reabsorption is that it is usually salt sensitive, with increased sodium intake exacerbating the hypertension. Increased reabsorption at sites beyond the macula densa, such as the distal tubules and collecting tubules, elicits chronic increased sodium chloride delivery to the macula densa, which, in turn, suppresses renin secretion.^12,21,23 Reduction of renin secretion to very low levels, characteristic of disorders associated with excessive distal or collecting tubular reabsorption, prevents further suppression of Ang II formation during high sodium intake, making BP salt sensitive.

Another feature of hypertension caused by increased tubular reabsorption (as occurs with excess aldosterone secretion) is that it is often associated with extracellular volume expansion. However, the initial volume expansion and increased CO usually subside because of pressure natriuresis and TPR increases because of the vascular autoregulatory mechanisms discussed previously. When increased tubular reabsorption is also associated with marked peripheral vasoconstriction, such as occurs with very high levels of Ang II, the degree of volume expansion depends on the relative effects of the vasoconstrictor on the peripheral blood vessels and the kidneys.^21,23 With severe peripheral vasoconstriction and decreased vascular capacitance, relatively small amounts of volume retention can lead to substantial hypertension.

Reduced Responsiveness of the Renin-Angiotensin-Aldosterone System Increases Salt Sensitivity of Blood Pressure

Figure 24–8 shows the importance of changes in Ang II formation in maintaining BP relatively constant during variations in salt intake from a very low level of 5 mmol/d up to 80, 240, and 500 mmol/d for 8 days at each level.^27,28 In normal dogs with a functional RAAS, there were only small increases in BP associated with this 100-fold range of sodium intakes. However, when Ang II was infused at a low level that initially had little effect on BP but prevented Ang II from being suppressed as sodium intake was raised, BP became very salt sensitive. After blockade of Ang II formation, BP also became salt sensitive, although pressure was maintained at a much lower level, especially when sodium intake was low.²⁸ Thus, one of the major functions of the RAAS is to permit wide variations in intake and excretion of sodium without large fluctuations in BP that would otherwise be needed to maintain sodium balance.

As discussed previously, focal nephrosclerosis or patchy preglomerular vasoconstriction, as occurs with renal infarction, leads to increased renin secretion in ischemic nephrons and very low levels of renin release by overperfused nephrons.¹² Thus, in ischemic, as well as overperfused, nephrons, the ability to adequately suppress renin secretion during high salt intake is impaired.

Another cause of reduced responsiveness of the RAAS is increased distal and collecting tubular sodium reabsorption as occurs with mineralocorticoid excess or mutations that increase distal and collecting tubule reabsorption (eg, Liddle syndrome). In these conditions, excess sodium retention causes almost complete suppression of renin secretion, resulting in an inability to further decrease renin release during high sodium intake. Consequently, BP becomes very salt sensitive.

Significance of Salt Sensitivity

Salt sensitivity of BP in humans is a quantitative phenotype, rather than following a bimodal categorization of salt sensitive or salt insensitive, and there is considerable heterogeneity of BP responses to changes in sodium intake in normotensive and hypertensive individuals.^29,30,31

Assessment of BP salt sensitivity in clinical studies is challenging. Although various methods have been used to assess salt sensitivity, none are widely used in clinical practice. Most salt-sensitivity protocols involve short-term changes in sodium intake, usually over a few days. Weinberger et al³¹ defined salt sensitivity as a 10 mm Hg or greater change in mean BP from the level measured after a 4-hour infusion of 2 L of normal saline compared with the level measured the morning after 1 day of a low-sodium (10 mmol) diet and administration of three doses of furosemide. With this definition, 51% of hypertensive and 26% of normotensive subjects were found to be salt sensitive.³¹ However, the repeatability of salt sensitivity in the same persons over long periods of time (years) is unclear, and it is not known whether short-term BP responses reliably predict the long-term effects of changes in salt intake. Measuring BP during prolonged changes in dietary sodium intake in outpatient protocols and clinical trials provides a more relevant assessment of BP salt sensitivity. However, chronic studies of salt sensitivity in humans lasting more than a few days are rare.

Clinical observations indicate that many demographic and pathophysiologic conditions are associated with salt sensitivity. Older individuals are usually more salt sensitive than young people, and blacks are often more salt sensitive than whites. However, there are many exceptions to these generalizations, and considerable heterogeneity exists in the BP responses to changes in salt intake.

Genetic factors independent of ethnicity have also been linked to BP salt sensitivity, especially monogenic disorders that increase distal and collecting tubule sodium reabsorption or that cause excess secretion of sodium-retaining hormones (eg, mineralocorticoids).³² Also, diabetes mellitus, renal diseases that cause nephron loss, and abnormalities of the RAAS are all associated with increased BP salt sensitivity.^29,33 Many of these examples appear to share two common pathways to salt sensitivity of BP: loss of functional nephrons or reduced responsiveness of the RAAS.

Salt Sensitivity and Target Organ Injury

Some studies suggest that salt sensitivity predicts which patients are at greatest risk for hypertensive target organ injury. Salt-sensitive hypertension is often associated with glomerular hyperfiltration and increased glomerular hydrostatic pressure (see Table 24–3); together, the hypertension and renal hyperfiltration promote glomerular injury and may eventually cause loss of nephron function. Clinical studies support this concept and demonstrate that whereas salt-sensitive individuals typically have increased glomerular hydrostatic pressure and albumin excretion when given a salt load, salt-resistant individuals have lower glomerular hydrostatic pressure and less urinary albumin excretion.³⁴

There is also evidence that salt-sensitive subjects die earlier than salt-resistant individuals. Weinberger et al³⁵ followed patients for more than 20 years and found that normotensive individuals with increased salt sensitivity died almost at the same rate as hypertensive individuals and much faster than salt-resistant individuals who were normotensive. Whether increased mortality was related to BP effects of salt or to other effects is still unclear. It is also not known whether chronic high salt intake, lasting over many years, may cause a person who is initially “salt insensitive” to become “salt sensitive” as a consequence of gradual renal injury.

Although impaired renal pressure natriuresis plays a central role in hypertension, not all disorders of pressure natriuresis originate within the kidneys. Inappropriate activation of multiple antinatriuretic hormone systems (eg, Ang II, aldosterone) that normally regulate sodium excretion or deficiency of natriuretic influences (eg, atrial natriuretic peptide [ANP], NO) on the kidneys can impair pressure natriuresis and cause chronic hypertension. Likewise, excessive SNS activation plays a major role in elevating BP in many hypertensive patients. The following sections discuss some of the neural, hormonal, and autacoid mechanisms that contribute to long-term BP regulation, their actions on the kidneys, and their potential roles in hypertension.

The Sympathetic Nervous System

The SNS is a major short- and long-term controller of BP. Sympathetic vasoconstrictor fibers are distributed to almost all regions of the vasculature, as well as to the heart and kidneys, and activation of the SNS can raise BP within a few seconds by causing vasoconstriction, increased cardiac pumping capability, and increased heart rate. Conversely, sudden inhibition of SNS activity can decrease BP to as low as half normal in less than 1 minute. Therefore, changes in SNS activity, caused by various reflex mechanisms, CNS ischemia, or by activation of higher centers in the brain, provide powerful and rapid, moment-to-moment regulation of BP.

The SNS also plays an important role in long-term BP regulation and in the pathogenesis of hypertension, in large part by activation of the renal sympathetic nerves.^12,36 There is extensive innervation of the renal blood vessels, juxtaglomerular apparatus, and renal tubules, and excessive activation of these nerves promotes sodium retention, increased renin secretion, and impaired renal-pressure natriuresis. Except for extreme circumstances, such as severe hemorrhage or other conditions associated with marked circulatory depression, activation of the renal sympathetic nerves is usually not great enough to cause major reductions in renal blood flow or GFR. However, even mild increases of the renal sympathetic activity stimulate renin secretion and sodium reabsorption in multiple segments of the nephron, including the proximal tubule, the loop of Henle, and distal segments.^12,36 Thus, the renal nerves provide a mechanism by which various reflex mechanisms and higher CNS centers may contribute to long-term BP regulation.

The preganglionic neurons that synapse with the renal sympathetic postganglionic fibers are located in the lower thoracic and upper lumbar segments of the spinal cord and receive multiple inputs from various regions of the brain, including the brainstem, forebrain, and cerebral cortex. These complex neural circuits provide multiple pathways by which neural reflexes and higher CNS centers can influence renal SNS activity and chronic BP regulation.

Evidence for a role of the renal nerves in hypertension comes from multiple studies showing that renal denervation (RDN) reduces BP in some models of experimental hypertension.^12,36 For example, complete RDN attenuates the development of hypertension in spontaneously hypertensive rats as well as in obese hypertensive dogs.^36,37,38 RDN may delay or attenuate increased BP in other forms of experimental hypertension, although some studies have not found an important role for the renal nerves in several forms of secondary hypertension. In Ang II hypertension, for example, decreased renal sympathetic activity appears to attenuate the rise in BP.³⁹

Human primary hypertension is often associated with increased renal sympathetic activity. In obese humans with resistant hypertension, catheter-based radiofrequency RDN lowered office BP for up to 24 months.^36,40 When 24-hour ambulatory BP was measured in a subgroup of patients, reductions in BP after RDN averaged -11/-7 mm Hg systolic/diastolic, although a recent trial failed to find a major effect of RDN on BP, compared to sham controls.⁴¹ However, these patients were already on at least three antihypertensive medications, including blockers of the RAAS, which may mediate at least part of the effect of the renal nerves on BP, and the extent of RDN was not verified. It appears that even under optimal conditions the usual radiofrequency method causes only 40-50% ablation of the renal nerves.^37,42 Increased efficacy of RDN (up to 75% ablation of the renal nerves) can be achieved if the radiofrequency ablation procedure is performed in the branches of the main renal artery close to the kidneys.⁴³ Longer periods of follow-up will be needed to determine if the renal nerves eventually regrow and reinitiate increases in BP, as has been observed in experimental animal models of RDN.

Whether RDN will prove to be an effective therapy for patients who are resistant to the usual pharmacological treatments remains to be determined. Although the mechanisms that activate renal sympathetic nerves in primary hypertension or in most experimental models are still unclear, we briefly discuss three that have attracted the interest of many researchers.

Role of Baroreceptor Reflexes in Hypertension

The importance of the arterial baroreceptors in buffering moment-to-moment changes in BP is clearly evident in baroreceptor-denervated animals, in which there is extreme BP variability during normal daily activities.⁴⁴ After baroreceptor denervation, BP increases to high levels or decreases to low levels with normal daily activities, although the average 24-hour mean arterial pressure is not markedly altered.

Although the arterial baroreceptors clearly provide a powerful means for acute BP regulation, their role in long-term BP regulation is controversial. Some studies suggest that the baroreceptors reset within a few days to the level of BP to which they are exposed and are reset to higher BP in chronic hypertension.⁴⁴ To the extent that resetting of baroreceptors occurs, this would attenuate their potency as a long-term controller of BP.

Other experimental studies, however, suggest that the baroreceptors do not completely reset and may contribute to chronic BP regulation. With prolonged increases in BP, the baroreflexes may contribute to reductions in renal sympathetic activity and promote sodium and water excretion, attenuating the increase in BP.⁴⁵ Thus, impairment of baroreflexes may cause increased lability of BP in hypertension and may fail to attenuate the increase in BP caused by other disturbances. However, there is currently little evidence that primary disturbances of baroreceptor function play a major role in causing chronic hypertension.

Chronic activation of the baroreceptors by electrical stimulation of the carotid sinus reduces BP in experimental hypertension.⁴⁶ In humans with hypertension that was resistant to drug treatment, electrical stimulation of baroreceptors also significantly reduced BP.⁴⁷ However, the primary role of arterial baroreceptors in hypertension, as in normotension, is to buffer deviations in BP from the set-point determined by renal pressure natriuresis.

Increased BP lability associated with baroreflex dysfunction, however, is accompanied by periodic large increases in BP that may cause gradual renal injury and eventually lead to chronic hypertension. Studies in experimental animals show, for example, that baroreceptor-denervated animals have significant structural changes in the kidneys, including glomerular injury.⁴⁸

Does Chronic Stress Cause Hypertension by Sympathetic Nervous System Activation?

Acute physiologic stresses, including pain, exercise, exposure to cold, and mental stress, can all lead to increased SNS activity and transient hypertension. It is also widely believed that chronic stress may lead to long-term increases in BP. Support for this concept comes largely from a few epidemiologic studies showing that air traffic controllers, lower socioeconomic groups, and other groups who are believed to lead more stressful lives also have increased prevalence of hypertension.⁴⁹ There is limited evidence, however, for a direct cause-and-effect relationship between psychosocial stress and chronic hypertension. Nevertheless, many researchers believe that stress is an important cause of hypertension in humans.

Obesity

Excess weight gain appears to be a major cause of human primary hypertension. The mechanisms responsible for obesity hypertension are closely linked to increased renal SNS activity.^12,50,51,52 Obese persons have elevated SNS activity in various tissues, including the kidneys and skeletal muscle, as assessed by microneurography, tissue catecholamine spillover, and other methods. Studies in experimental animals and humans indicate that combined α- and β-adrenergic blockade markedly attenuates hypertension associated with obesity.^50,53 Moreover, bilateral renal denervation greatly attenuates sodium retention and hypertension in obese dogs and obese patients with primary hypertension.^37,40 Thus, obesity increases renal sodium reabsorption, impairs pressure natriuresis, and causes hypertension partly by increasing renal SNS activity, as discussed in more detail later in this chapter.

The Renin-Angiotensin-Aldosterone System

The RAAS is perhaps the most powerful hormone system for regulating body fluid volumes and BP, as evidenced by the effectiveness of various RAAS blockers in reducing BP in normotensive and hypertensive subjects. Although the RAAS has many components, its most important effects on BP regulation are exerted by Ang II and aldosterone.

Ang II is a powerful vasoconstrictor and helps maintain BP in conditions associated with acute volume depletion (eg, hemorrhage), sodium depletion, or circulatory depression (eg, heart failure). The long-term effects of Ang II on BP, however, are closely intertwined with volume homeostasis through direct and indirect effects on the kidneys.^27,54,55

When the RAAS is fully functional, sodium balance can be maintained over a wide range of intakes with minimal changes in BP (see Fig. 24–8). Blockade of the RAAS, with Ang II–receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors, increases renal excretory capability so that sodium balance can be maintained at reduced BP.²⁸ However, blockade of the RAAS also makes BP salt sensitive. Thus, the effectiveness of RAAS blockers in lowering BP is greatly diminished by high salt intake. Conversely, reducing sodium intake or addition of a diuretic improves the effectiveness of RAAS blockers in reducing BP.

Inappropriately high levels of Ang II reduce renal excretory capability and impair pressure natriuresis, thereby necessitating increased BP to maintain sodium balance. The mechanisms that mediate the potent antinatriuretic effects of Ang II include direct and indirect effects to increase tubular reabsorption as well as renal hemodynamic effects.^27,28

Ang II Stimulates Renal Sodium Reabsorption

Physiologic activation of the RAAS usually occurs as a compensation for conditions that cause volume depletion or underperfusion of the kidneys, such as sodium depletion, hemorrhage, or heart failure. Increased Ang II formation helps restore renal perfusion by causing salt and water retention, which helps prevent reductions in BP. Ang II causes salt and water retention by increasing renal sodium reabsorption through stimulation of aldosterone secretion, by direct effects on epithelial transport, and by hemodynamic effects.

Ang II–mediated constriction of efferent arterioles reduces renal blood flow and peritubular capillary hydrostatic pressure and increases peritubular colloid osmotic pressure as a result of increased filtration fraction.²⁷ These changes, in turn, increase the driving force for fluid reabsorption across tubular epithelial cells. Reductions in renal medullary blood flow caused by efferent arteriolar constriction or by direct effects of Ang II on the vasa recta may also enhance reabsorption in the loop of Henle and collecting ducts.²⁷

Ang II also directly stimulates tubular sodium reabsorption. This effect occurs at low Ang II concentrations and is mediated in by actions on the luminal and basolateral membranes.^12,27,56 In the proximal tubules, Ang II stimulates Na⁺-H⁺ exchange on the luminal membrane and increases sodium-potassium ATPase activity as well as sodium bicarbonate cotransport on the basolateral membrane (Fig. 24–9).^12;27;56 These effects are partly mediated by inhibition of adenyl cyclase and increased phospholipase C activity.

Sodium reabsorption in the loop of Henle, macula densa, and distal nephron segments is also stimulated by Ang II. At physiologic concentrations, Ang II increases bicarbonate reabsorption in the loop of Henle and stimulates Na⁺-K⁺-2 Cl transport in the medullary thick ascending loop of Henle.^12,27,56 Ang II stimulates multiple ion transporters in the distal parts of the nephron, including H⁺-ATPase activity, as well as epithelial sodium channel activity in the cortical collecting ducts.^12,27,56

Renal Hemodynamic Effects of Ang II

Ang II is a powerful renal vasoconstrictor but in most physiologic conditions, the constriction is confined mainly to the postglomerular efferent arterioles. For example, efferent arteriolar constriction by Ang II acts in concert with other autoregulatory mechanisms, such as tubuloglomerular feedback and myogenic activity, to prevent excessive reductions in GFR when kidney perfusion is threatened.²⁷ In these cases, administration of ARBs or ACE inhibitors may actually reduce GFR further, even though renal blood flow is preserved. The impairment of GFR after RAAS blockade is caused, in part, by inhibition of the constrictor effects of Ang II on efferent arterioles as well as reduced BP.

The weak constrictor action of Ang II on preglomerular vessels is related, in part, to selective protection of these vessels by autacoid mechanisms such as prostaglandins (PGs) or endothelial-derived NO.²⁷ When the ability of the kidneys to produce these autacoids is impaired by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or by chronic vascular disease (eg, atherosclerosis), increased Ang II may reduce GFR by constricting afferent arterioles.

Blockade of Ang II May Attenuate Glomerular Injury in Overperfused Kidneys

RAAS blockade is often beneficial when nephrons are hyperfiltering, especially if Ang II is not appropriately suppressed. For example, in diabetes mellitus and certain forms of hypertension associated with glomerulosclerosis and nephron loss, Ang II blockade decreases BP, efferent arteriolar resistance, and glomerular hydrostatic pressure, and it attenuates glomerular hyperfiltration.⁵⁴ Clinical and experimental studies indicate that RAAS blockers are more effective than other antihypertensive agents in preventing glomerular injury, even with similar reductions in BP.^57,58,59 This appears to be partly caused by a greater reduction in glomerular hydrostatic pressure as a result of vasodilation of efferent arterioles after RAAS blockade.

Mechanisms of Ang II–mediated Target Organ Injury

Ang II has been suggested to cause injury to the kidneys and other organs through direct actions in addition to hemodynamic effects. Although clinical and experimental studies have demonstrated greater renal protective effects of RAAS blockers compared with other antihypertensive drugs, efferent arteriolar vasodilation and decreased glomerular hydrostatic pressure may have contributed to these beneficial effects. In studies in which BP was measured very accurately, using 24-hour telemetry, the renal protective effects of RAAS blockade appear to be largely a result of reductions in BP.⁶⁰

An observation that is difficult to reconcile with the concept that Ang II directly mediates target organ injury, independent of BP, is the finding that physiologic activation of the RAAS is not associated with vascular or renal injury as long as the BP is not elevated. For example, sodium depletion does not cause renal, cardiac, or vascular injury despite marked increases in renal Ang II levels. Also, elegant studies in genetically engineered mice indicate that chronic Ang II infusion does not cause cardiac hypertrophy and fibrosis in the absence of increased BP.⁶¹ For example, when large amounts of Ang II were infused into WT mice that received transplanted kidneys from angiotensin II type 1 receptor (AT₁R) knockout mice (ie, AT₁Rs were present in the heart and other organs but not in the kidneys), Ang II infusion did not chronically increase BP or cause cardiac hypertrophy and fibrosis.⁶¹ However, when AT₁Rs were present only in the kidneys and not in the heart or other organs, Ang II infusion caused chronic hypertension as well as cardiac hypertrophy and fibrosis.⁶¹ These observations indicate that in the absence of hypertension, Ang II does not cause cardiac hypertrophy or fibrosis. Thus, the hemodynamic effects appear to account for most of the target injury that occurs in Ang II–dependent hypertension.

Aldosterone and Mineralocorticoid Receptor Blockade in Hypertension

Aldosterone, the primary mineralocorticoid in humans, is a powerful sodium-retaining hormone and has important effects on renal pressure natriuresis and BP regulation. The primary sites of actions of aldosterone on sodium reabsorption are the principal cells of the distal tubules, cortical collecting tubules, and collecting ducts where aldosterone stimulates sodium reabsorption and potassium secretion. Aldosterone binds to intracellular mineralocorticoid receptors (MRs) and activates transcription by target genes, which, in turn, stimulate synthesis or activation of the Na⁺-K⁺-ATPase pump on the basolateral epithelial membrane and activation of amiloride-sensitive sodium channels on the luminal side of the epithelial membrane.⁶² These effects are termed genomic because they are mediated by activation of gene transcription and require 60 to 90 minutes to occur after aldosterone administration.

Aldosterone may also exert rapid nongenomic effects on the cardiovascular and renal systems. Aldosterone increases the sodium current in principal cells of the cortical collecting tubule through activation of the amiloride-sensitive channel and stimulates the Na⁺-H⁺ exchanger in a few minutes after application.^62,63 In vascular smooth muscle cells, aldosterone stimulates sodium influx by activating the Na⁺-H⁺ exchanger in less than 4 minutes. The putative membrane receptor and the cell-signaling mechanisms responsible for these rapid nongenomic actions of aldosterone have not been identified, especially with physiologic levels of aldosterone. Thus, the importance of the nongenomic effects of aldosterone on long-term regulation of renal pressure natriuresis and BP are still unclear.

The overall effects of aldosterone on pressure natriuresis are similar to those observed for Ang II. With low sodium intake, increased aldosterone helps prevent sodium loss and reductions in BP. Conversely, during high sodium intake, suppression of aldosterone helps prevent excessive sodium retention and attenuates increased BP.

Excess aldosterone secretion reduces the slope of pressure natriuresis so that BP becomes salt sensitive. Consequently, increasing plasma aldosterone 6- to 10-fold causes marked hypertension when sodium intake is normal or elevated but has little effect on BP when sodium intake is low.^21,64

The role of aldosterone and activation of MRs in human hypertension has been a topic of considerable interest. Some investigators suggest that hyperaldosteronism or excess activation of MRs may be more common than previously believed, especially in patients with hypertension that is resistant to treatment with the usual antihypertensive medications. For example, the prevalence of primary aldosteronism is reported to be almost 20% among patients referred to specialty clinics for resistant hypertension. Many of these patients, however, are overweight or obese.⁶⁵

Regardless of the prevalence of primary aldosteronism, MR antagonism may provide an important therapeutic tool for preventing target organ injury and reducing BP in hypertension.^65,66 For example, MR antagonism attenuated sodium retention, hypertension, and glomerular hyperfiltration in obese dogs fed a high-fat diet even though plasma aldosterone concentration was only slightly elevated.⁶⁷ However, even mild increases of plasma aldosterone may increase BP when accompanied by high sodium intake and volume expansion because aldosterone greatly enhances salt sensitivity of BP. In obese patients, there may be enhanced sensitivity to the effects of aldosterone because of increased abundance of epithelial sodium channels (ENaCs), which would amplify the effects of MR activation on sodium reabsorption and BP. It is also possible that glucocorticoids may contribute to MR activation in obese patients. There is also evidence that obesity may activate MR independently of the aldosterone or glucocorticoids.⁶⁸

The Endothelin System

Endothelin (ET) peptides are derived from a 203–amino acid peptide precursor, preproendothelin, which is cleaved after translation to form proendothelin.⁶⁹ A converting enzyme located within the endothelial cells cleaves proendothelin (or big endothelin) to produce ET.^70,71 Although all three members of the ET family of peptides—ET-1, ET-2, and ET-3—are expressed in the cardiovascular system, ET-1 is the predominant isoform.

ET-1 is the most powerful vasoconstrictor produced in humans, and its levels are increased in hypertension.^72,73 Although tissue concentrations of ET-1 have been reported to be elevated in some forms of hypertension, circulating levels of ET-1 are typically not elevated in patients with essential hypertension or most forms of experimental hypertension unless renal failure, endothelial damage, or atherosclerosis are present.^72,73,74,75 Circulating ET-1 levels, however, do not reflect the local vascular production of the peptide. Indeed, ET-1 acts in a paracrine fashion, regulating nearby vascular smooth muscle cells.

ET-1 Receptor Subtypes and Physiological Actions

ET-1 can either elicit a hypertensive effect by activating ET type A (ET_A) receptors in the kidneys or an antihypertensive effect via ET type B (ET_B) receptor activation. Thus, the ability of ET-1 to influence BP regulation is highly dependent on where ET-1 is produced and which ET receptors are activated (Fig. 24–10). ET-1 receptor binding sites have been identified throughout the body, with the greatest numbers of receptors in the kidneys and lungs.^75,76 Although the biochemical and molecular nature of ET-1 is well characterized, its physiologic importance in regulating renal and cardiovascular function has yet to be fully elucidated.

ET-1 produces vasoconstriction, impairs renal pressure natriuresis, and increases BP via ET_A receptor activation. ET_A receptors are located primarily on vascular smooth muscle cells and mediate ET-1 vasoconstriction and cellular proliferation in various disease states.^75,76

ET-1, via ET_A receptor activation, exerts multiple actions within the kidney that, if sustained chronically, could contribute to the development of hypertension and progressive renal injury. ET-1 decreases GFR and renal plasma flow through stimulation of vascular smooth muscle and mesangial cell contraction. Long-term effects of ET-1 on the kidney include stimulation of mesangial cell proliferation and extracellular matrix deposition, as well as vascular smooth muscle hypertrophy in renal resistance vessels.^75,76

Expression of ET-1 is greatly enhanced in several animal models of severe hypertension with renal vascular hypertrophy and in models of progressive renal injury.^77,78,79,80 In addition, treatment with ET receptor antagonists attenuated the hypertension and small artery morphologic changes and improved kidney function in these models.^{77,78,79,80,81,82,83,84} ET_B receptors are located on multiple cell types throughout the body, including endothelial cells and renal epithelial cells. ET_B activation causes vasodilation, enhances pressure natriuresis, and decreases BP. Although much attention has been given to ET_A receptor activation in the pathophysiology of cardiovascular and renal disease, several studies indicate an important antihypertensive role for the ET_B receptor. The most compelling evidence for a major role of ET_B receptors in regulating BP comes from reports that transgenic mice deficient in ET_B receptors develop severe salt-sensitive hypertension and that pharmacologic antagonism of ET_B receptors produces significant hypertension in rats.^85,86,87

Bagnall et al reported that ablation of ET_B receptors exclusively from endothelial cells produced endothelial dysfunction but did not cause hypertension.⁸⁸ In contrast to models of total ET_B receptor ablation, the BP response to a high-salt diet was unchanged in endothelial cell-specific ET_B receptor knockouts compared with control mice. These findings suggest that ET_B receptors in nonendothelial cells are important for BP regulation. Supporting this concept is the finding that collecting duct ET_B knockout mice on a normal sodium diet were hypertensive and a high-sodium diet worsened the hypertension.⁸⁹ These findings provide strong evidence that the intrarenal effect of ET_B receptor activation on the collecting duct is an important physiologic regulator that increases renal sodium excretion and reduces BP. These effects of collecting duct–derived ET on BP and sodium excretion appear to be mediated by NO.⁹⁰

ET-1 and Salt-Sensitive Hypertension

Several lines of evidence suggest that ET-1 may contribute to salt-sensitive hypertension. Dahl salt-sensitive (DS) rats placed on a high-sodium diet develop attenuated pressure natriuresis, hypertension, and progressive renal injury.^77,78 Evidence suggests that ET-1, acting via an ET_A receptor, may play a role in mediating the renal injury of DS hypertension. Prepro-ET-1 mRNA and vascular responsiveness to ET-1 are increased in the renal cortex of DS rats compared with Dahl salt-resistant (DR) rats, and a positive correlation between ET-1 generation in the renal cortex and the extent of glomerulosclerosis has been reported in DS hypertensive rats.⁷⁷ Acute infusion of a nonselective ET_A-ET_B receptor antagonist directly into the renal interstitium improved renal hemodynamic and excretory function in DS rats but not in DR rats. Moreover, chronic blockade of ET_A receptors attenuated hypertension and proteinuria and ameliorated glomerular and tubular damage associated with high salt intake in DS rats.⁷⁸ An important unanswered question is whether the beneficial effect of ET_A receptor blockade in reducing renal injury is mediated through lower BP or through direct renal mechanisms.

Renal ET-1 synthesis is enhanced in various animal models of chronic hypertension including Ang II hypertension, deoxycorticosterone acetate (DOCA) hypertension, and placental ischemic-induced hypertension.^79,80,81,82 Hypertension in these models is markedly attenuated or completely abolished by ET_A receptor antagonists.

Role of Endothelin in Human Hypertension

Several selective and mixed endothelin receptor antagonists have been developed and utilized in clinical trials for therapy in renal disease, systemic and pulmonary arterial hypertension, and heart failure.^91,92 Although ET-1 clearly plays a significant role in the pathogenesis of some forms of experimental hypertension, especially salt-sensitive models, its role in human primary hypertension is unclear. Bosentan, a combined ET_A-ET_B receptor antagonist, significantly lowered BP in a large double-blind clinical trial, indicating that ET system helps maintain BP in human hypertension.⁹³ However, the magnitude of the BP reduction by bosentan was almost the same as that observed in normotensive humans. This observation suggests that ET may not play a major role in raising BP in most patients with essential hypertension, although bosentan blocks both ET_A and ET_B receptors, and antagonism of antihypertensive ET_B receptors may have masked an important role of ET on BP via ET_A receptor activation.

In another study, 6 weeks of darusentan, a selective ET_A receptor antagonist, was effective in lowering both systolic and diastolic BP.⁹⁴ There are currently no clinical studies that directly compare selective and mixed ET receptor antagonism in the treatment of hypertension, although both approaches clearly reduce BP. Therefore, the importance of ET-1 in human essential hypertension deserves further investigation.⁹³

Role of Endothelin in Pulmonary Arterial Hypertension

Although the importance of ET-1 in essential hypertension remains unclear, ET-1 appears to play an important role in pulmonary arterial hypertension (PAH). PAH is characterized by a progressive increase in pulmonary vascular resistance resulting from vascular remodeling, vasoconstriction, and cellular proliferation.⁹⁴ Depending on the severity of the disease, PAH may progress to right ventricular failure and death. Studies in animal models of PAH and in humans suggest that ET-1 plays an important role in mediating the vascular remodeling, vasoconstriction, and cellular proliferation associated with PAH.⁹² Macitentan, a nonselective ET_A/B receptor antagonist with beneficial effects in experimental PAH has been recently tested in a Phase III clinical Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial in patients with PAH. Macitentan significantly reduced morbidity and mortality in patients with PAH. Clinical trials utilizing other ET_A/B receptor antagonists have also reported beneficial effects in PAH patients.⁹⁵ Thus, ET-1 receptor antagonists have proven to be efficacious in treating patients with PAH.

Nitric Oxide

Vascular NO is mainly produced from L-arginine by endothelial NO synthase (eNOS). Three distinct genes encode NOS isozymes that catalyze production of NO from L-arginine.⁹⁶ These include neuronal NOS (nNOS or NOS-1), cytokine-inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3). Production of NO from L-arginine by NOS also requires the presence of various cofactors, including tetrahydrobiopterin (BH₄), flavin adenine dinucleotide, flavin mononucleotide, calmodulin, and iron protoporphyrin IX. Tonic release of eNOS-derived NO by the vascular endothelium plays a major role in regulating vascular function, and nNOS and NOS-derived NO from renal epithelial cells regulate sodium transport and renal hemodynamics.⁹⁶ Long-term inhibition of NOS causes sustained hypertension associated with impaired renal pressure natriuresis.⁹⁷ The magnitude of the increase in BP during NO inhibition depends on sodium intake, indicating that NO also regulates sodium balance and renal pressure natriuresis.

Nitric Oxide Enhances Pressure Natriuresis

Deficiency of NO synthesis impairs pressure natriuresis by several mechanisms, including hemodynamic and tubular effects, each of which may be modulated by processes that are intrinsic or extrinsic to the kidneys (Fig. 24–11). For example, reductions in NO synthesis may decrease renal sodium excretory function by increasing renal vascular resistance directly or by enhancing renal vascular responsiveness to vasoconstrictors such as (Ang) II or norepinephrine.^{98,99,100,101} Reductions in NO synthesis also increase renal tubular sodium reabsorption via direct effects on tubular transport and through changes in intrarenal physical factors, such as renal interstitial hydrostatic pressure (RIHP) and medullary blood flow.^{98,99,100,101} Inhibition of NO synthesis reduces RIHP and urinary sodium excretion.¹⁰¹

Salt-Sensitive Hypertension Caused by Impaired Nitric Oxide Production

Several lines of evidence suggest that impaired NO synthesis plays an important role in the pathogenesis of salt-sensitive hypertension.¹⁰¹ Increased renal NO production or release, as evidenced by increased urinary excretion of NO metabolites or the NO second messenger cyclic guanosine monophosphate has been reported to be essential for maintenance of normotension during a dietary salt challenge. Prevention of this increase in renal NO production resulted in salt-sensitive hypertension. Genetic models of hypertension, such as DS rats, have impaired pressure natriuresis associated with NO deficiency. Stimulation of NO production with chronic L-arginine supplementation normalizes the blunted pressure natriuretic response in DS rats as a result of improvement in the kidney’s ability to generate increased RIHP in response to increased renal perfusion pressure.¹⁰¹

Evidence suggests that NO synthesis is impaired in some vascular beds in human primary hypertension. The extent to which these changes are secondary to increased BP or reflect important mechanisms for the pathogenesis of hypertension, however, remains unclear.

Oxidative Stress

Increased levels of reactive oxygen species (ROS) may play a role in initiation and progression of cardiovascular dysfunction associated with hyperlipidemia, diabetes mellitus, and hypertension.^102,103 In some forms of hypertension, increased ROS appear to be derived mainly from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, which could serve as a trigger for uncoupling endothelial NOS by oxidants.¹⁰³ Four members of the NADPH oxidase (Nox) enzyme family have been identified as important sources of ROS in the vasculature: Nox1, Nox2, Nox4, and Nox5. Multiple factors control the expression and activity of these enzymes and of their regulatory subunits such as p22phox, p47phox, Noxa1, and p67phox.

ROS produced by migrating inflammatory cells or vascular cells have distinct effects on different cell types.¹⁰⁴ These effects include endothelial dysfunction, increased renal tubule sodium transport, cell growth and migration, inflammatory gene expression, and stimulation of extracellular matrix formation. ROS, by affecting vascular and renal tubule function, can also impair renal pressure natriuresis, alter systemic hemodynamics, and raise BP (Fig. 24–12).¹⁰⁵

Considerable evidence supports a role for ROS in various animal models of hypertension.¹⁰⁵ The DS rat, for example, has increased vascular and renal superoxide production and increased levels of H₂O₂. Renal expression of superoxide dismutase is decreased in kidneys of DS rats, and long-term administration of Tempol, a superoxide dismutase mimetic, significantly decreases BP and attenuates renal damage. Another salt-sensitive model, the stroke-prone spontaneously hypertensive rat, has elevated levels of superoxide and decreased total plasma antioxidant capacity. Superoxide production is also increased in the DOCA-salt hypertensive rat and treatment with apocynin, an NADPH oxidase inhibitor, decreases BP. ROS also appear to play an important role in chronic Ang II hypertension. Ang II is a potent stimulus of NADPH oxidase and long-term administration of Tempol significantly decreases the chronic BP response to Ang II.^105,106

Although elevated production of ROS is believed to play an important role in hypertension, clinical studies on chronic antioxidant therapy have failed to confirm this hypothesis.^107,108 An imbalance between total oxidant production and the antioxidant capacity in human primary hypertension has been reported in some, but not all, studies. Equivocal findings in human studies are partly caused by the difficulty of assessing oxidative stress. Measurement of ROS in tissues is a challenge because of their low levels and relatively short half-lives.^107,108 Most human studies have found that chronic antioxidant therapy with vitamin E and C supplementation has little or no effect on BP.^107,108

Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF or VEGF-A) has numerous physiological actions, including inducing endothelial cell permeability, proliferation, angiogenesis, lymphogenesis, and vasodilation.¹⁰⁹ VEGF belongs to a family of secreted glycoproteins, including VEGF-B, -C, and -D and placenta growth factor (PlGF). VEGF signaling is mediated via two receptors, VEGFR1/Flt1 and VEGFR2/Flk1. Drug therapies that specifically target VEGF inhibit tumor angiogenesis and have been highly beneficial in treating various cancers. Despite their clinical benefit, the safety of these targeted agents is of special concern, especially for longer term treatment. Importantly, VEGF inhibitor therapy has been associated with hypertension and control of BP after administration of these drugs remains a challenge.¹¹⁰

Although hypertension appears to be one of the most common side effects of VEGF inhibitors, the pathophysiologic mechanisms underlying increases in BP have not been fully elucidated.^110,111 Because the endothelium is a major target for VEGF actions, it is likely that decreases in production of endothelium-derived relaxing factors such as NO and PGs or enhanced production of vasoconstricting factors such as thromboxane and ET-1 play a role in the hypertensive response to drugs that block the VEGF-pathway.¹¹² Facemire and colleagues reported that administration of a specific antibody against the major VEGF receptor, VEGFR2, to normal mice caused a rapid and sustained increase in BP that was associated with significant reductions in expression of endothelial and neuronal NOS in the kidney.¹¹² They also reported that L-NAME administration abolished the difference in BP between the vehicle- and anti-VEGFR2–treated groups. These findings suggest that VEGF, acting via VEGFR2, plays a critical role in influencing basal levels of BP control by enhancing NOS expression and NO activity. Moreover, the results suggest that reducing NO production or availability may be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF.

Although the exact physiologic mechanisms whereby VEGF inhibition leads to hypertension are still unclear, in all forms of hypertension examined to date, including experimental models and human essential hypertension, there is a hypertensive shift in the renal pressure natriuresis relationship. In the study of Facemire and colleagues, the anti-VEGFR2 antibody caused a rightward, parallel shift in the chronic pressure natriuresis relationship.¹¹² The parallel shift in the chronic pressure natriuresis relationship is consistent with the idea that increased preglomerular vascular resistance may be involved in mediating the hypertension.

The altered pressure natriuresis relationship in response to blockade of VEGF receptors may be the result of endothelial dysfunction, leading to decreases in production of endothelium-derived relaxants such as NO (Fig. 24–13). Supporting this possibility is the fact that the hypertension in response to the anti-VEGFR2 antibody was associated with significant reductions in expression of endothelial and neuronal NOS in the kidney. These changes tend to reduce renal blood flow and GFR and impair the kidney’s ability to excrete sodium and water. Unfortunately, the effect of the anti-VEGFR2 antibody on renal hemodynamics was not reported in the study of Facemire and colleagues.¹¹²

Another important endothelial-derived factor that may play a role in mediating the hypertension produced by VEGF inhibition is the vasoconstrictor ET-1. Kappers et al published the results of a series of clinical, animal, and in vitro studies suggesting a strong correlation between ET-1 and the hypertension associated with sunitinib, an orally active multitarget receptor tyrosine kinase inhibitor that inhibits phosphorylation of the VEGF receptor.¹¹³ Verdonk et al also investigated the relationship between disturbed angiogenic balance, BP, and ET-1 in pregnant women with a high (≥ 85) or low (< 85) sFlt1/PlGF ratio. Plasma ET-1 levels were increased in women with a high ratio.¹¹⁴ In addition, plasma ET-1 correlated positively with sFlt1, an endogenous inhibitor of VEGF that is elevated in preeclamptic women. Finally, the hypertension seen with the multitarget RTKI ABT-869 (known to target the VEGF receptor) is prevented by pretreatment with the selective ET_A receptor antagonist atrasentan.¹¹⁵ Thus, another potential mechanism whereby VEGF blockade could increase BP is by enhancing ET-1 synthesis. However, the relative importance of the ET system in mediating increases in BP in response to VEGF pathway inhibitors remains to be determined.

Another potential mechanism for impaired pressure natriuresis after inhibition of VEGF is altered glomerular structure and function (see Fig. 24–13). VEGF and VEGF receptors are highly expressed in the kidney. VEGF is expressed in glomerular podocytes, and VEGF receptors are present on endothelial, mesangial, and peritubular capillary cells. Signaling between endothelial cells and podocytes is thought to be important for maintenance of the filtration function of the glomerulus, and inhibitors of VEGF signaling has been shown to alter glomerular structure and function.

In summary, current evidence suggests that VEGF may have important physiologic roles in adult humans. Results from VEGF neutralization studies in animals and clinical trials in humans have demonstrated significant endothelial dysfunction and hypertension, implicating VEGF in maintaining normal endothelial function and BP regulation in adults. Further elucidation of the mechanisms whereby VEGF achieves this important physiological function could provide new drug targets to minimize the risk of significant hypertension and proteinuria in patients treated with VEGF pathway inhibitors.

Atrial Natriuretic Peptide

ANP is a 28–amino acid peptide synthesized and released from atrial cardiocytes in response to stretch. ANP enhances sodium excretion through extrarenal and intrarenal mechanisms.¹¹⁶ ANP increases GFR but has little effect on renal blood flow. However, an increase in GFR is not a prerequisite for ANP to enhance sodium excretion. ANP may also inhibit renal tubular sodium reabsorption directly by inhibiting active tubular transport of sodium or indirectly via alterations in medullary blood flow, physical factors, and hormones such as Ang II and aldosterone.^{116,117,118,119}

Atrial Natriuretic Peptide Enhances Pressure Natriuresis and Lowers Blood Pressure

Plasma levels of ANP are elevated in numerous physiologic conditions associated with enhanced sodium excretion.^{116,117,118,119} Acute blood volume expansion consistently elevates circulating levels of ANP. Some, but not all, investigators report that chronic increases in dietary sodium intake also increase circulating levels of ANP. Infusions of exogenous ANP at rates that result in physiologically relevant plasma concentrations, comparable to those observed during volume expansion, elicit significant natriuresis, especially in the presence of other natriuretic stimuli, such as high renal perfusion pressure. Long-term physiologic elevations in plasma ANP also enhance renal pressure natriuresis and reduce BP.¹²⁰ ANP has been shown to buffer renin-dependent hypertension.¹²¹

Blockade of the Atrial Natriuretic Peptide System Produces Salt-Sensitive Hypertension

Genetic mouse models that exhibit altered expression of ANP or its receptors (NPR-A, NPR-C) have provided compelling evidence for a role of ANP in chronic regulation of renal pressure natriuresis and BP.¹²² Whereas transgenic mice overexpressing ANP are hypotensive relative to their WT litter mates, mice harboring functional disruptions of the ANP or NPR-A genes are hypertensive. ANP gene knockout mice develop salt-sensitive hypertension in association with failure to adequately suppress the RAAS. Although these findings suggest that genetic deficiencies in ANP or its receptors could play a role in the pathogenesis of hypertension, the role of ANP in human hypertension remains unclear.¹²³

Inadequate renin and Ang II suppression in obese hypertensive men was associated with a relative ANP deficiency.¹²⁴ Burnett and colleagues found that human hypertension is characterized by a lack of activation of the antihypertensive cardiac hormones ANP and brain natriuretic peptide.¹²⁰ Moreover, several studies have found ANP gene variants to be associated with hypertension.¹¹⁸ Although these studies suggest a potential role for ANP deficiency in hypertension, further studies are necessary to determine the role of ANP in human hypertension.

Innate and Adaptive Immunity

A strong association between innate or adaptive immune system activation with renal inflammation, reduced pressure natriuresis, and hypertension has been demonstrated in several experimental models, including Ang II, aldosterone, salt-sensitive, and spontaneously hypertensive rodent models.^{125,126,127,128,129,130} An important characteristic commonly observed in these models is increased infiltrating immune cells, including macrophage and T lymphocytes, in the kidneys. In support of a role for T cells in the pathogenesis of hypertension are studies demonstrating that treatment with mycophenolate mofetil attenuates hypertension in association with reduced renal cortical T-cell infiltration in DS rats.¹²⁶

T cells also play an important role in Ang II hypertension. RAG1^-/- mice have an attenuated BP response to Ang II, which is fully restored with adoptive transfer of T cells.^131,132 Harrison and colleagues have proposed that Ang II increases T-cell activation and infiltration into perivascular fat.^131,132 T cells produce cytokines and release other mediators such as ROS that may affect smooth muscle cells and the endothelium of adjacent blood vessels. In support of this hypothesis, etanercept, a tumor necrosis factor-alpha (TNF-α) antagonist, has been reported to prevent Ang II–induced increases in BP and vascular superoxide production.¹³³

T cells contain components of the RAAS such as the Ang I-converting enzyme, renin, the renin receptor, and angiotensinogen. Hoch et al recently reported that T cells can produce Ang II and that AT₁Rs are expressed within the T cell, suggesting an intracrine RAS.¹³⁴ They also demonstrated that Ang II has direct actions on T-cell function, including activation, expression of tissue-homing markers, and production of TNF-α. These authors proposed that that T-cell production of Ang II, superoxide, and TNF-α could contribute to inflammation in other settings in which T cells accumulate such as in arthritis, transplant rejection, and experimental myocarditis.

Crowley and colleagues examined the importance of activation of AT₁Rs on hematopoietic cells in mediating Ang II-dependent hypertension by utilizing bone marrow chimeras deficient only in hematopoietic AT₁Rs. They reported that Ang II hypertension was exaggerated in the mice with bone marrow–specific AT₁R deficiency, suggesting a protective role for Ang II-stimulated hematopoietic cells.¹³⁵

A subset of T cells called T-regulatory cells (CD4+CD25+Foxp3+ cells) has an important role to suppress autoreactive T cells and promote immune tolerance.¹³⁵ T-regulatory cell function is impaired in human autoimmune disorders associated with hypertension. T-regulatory cells are reduced in the renal cortex of Ang II-hypertensive animals and adoptive transfer to increase T-regulatory cells reduces BP in association with reduced renal inflammatory cytokines. These findings support the concept that impaired T-regulatory function may contribute to the pathogenesis of hypertension in autoimmune disorders.

The role of self-antigens in promoting hypertension by activating the adaptive immunity has been recently examined. Agonistic antibodies directed to adrenergic and angiotensin receptors and immunoglobulin (Ig) G and IgM autoantibodies are elevated in primary and secondary forms of hypertension. Utilizing a murine model of systemic lupus erythematosus (SLE), characterized by a multiorgan inflammation in response to self-antigens and autoantibody (antinuclear) production, Ryan and colleagues showed that depleting B cells before the development of SLE with the administration of anti-CD20 antibody reduced formation of autoantibodies, decreased TNF-α expression, and ameliorated hypertension.¹³⁶ These data suggest that development of autoimmunity and the resultant increase in renal inflammation are important underlying factors in the hypertension that occurs during SLE.

Th17 cells represent a newly characterized subset of T cells that produce the cytokine IL-1. IL-17 is elevated in several experimental models of hypertension such as Ang II and placental ischemia induced hypertension. Chronic infusion of IL-17 induced hypertension and endothelial dysfunction in mice and placental oxidative stress and hypertension in pregnant rats.¹³⁷ To investigate the role of IL-17 in Ang II hypertension, Harrison and colleagues examined the chronic effects of Ang II in IL-17a^-/- and WT mice.¹³⁸ These mice exhibited a similar initial increase in BP as WT mice in response to Ang II; however, after 7 days, BP dropped in IL-17a^-/- mice. The Ang II-induced hypertension was reduced and aortic T-cell infiltration observed in WT mice was abolished in IL-17a^-/- mice, as were increases in vascular oxidative stress and endothelial dysfunction.

Although there are a growing number of experimental studies in variety of animal models suggesting an important role for the immune system in the pathogenesis of hypertension, comparable studies in humans are limited. Thus, the importance of the immune system and inflammatory cytokines in the pathogenesis of primary and secondary human hypertension remains an important unanswered question.

In a small percentage of patients, the clinical features, history, and physical examination point to a specific cause of increased BP, and the hypertension is therefore said to be secondary. Some types of secondary hypertension have a definite genetic basis, and others are associated with specific neurohormonal or kidney disorders. In some instances, hypertension is caused by drugs or treatments that the patient receives. Nearly all forms of secondary hypertension, however, are characterized by impaired renal function or altered activity of the SNS or hormones that impair the ability of the kidneys to excrete salt and water.

Table 24–4 lists some of the most frequently diagnosed causes of secondary hypertension, including those caused by drugs that either themselves increase BP or exacerbate underlying disorders that contribute to hypertension. These drugs include NSAIDs, oral contraceptives, glucocorticoids, and sympathomimetics. This chapter discusses only a few of the more common causes of secondary hypertension.

Renovascular Hypertension

Renovascular hypertension, although accounting for only about 5% of all hypertension, is one of the most common causes of secondary hypertension. The pathophysiology of renovascular hypertension is related to reductions in renal perfusion that result from stenosis of the main renal artery, one of its branches, or stenosis/injury of other smaller preglomerular blood vessels and glomeruli. The majority of renal vascular lesions reflect either fibromuscular dysplasia or atherosclerosis.^139,140 The predominant lesion found in the main renal artery or its branches in patients older than 50 years of age is atherosclerotic disease. More subtle functional (constriction) or structural changes in smaller blood vessels (eg, afferent arterioles, glomeruli), however, are difficult to detect clinically and can contribute to increased BP.

Renovascular hypertension may be unilateral or bilateral and may result in homogeneous or nonhomogeneous ischemia of nephrons. As discussed earlier in the chapter, there are some important differences in the pathophysiology of homogeneous compared with nonhomogeneous renal ischemia. Experimental counterparts of these two clinical forms of renovascular hypertension can be found in the one-kidney, one-clip and the two-kidney, one-clip models of Goldblatt hypertension, respectively.

Renal Artery Stenosis in a Single Remaining Kidney

In the one-kidney, one-clip model of Goldblatt hypertension and in patients with stenosis of a single remaining kidney, there is a fairly homogeneous reduction in perfusion of all nephrons, leading to an elevation of BP that is proportional to the severity of the stenosis. In experimental one-kidney, one-clip Goldblatt hypertension, BP increases rapidly after clipping the renal artery and remains stable as long as the stenosis does not worsen. Moreover, the BP returns to normal when the stenosis is removed.

Renal artery constriction, if severe enough to reduce renal perfusion pressure below the range of autoregulation (~70 mm Hg), initially decreases renal blood flow, GFR, and sodium excretion while increasing renin secretion. However, if the stenosis is not too severe, sodium excretion returns to normal, and if sodium intake is normal and adequate volume is available, renin secretion also returns to nearly normal in the established phase of hypertension.^24,141 At this point, the hypertension is stable and most indices of renal function are relatively normal, including pressure distal to the stenosis.

Increased Ang II accounts for most of the rapid increase in BP after stenosis of the renal artery. However, even after blocking the RAAS, BP still increases (although more slowly) until renal perfusion pressure returns to nearly normal. This increase in renal perfusion pressure, at the expense of systemic arterial hypertension, permits normal excretion of sodium and water to be maintained. As long as sodium intake is normal, activation of the RAAS serves mainly to increase the rate at which BP is elevated. In the established phase of hypertension, blockade of the RAAS causes only small reductions in BP, similar to the decreases observed in normal subjects after Ang II blockade.¹⁴²

The importance of volume expansion in elevating BP in one-kidney, one-clip Goldblatt hypertension depends on sodium intake. Whereas with normal or high sodium intake, significant extracellular volume expansion occurs, a low-sodium diet converts this model of hypertension from one that is volume dependent to one that is highly Ang II dependent. When the stenosis is severe and adequate renal perfusion cannot be restored (even with increased systemic arterial pressure), renin secretion continues to increase, as does BP, leading eventually to malignant hypertension and renal failure. Thus, the ability to return renal perfusion pressure to normal, or nearly normal, by volume retention or activation of the RAAS is critical to maintaining homeostasis when there is renal artery stenosis in a single remaining kidney.

The same sequence as described above occurs when there are widespread homogeneous increases in preglomerular resistance caused by bilateral renal artery stenosis or aortic coarctation above both renal arteries.^21,24

Nonhomogeneous Nephron Ischemia

In patients with nonhomogeneous increases in preglomerular resistance or in the two-kidney, one-clip model of Goldblatt hypertension, the pathophysiology of hypertension is more complicated. Nonhomogeneous nephron ischemia may be a result of stenosis of one renal artery and normal perfusion of the contralateral kidney or of patchy increases in preglomerular resistance within the kidneys, with some nephrons being underperfused and others having normal or increased blood flow. Thus, these forms of hypertension are characterized by ischemia of some nephrons and normal or increased blood flow in adjacent nephrons or in the nonstenotic kidney.

In experimental models with unilateral renal artery stenosis, the ischemic nephrons (or the entire underperfused kidney in the case of a unilateral renal artery stenosis) are exposed to reduced perfusion pressure, secrete more renin, and excrete less sodium and water than kidneys with normal blood flow. In contrast, the nonischemic nephrons (or nonstenotic kidney) are exposed to increased renal perfusion pressure, decreased renin secretion, and increased sodium excretion. However, even with increased perfusion pressure, the function of the nonischemic nephrons (or unclipped, nonstenotic kidney) is impaired because of increased circulating Ang II, which exerts an antinatriuretic effect and helps sustain hypertension.

The higher BP experienced by the nonstenotic kidney may eventually damage its nephrons, which then sustains increased BP even after correction of the stenosis in the other kidney. However, correction of the stenosis plus nephrectomy of the nonstenotic kidney usually normalizes BP.¹⁴³

Administration of ACE inhibitors or ARBs as a treatment for renovascular hypertension may improve structure and function of the nonstenotic kidney but in some cases may also produce shrinkage of the stenotic kidney, resulting in fibrosis and deterioration of its function. This is partly a result of decreased BP, which may reduce renal perfusion pressure distal to the lesion to a level below the range of autoregulation. Blockade of the RAAS also dilates efferent arterioles, which contributes to a decline in GFR in the stenotic kidney. In some patients with severe renal vascular lesions, administration of ACE inhibitors or ARBs may cause severe decreases in renal function, especially when there is also volume depletion because of concomitant use of diuretics. Therefore, renal function should be monitored frequently after administration of RAAS inhibitors in patients suspected of having renovascular hypertension. Fortunately, these effects appear to be reversible upon cessation of ACE inhibition or ARB, and in many patients, the beneficial BP lowering effects of RAAS blockade can be achieved without precipitating further loss of kidney function.

Adrenal Cortex Hypertension

Aldosterone normally exerts nearly 90% of the mineralocorticoid activity of the adrenocortical secretions. However, cortisol, the major glucocorticoid secreted by the adrenal cortex, can also provide significant mineralocorticoid activity in some conditions. Aldosterone’s mineralocorticoid activity is about 3000 times greater than that of cortisol, but the plasma concentration of cortisol is nearly 2000 times that of aldosterone. Normally, the renal MR is “protected” from activation by cortisol as a result of 11β-HSD2, which converts active cortisol into inactive cortisone. However, when 11β-HSD2 activity is reduced or when cortisol levels are very high, the MR may be activated by cortisol.

Primary Aldosteronism (Conn Syndrome)

Primary aldosteronism, also called Conn syndrome in honor of Jerome Conn who first described this condition in 1955, results from hypersecretion of aldosterone in the absence of a known stimulus. The excess aldosterone secretion almost always comes from the adrenal cortex and is usually associated with a solitary adenoma or bilateral hyperplasia of the adrenal cortex. Secondary aldosteronism refers to increased aldosterone secretion as a result of a known stimulus, such as increased Ang II. This is the most common form of aldosteronism seen in clinical practice and occurs in various conditions associated with increased renin secretion, such as congestive heart failure, sodium depletion, or renal artery stenosis.

Primary aldosteronism may occur as a result of an aldosterone-­producing adenoma (APA) or unilateral or bilateral adrenal hyperplasia (BAH).¹⁴⁴ The effects of excess aldosterone were discussed earlier, but the most important actions with regard to chronic BP regulation are increased sodium reabsorption, increased potassium secretion by the principal cells of the renal tubules, and increased hydrogen ion secretion by the intercalated cells of the renal tubules. These effects cause expansion of extracellular fluid volume, hypertension, suppression of renin secretion, hypokalemia, and metabolic alkalosis—hallmarks of primary aldosteronism. Most of these effects are highly salt sensitive, and low sodium intake greatly attenuates the hypertension and hypokalemia associated with primary aldosteronism.

Diagnosis of primary aldosteronism is made by a multistep process that ends with adrenal venous sampling.¹⁴⁵ APA and BAH together account for more than 95% of primary aldosteronism. Patients with APA are often treated by surgical removal of the adenoma whereas those with BAH are treated pharmacologically with MR antagonists.¹⁴⁴ With wider screening for primary aldosteronism, approximately 70% of cases of aldosterone excess appear to be caused by BAH, with APA comprising most of the remainder.¹⁴⁴

In most studies of unselected patients, the classic form of primary aldosteronism was found in less than 1% of hypertensive patients.¹²³ Some adrenal glands in patients with primary aldosteronism may have varying degrees of hyperplasticity, and the term idiopathic hyperaldosteronism (IHA) was coined to describe this condition. Clinically, APA and IHA are difficult to distinguish, although patients with APA often have more severe hypertension and hypokalemia than those with IHA.

Measurements of the aldosterone-renin ratio have been used in an attempt to define more subtle cases of primary aldosteronism.^123,146 This approach has led to the suggestion that excess aldosterone secretion may account for as much as 5% to 10% of essential hypertension. However, there is considerable debate about whether patients with increased aldosterone-renin ratios truly have primary aldosteronism. In many of these patients, the major reason for the increased aldosterone–renin ratio is the low level of renin, rather than excess aldosterone secretion.¹²³

Increased Arterial Pressure and “Escape” from Sodium Retention during Hyperaldosteronism

Although aldosterone is a powerful sodium-retaining hormone, sodium excretion eventually returns to match sodium intake even in patients with APA and very high levels of aldosterone. This “escape” from sodium retention is secondary to increases in extracellular fluid volume and pressure natriuresis.⁶⁴ After extracellular fluid volume increases 5% to 15% above normal, BP also increases 15 to 25 mm Hg, and the elevated BP returns renal output of salt and water to normal despite excess aldosterone (Fig. 24–14). The importance of pressure natriuresis in permitting aldosterone escape was demonstrated experimentally by servo-controlling renal perfusion pressure; when renal perfusion pressure was servo-controlled, aldosterone infusion caused continued sodium retention and progressive increases in cumulative sodium balance and extracellular fluid volume, resulting in severe circulatory congestion and edema.⁶⁴ Failure of the kidneys to escape from aldosterone-induced sodium retention also occurs in patients with heart failure who, because of a severely weakened heart, cannot increase BP sufficiently to reestablish salt and water balance.

Sustained Hypokalemia and Metabolic Alkalosis with Hyperaldosteronism

Excess aldosterone not only increases secretion of potassium ions by the principal cells of the renal tubules but also stimulates transport of potassium from the extracellular fluid into most cells of the body. This shift of potassium from the extracellular to intracellular fluid accounts for a significant part of the hypokalemia in hyperaldosteronism.

Excess aldosterone secretion also stimulates secretion of hydrogen ions in exchange for sodium as well as bicarbonate reabsorption in the intercalated cells of the renal collecting tubules and collecting ducts. This decreases hydrogen ion concentration in the extracellular fluid causing metabolic alkalosis.

Patients with IHA often have a milder form of aldosteronism than those with APA, although there may be overlap in severity of the clinical features of these two groups. In patients with APA, plasma aldosterone concentration is not usually increased in response to upright posture because of marked suppression of renin secretion and insensitivity of the aldosterone-secreting adenoma to Ang II. In contrast, patients with IHA usually have a significant increase in aldosterone concentration during upright posture, suggesting that adrenal sensitivity to Ang II is maintained.¹⁴⁷ These differences between IHA and APA in adrenal responsiveness to RAAS activation have been used to discriminate between these two forms of primary aldosteronism.

Cushing Syndrome (Glucocorticoid Excess)

Cushing syndrome is characterized by excess secretion of glucocorticoids. Hypertension occurs in approximately 80% of patients with Cushing syndrome and is difficult to control.¹⁴⁸ The morbidity associated with cortisol excess is substantial, and risk for death is largely due to excess cardiovascular events, including heart attack and stroke.

Cushing syndrome may be caused by administration of excess cortisol (eg, for treatment of various inflammatory disorders) or by excess endogenous cortisol secretion. The most common cause of endogenous cortisol excess is overproduction of adrenocorticotropic hormone (ACTH) from a pituitary adenoma, a condition referred to as Cushing disease. Increased ACTH causes adrenal hyperplasia and stimulates cortisol secretion. Cushing disease may also occur as a result of ectopic secretion of ACTH by tumors outside the pituitary, such as an abdominal carcinoma.

ACTH-independent hypercortisolism may also be caused by adenomas of the adrenal cortex. Primary overproduction of cortisol by the adrenal glands, independent of ACTH, accounts for approximately 20% to 25% of cases of Cushing syndrome and is usually associated with suppressed ACTH levels caused by cortisol-induced feedback inhibition of ACTH secretion from the anterior pituitary gland. Administration of large doses of dexamethasone, a synthetic glucocorticoid, can be used to distinguish between ACTH-dependent and ACTH-independent Cushing syndrome. In patients with overproduction of cortisol because of an ACTH-secreting pituitary adenoma or hypothalamic-pituitary dysfunction, even large doses of dexamethasone usually do not suppress ACTH secretion. In contrast, patients with primary adrenal overproduction of cortisol (ACTH independent) usually have low or undetectable levels of ACTH. However, the dexamethasone test may occasionally give an incorrect diagnosis because some ACTH-secreting pituitary tumors respond to dexamethasone with suppression of ACTH secretion.

Glucocorticoids modulate a wide variety of cell processes and the precise mechanisms by which hypercortisolism causes hypertension are incompletely understood. One potential mechanism is activation of the MR; the high levels of cortisol in Cushing syndrome may overwhelm the ability of the renal 11β-HSD2 to convert active cortisol into inactive cortisone at the MR so that cortisol stimulates the MR and causes sodium retention, volume expansion, hypertension, and hypokalemia. High levels of cortisol may also increase the responsiveness to various pressor stimuli, including Ang II and norepinephrine.¹⁴⁹

Studies in experimental animals suggest that excess cortisol may also raise BP through mechanisms that may be at least partially independent of activation of classical glucocorticoid or MR.¹⁵⁰ Most of the available evidence, however, suggests that sodium retention plays a key role, although the precise mechanisms that lead to sodium retention are incompletely understood.

Other Forms of Adrenocortical Hypertension

There are several other rare forms of adrenocortical hypertension, as discussed in Genetic Causes of Hypertension (below). Some of these genetic disorders include familial hyperaldosteronism, glucocorticoid-remediable aldosteronism, deoxycorticosterone-secreting tumors, and the syndrome of apparent mineralocorticoid excess (AME) where glucocorticoids activate the MR because of a deficiency of 11β-HSD2. The clinical characteristics of these conditions are similar to those observed with primary increases in aldosterone secretion.

Pheochromocytoma

Although rare, occurring in only 0.05% of hypertensive patients,^49,151 pheochromocytoma can provoke fatal hypertensive crises if unrecognized and untreated. Pheochromocytoma can arise from neuroectodermal chromaffin cells, which are part of the sympathoadrenal system. The chromaffin cells have the capacity to synthesize and store catecholamines and are normally found mainly in the adrenal medulla. Although most chromaffin cell tumors are found in the adrenal medulla, as many as 15% to 30% may be extraadrenal, located along the sympathetic chain or, rarely, in other sites.^49,151

The symptoms and severity of hypertension associated with pheochromocytoma are highly variable, depending on the secretory pattern and amount of catecholamines released.^151,152 With tumors that continuously release large amounts of catecholamines, there may be sustained hypertension with few paroxysms or sudden bursts of very high BP. Tumors that are less active may have cyclical release of catecholamines that induce paroxysms of hypertension.

The clinical presentation also depends on whether the predominant catecholamine secreted is norepinephrine or epinephrine. Whereas norepinephrine produces α-adrenergically mediated vasoconstriction with diastolic hypertension, epinephrine produces β-adrenergically mediated cardiac stimulation with mainly systolic hypertension and tachycardia, along with sweating, tremors, and flushing. Patients with predominantly epinephrine-secreting tumors sometimes have hypertension alternating with hypotension, and approximately 5% of patients with pheochromocytoma remain normotensive.⁴⁹

Pheochromocytoma patients often have decreased blood volume, consistent with the potent peripheral vasoconstrictor effects of norepinephrine, which reduces vascular capacitance. Orthostatic hypotension is common among patients with pheochromocytoma and is related not only to decreased blood volume but perhaps also to desensitization of adrenergic receptors secondary to the chronic excess of catecholamines.

Although a high level of circulating catecholamine is the ultimate cause of hypertension in pheochromocytoma, BP is often only modestly correlated with plasma catecholamine levels. However, periodic bursts of catecholamine release may cause moderate to severe hypertension and lead to target organ injury. Consequently, diagnosis and effective treatment of pheochromocytoma are essential.

Preeclampsia

Preeclampsia is a complex maternal syndrome characterized by multiple disorders, including proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and cerebral or visual symptoms; however, it is most identifiable by the development of new-onset hypertension (systolic BP ≥ 140 mm Hg/diastolic BP ≥ 90 mm Hg) after the 20th week of gestation.¹⁵³ Progression of the disease may lead to eclampsia, in which seizures develop in association with a high risk of fetal and maternal mortality. Despite being a leading cause of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia have not yet been fully elucidated. Hypertension associated with preeclampsia remits after delivery, implicating the placenta as a central culprit in the disease.^154,155

Although numerous factors, including genetic, immunologic, behavioral, and environmental factors, have been implicated in the pathogenesis of preeclampsia, reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of spiral arterioles appears to play a key role.^154,155 Placental ischemia is thought to cause widespread activation or dysfunction of the maternal vascular endothelium, which results in enhanced formation of ET-1, thromboxane, and superoxide, increased vascular sensitivity to Ang II, and decreased formation of vasodilators such as NO and prostacyclin. These endothelial abnormalities, in turn, cause hypertension by impairing renal function while increasing TPR.

One of the most intensely studied pathways in preeclampsia is that related to VEGF signaling.^154,155 VEGF and PlGF, besides their role in angiogenesis, are also important in the maintenance of proper endothelial cell function and health. This signaling pathway came to prominence with the discovery of elevated circulating and placental levels of the soluble form of the VEGF receptor, fms-related tyrosine kinases (sFlt)-1 in preeclampsia.¹⁵⁶ sFlt-1 is a circulating soluble receptor for both VEGF and PlGF, which when increased in maternal plasma leads to less circulating free VEGF and free PlGF, thus preventing their availability to stimulate angiogenesis and maintain endothelial integrity. In the kidney, this inactivation of free VEGF is believed to cause endotheliosis and proteinuria. In addition, sFlt-1 administration to pregnant rats decreases free VEGF and free PlGF in the blood and produces hypertension and proteinuria.¹⁵⁷ Moreover, recombinant VEGF 121 infusion lowers BP and improves renal function in rats with placental ischemia-induced hypertension and elevated levels of sFlt-1.

There is also growing evidence for an important role of ET-1 in the pathophysiology of preeclampsia.¹⁵⁸ Multiple studies have examined circulating levels of ET-1 in normal pregnant and preeclamptic cohorts and found elevated levels of plasma ET-1 in the preeclamptic group, with some studies indicating that the level of circulating ET-1 correlates with the severity of disease symptoms, though this is not a universal finding. ET-1, however, is produced locally, and plasma levels typically do not reflect tissue levels of the peptide. Animal studies have shown that a myriad of experimental models of preeclampsia (placental ischemia, sFlt-1 infusion, TNF-α infusion, and AT1-AA infusion) are associated with elevated tissue levels of ET-1.¹⁵⁸ Finally, the fact that hypertension in pregnant rats, induced by placental ischemia or chronic infusion of sFlt-1, TNF-α, or AT1-AA can be attenuated by ET_A receptor antagonism, strongly suggests that ET-1 may be a final common pathway linking factors produced during placental ischemia to elevations in BP.¹⁵⁸

Unfortunately, effective treatments for patients with preeclampsia remain elusive. In light of the recent developments in our understanding of the pathophysiology of preeclampsia, treatment strategies aimed at improving endothelial dysfunction, safely lowering BP, and reducing maternal and perinatal morbidity should be further explored.

Gene Variants and Human Primary Hypertension

With the development of superb tools for genetic studies and sequencing of the human genome, there has been great enthusiasm for the possibility that genetic causes of primary hypertension can be identified.¹⁵⁹ Proponents of the genetic basis for primary hypertension have implied that advances in genetics will offer unparalleled insights into the pathophysiology of hypertension and development of more effective individualized treatments for hypertension. However, despite great effort, there has been limited success in identifying genes that cause human primary hypertension. The success that has been achieved thus far has been mainly identification of rare monogenic forms of hypertension. A detailed discussion of this topic is beyond the scope of the chapter, but others have discussed some reasons why the “geneticism of hypertension” approach has had limited success.¹⁶⁰

When one considers the complexity of the multiple neural, hormonal, renal, and vascular mechanisms that contribute to short- and long-term BP regulation, it is perhaps not surprising that finding a few variant genes (alleles) to account for a substantial portion of BP variation has been challenging. The complexity of the problem is further amplified by the fact that genetic components of BP variation are likely to be mediated not by only single-gene variations but also by polymorphic genetic differences, complex interactions among several genes, and interaction among genetic and environmental factors. The observation that hypertension does not occur with significant frequency in multiple populations living in nonindustrialized regions of the world suggests that environmental influences play a major role in the development of common forms of hypertension.

What is the evidence that gene variants play a major role in human primary hypertension? Multiple studies provide evidence that the closer the genetic relatedness, the greater the similarity of BP.^161,162 For monozygotic twins (with genetic similarity of 100%), the correlation coefficient for systolic BP has ranged from 0.5 to 0.8 (average, 0.6); for dizygotic twins, it has ranged from 0.19 to 0.46 (average, 0.35); and for nontwin siblings (genetic similarity of around 50%), the correlation coefficient has averaged around 0.23. There is also a better correlation of BP values in biologic children than in adopted children. However, the importance of shared family environment is also evident from the BP correlations observed in genetically unrelated adopted siblings.

Comprehensive familial analyses that include other relatives in addition to twins suggest that environment may contribute to as much as 30% of BP variance, and genetic factors may contribute 40% to 50% of BP variance.^161,162 However, despite the use of sophisticated mathematical models for these calculations, the possibility of nonlinear gene-environmental interactions makes it difficult to quantify the precise roles of genes and environment in BP variation.

Hypertension has been suggested to result from the additive effects of multiple variant genes acting in concert to elevate BP. Each gene variant is presumed to have a relatively weak impact on BP but may produce significant hypertension when they act together in the presence of the necessary environmental conditions. This polygenic model also applies to other complex diseases (eg, diabetes or cancer) in which multiple genes and environmental factors may play a role in the development of the disease.

Although the hypertension research literature is replete with studies showing associations of gene polymorphisms and BP, the genetic alterations that contribute to primary hypertension remain unknown.¹⁶¹ Most of these genetic studies have produced mixed results, even for widely studied polymorphisms such as the ACE insertion or deletion and angiotensinogen polymorphisms. All of the polymorphisms studied thus far show weak associations, if any, with BP, and many of the early studies showing statistically significant associations have not been confirmed. Large-scale genome-wide association studies, in which hundreds of thousands of common genetic variants are genotyped and analyzed for BP association, have shown limited success in identifying genes that contribute to hypertension.^163,164,165 At best, the gene variations discovered thus far explain only a tiny part of the BP variation found in humans.

Epigenetic modification of gene expression may help to explain some of the “missing heritability” of human BP variation.^166,167 Epigenetics is the study of heritable changes in gene expression caused by factors that orchestrate changes in DNA expression without altering the underlying DNA sequence.^166,167 Nucleic acid methylation, histone modification, nucleosome positioning, transcriptional control with DNA-binding proteins and noncoding RNAs, and translation control with microRNAs and RNA-binding proteins could potentially contribute to epigenetic changes in gene expression. Evidence from rodent studies suggests that some epigenetically influenced phenotypes (eg, obesity, insulin resistance) may even be passed on to more than one generation of offspring.¹⁶⁸ However, the importance of epigenetic changes in contributing to human primary hypertension is still unclear and is a rapidly emerging area of investigation.¹⁶⁹

Monogenic Disorders That Cause Hypertension

At least 10 monogenic disorders have been identified that have either high or low BP as part of the phenotype.^170,171 Table 24–5 shows some of the monogenic disorders associated with high BP. An interesting feature of these genetic disorders is that they increase either electrolyte transport in the renal tubule or the synthesis or activity of mineralocorticoid hormones. The final common pathway to hypertension in these disorders appears to be increased renal sodium reabsorption. Monogenic hypertension, however, is rare, and all of the known forms together account for less than 1% of human hypertension.

Familial Hyperaldosteronism Type I

Also called glucocorticoid remediable aldosteronism, familial hyperaldosteronism type I (FH-I) is an inherited autosomal dominant trait caused by a chimeric gene derived from a meiotic mismatch and unequal crossing between the promoter of the 11β-hydroxylase (CYP11B1) controlled by the structural portion of the aldosterone synthase gene (CYP11B2).¹⁷² This causes aldosterone secretion to be regulated by ACTH. Because ACTH is suppressed by glucocorticoids, administration of glucocorticoids is effective in reducing aldosterone secretion in patients with FH-I.

Patients with FH-I exhibit many of the same characteristics as those with primary aldosteronism, including elevated aldosterone, hypokalemia, volume expansion, metabolic alkalosis, and low plasma renin. Although some patients with FH-I have severe hypertension, others have only moderate hypertension or may even be normotensive.¹⁷³ The reasons for this wide range of BP in patients are unclear but could be related to variable expression of the chimeric gene or to other differences in genetic background that would place their inherited BP in the low or normal range in the absence of the FH-I mutation. The final BP could therefore be the combined result of the low or normal inherited BP, the hypertensive effect of the FH-I mutation, and other environmental factors such as salt intake. Patients with FH-I respond well to both thiazide diuretics and MR antagonists such as spironolactone or eplerenone.

Familial Hyperaldosteronism Type II

Familial hyperaldosteronism type II (FH-II) is a rare disease in which hypertension is caused by excessive secretion of aldosterone that is not suppressed by glucocorticoid administration, distinguishing it from FH-I.¹⁷⁴ Patients with FH-II have the same clinical symptoms as patients with primary hyperaldosteronism caused by bilateral adrenal hyperplasia. The genetic abnormality causing FH-II has been localized to chromosome 7p22.¹⁷⁴ Although hypertension in FH-II is unresponsive to glucocorticoids, MR antagonists are effective in reducing BP and correcting the metabolic disturbances.

Congenital Adrenal Hyperplasia

This disorder describes a group of syndromes caused by defects in cortisol biosynthesis. Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder. When 21-hydroxylase (CYP21A2), the most common cause of CAH, is deficient, patients are normotensive.^175,176 When 11β-hydroxylase (CYP11B1) and 17 β-hydroxylase (CYP17) are deficient, production of deoxycorticosterone, which has mineralocorticoid activity, is increased, leading to hypertension. Defects in CYP11B1 and CYP17 cause inhibition of cortisol production with subsequent reduction in feedback inhibition of ACTH secretion by the anterior pituitary and hypothalamus. Increased ACTH secretion then stimulates production of steroid precursors proximal to the blocked step, leading to excessive levels of deoxycorticosterone.

Both forms of CAH are associated with early-onset hypertension and hypokalemia. Signs of androgen excess distinguish the two disorders; whereas 11β-hydroxylase deficiency causes virilization in girls and precocious puberty in boys, 17α-hydroxylase deficiency causes sex hormone deficiency, primary amenorrhea, and delayed sexual development in girls and ambiguous genitalia in boys. Genetic diagnosis of both conditions relies on testing for mutations that either severely depress or abolish enzyme activity. Both conditions can be effectively treated by administering glucocorticoids that normalize ACTH secretion and ACTH-mediated buildup of cortisol precursors proximal to the enzymatic deficiency, including deoxycorticosterone.

Liddle Syndrome

This is an autosomal dominant form of monogenic hypertension that results from mutations in the amiloride-sensitive ENaC. Several mutations that result in the elimination of 45 to 75 amino acids from the cytoplasmic carboxyl terminus of β- or γ-subunits of the channel have been reported. Mutations that increase ENaC activity, in turn, cause excessive distal and collecting tubule sodium reabsorption and hypertension.^177,178

Liddle syndrome is characterized by the early onset of hypertension with hypokalemia and suppression of plasma renin activity and aldosterone. Suppression of aldosterone and lack of responsiveness to MR antagonists differentiates this syndrome from primary aldosteronism. Hypertension and the hypokalemia vary in severity, depending on salt intake, and can be treated with amiloride or triamterene, specific inhibitors of ENaC.

Apparent Mineralocorticoid Excess

AME is an autosomal recessive form of monogenic hypertension that results from a mutation in the renal-specific isoform of the 11β-hydroxysteroid dehydrogenase gene.¹⁷⁹ This enzyme normally converts cortisol to the inactive metabolite cortisone and “protects” the MR from being activated by cortisol. The renal epithelial MR receptor in the distal and collecting tubules has a similar affinity for aldosterone and cortisol, and cortisol concentrations are normally much higher than aldosterone. Therefore, deficiency of 11β-hydroxysteroid dehydrogenase allows the tubular MR to be occupied and activated by cortisol, causing sodium retention, low renin, low aldosterone, and a form of hypertension that is salt sensitive.

A nongenetic form of the AME syndrome occurs in persons ingesting large amounts of licorice, which contains glycyrrhetinic acid, an inhibitor of the enzyme 11β-hydroxysteroid dehydrogenase. Both forms of AME are effectively treated with MR antagonists such as spironolactone or eplerenone.

Pseudohypoaldosteronism Type II

Also called Gordon syndrome, pseudohypoaldosteronism type II is a rare Mendelian form of hypertension that is salt sensitive and associated with hyperkalemia (despite normal GFR), hyperchloremia, metabolic acidosis, and suppressed plasma renin and aldosterone levels. The disorder is caused by mutations in two genes encoding the serine/threonine protein kinases WNK1 and WNK4.¹⁸⁰

The phenotypes of excessive salt retention and hypertension are caused by loss of normal inhibition or to constitutive activation of the renal tubular NaCl cotransporter by mutant WNK1 or WNK4 genes; thiazide diuretics, which inhibit distal nephron NaCl reabsorption, are especially effective in reducing BP in patients with pseudohypoaldosteronism type II. The mutant WNKs may also have a direct effect on the renal outer medullary potassium channel, the major potassium secretory channel in the distal nephron, because hyperkalemia is another major feature of pseudohypoaldosteronism type II.^175,180 The fact that hyperkalemia is invariably present in pseudohypoaldosteronism type II is often used to distinguish it from other monogenic forms of hypertension.

Mineralocorticoid Receptor Activating Mutation

This monogenic disorder is caused by a substitution of leucine for serine at codon 810 of the MR.¹⁸¹ This mutation alters the shape and the specificity of the MR and eliminates the usual requirement for the 21-hydroxyl group of aldosterone to interact with the MR. This explains why other steroids, such as progesterone, activate the MR and why spironolactone, which is normally an MR antagonist, acts as an MR agonist in this disorder. Thus, treatment of these patients with spironolactone or increased levels of progesterone, as occurs in pregnancy, worsens the sodium retention, hypokalemia, and hypertension.

Widespread human primary (essential) hypertension appears to be associated with industrialization. Nearly all studies of industrialized populations have demonstrated that BP and the prevalence of hypertension increase with age.¹ Hunter-gatherers living in nonindustrialized societies, however, rarely develop hypertension or progressive increases in systolic and mean pressures that occur in the majority of individuals living in industrialized societies.¹⁸² This observation suggests that environmental factors play a major role in increasing BP in many patients with primary hypertension. This does not, however, imply that genetic factors are unimportant in primary hypertension. Genetic variation is responsible for differences in baseline BP that result in normal BP distribution in a population. When hypertension-producing environmental factors are added to the population baseline BP, the normal distribution is shifted toward higher BP. Moreover, variations in the impact of environmental factors flatten the BP curve and cause even greater variability in the overall population BP.

What are the factors that cause BP to increase in the majority of people as they age in industrialized societies? How do they affect the physiologic controllers of BP? As discussed earlier, many of the long-term BP controllers either directly or indirectly influence renal function. In patients with primary hypertension, there is a resetting of renal pressure natriuresis so that sodium balance is maintained at higher BP.^12,21 In some individuals, this resetting is related to increased renal tubular reabsorption because of abnormalities intrinsic to the kidneys or to altered neurohumoral control of the kidneys. In other instances, resetting of pressure natriuresis is associated with renal vasoconstriction and reductions in GFR, as a result of intrarenal mechanisms or of nervous and hormonal mechanisms acting on the kidneys. After hypertension is established, many of these changes are difficult to detect because increased BP often returns renal function to normal.

Some of the key environmental factors that affect BP include excess weight gain, high sodium intake, and excess alcohol intake.

Excess Weight Gain is a Major Cause of Primary Hypertension

Current estimates indicate that more than 1.4 billion people in the world are overweight or obese.¹⁸³ In the United States, more than 67% of adults are overweight, and one-third of the adult population is obese, with body mass indices (BMIs) above 30.¹⁸⁴ Population studies show that excess weight gain is a good predictor for development of hypertension, and the relationship between BMI and systolic and diastolic BP is nearly linear in diverse populations throughout the world.^50,185 Risk estimates from the Framingham Heart Study, for example, suggest that approximately 78% of primary hypertension in men and 65% in women can be ascribed to excess weight gain.¹⁸⁶ Clinical studies indicate that maintenance of a BMI less than 25 kg/m² is effective in primary prevention of hypertension and that weight loss reduces BP in most hypertensive subjects.^187,188

One question often raised is why some overweight or obese persons are not hypertensive by the usual standards (ie, BP > 140/90 mm Hg) if obesity is a major cause of hypertension. Perhaps this is not surprising if one considers that BP is normally distributed and that excess weight gain shifts the frequency distribution of BP toward higher levels (Fig. 24–15). However, even obese individuals who are considered “normotensive” have higher BP than they would at a lower body weight, and weight loss lowers BP in normotensive as well as hypertensive obese subjects.¹⁸⁹

Adipose tissue distribution is also important. Most population studies that have investigated the relationship between obesity and BP have measured BMI rather than visceral or retroperitoneal fat, which appear to be better predictors of increased BP than subcutaneous fat.¹⁹⁰

Although the importance of obesity, especially excess visceral fat, is well established as a cause of primary hypertension, the pathophysiologic mechanisms involved are only beginning to be elucidated. Table 24–6 summarizes some of the changes in hemodynamics, neurohumoral systems, and renal function that occur with excess weight gain in humans and experimental animals.

Mechanisms of Impaired Renal Pressure Natriuresis in Obesity Hypertension

Increased renal tubular sodium reabsorption plays a major role in initiating the rise in BP associated with excess weight gain, and obese individuals require higher than normal BP to maintain sodium balance. Three mechanisms appear to be especially important in increasing sodium reabsorption and impairing renal pressure natriuresis in obesity hypertension: (1) increased SNS activity, (2) activation of the RAAS, and (3) physical compression of the kidneys by fat accumulation within and around the kidneys and by increased abdominal pressure (Fig. 24–16). Also, chronic kidney disease may, over a much longer time, amplify the BP effects of these mechanisms and make obesity-associated hypertension more difficult to control and less easily reversed by weight loss.^189,191

Sympathetic Nervous System Activation in Obesity Hypertension

Several observations in experimental animals and in humans indicate that increased SNS activity contributes to obesity hypertension^50,52: (1) SNS activation, especially renal sympathetic activity, is increased in obese subjects; (2) pharmacologic blockade of adrenergic activity lowers BP to a greater extent in obese compared with lean individuals; and (3) markedly attenuates sodium retention and hypertension associated with a high-fat diet in experimental animals.

Increased SNS activity appears to be highly differentiated in obesity. For example, cardiac sympathetic activity may not be substantially elevated, but SNS activity is usually increased in kidneys and skeletal muscles of obese subjects.¹⁹² Obesity-induced SNS activation is usually not sufficient to cause vasoconstriction in most tissues, such as the kidneys or skeletal muscle, but does contribute to renin secretion and increased renal tubular sodium reabsorption.^50,52

Current evidence indicates that the chronic BP effects of SNS activation in obesity are mediated mainly by renal nerves. Bilateral RDN greatly attenuated sodium retention and hypertension in obese dogs fed a high fat diet.^8,37 Similar results were observed in obese humans with resistant hypertension in which catheter-based radiofrequency RDN lowered office systolic BP by 25 to 30 mm Hg and diastolic BP by 10 to 12 mm Hg for up to 24 months.⁴⁰ Although a recent trial failed to find a major effect of RDN on BP in obese resistant hypertensive subjects,⁴¹ compared to sham controls, these patients were already on at least three antihypertensive medications, including blockers of the RAAS, which may mediate part of the effect of the renal nerves on BP.

Several potential mediators of SNS activation in obesity have been suggested, including (1) hyperinsulinemia; (2) Ang II; (3) increased levels of free fatty acids; (4) impaired baroreceptor reflexes; (5) activation of chemoreceptor-mediated reflexes associated with sleep apnea and intermittent hypoxia; and (6) cytokines released from adipocytes (ie, “adipokines”) such as leptin, TNF-α, and IL-6. Although the importance of most of these factors is still uncertain, leptin and the CNS proopiomelanocortin (POMC) pathway may contribute to obesity-induced SNS activation and hypertension (Fig. 24–17).

Leptin is released from adipocytes and acts on the hypothalamus and other regions of the brain to reduce appetite and increase SNS activity.⁵¹ In rodents, increasing plasma leptin concentration to levels comparable to those found in severe obesity not only increases SNS activity but also increases BP.^193,194 Moreover, the hypertensive effects of leptin are enhanced when NO synthesis is inhibited,¹⁹⁵ as often occurs in obese subjects with endothelial dysfunction.

Another observation that points toward leptin as a potential mechanism of obesity hypertension is the finding that leptin-deficient, obese mice and obese mice with mutations of the leptin receptor usually have little or no increase in BP compared with lean control subjects.⁵⁰ Similar results have been found in obese children with leptin gene mutations who have early-onset morbid obesity but normal BP. Moreover, children with leptin gene mutations did not have hypertension despite having other characteristics of the metabolic syndrome, including severe insulin resistance, hyperinsulinemia, and hyperlipidemia.¹⁹⁶ These observations suggest that the functional effects of leptin may be important in linking obesity with SNS activation and hypertension.

Leptin’s stimulatory effect on SNS activity appears to be mediated by activation of POMC neurons in the hypothalamus and brainstem; these neurons release α-melanocyte stimulating hormone, which then activates melanocortin 4 receptors (MC4R) in second-order neurons in the hypothalamus and brainstem. Deletion of leptin receptors specifically in POMC neurons completely abolished the hypertensive effects of leptin.¹⁹⁷ Also, antagonism of the MC4R or genetic deletion of MC4R completely abolished leptin’s chronic BP effects.^198,199 These findings indicate that activation of POMC neurons and subsequent stimulation of the MC4R mediate most of the effects of leptin to activate SNS activity and raise BP.^50,200

Studies in humans also suggest that MC4R activation may contribute to obesity-induced hypertension. The prevalence of hypertension is markedly lower in MC4R-deficient humans compared with control subjects despite severe obesity and associated metabolic disorders.²⁰¹ Moreover, subcutaneous administration of an MC4R agonist for 7 days caused significant increases in BP similar to those observed in rodents. Thus, in humans and rodents, chronic activation of the MC4R increases BP, and the presence of a functional MC4R system appears to be necessary for obesity to increase SNS activity and BP.²⁰¹

Renin-Angiotensin-Aldosterone System Activation in Obesity

Obese subjects, especially those with visceral obesity, often have mild to moderate increases in plasma renin activity, angiotensinogen, ACE activity, Ang II, and aldosterone levels.^50,189 Activation of the RAAS in obese subject occurs despite sodium retention, volume expansion, and hypertension, all of which would normally tend to suppress renin secretion and Ang II formation.

An important role for Ang II in stimulating renal sodium reabsorption and in mediating obesity hypertension is supported by studies in experimental animals demonstrating that Ang II receptor blockade or ACE inhibition blunts sodium retention, volume expansion, and increased BP during the development of obesity.^50,189 Unfortunately, there have been no large-scale clinical studies comparing the effectiveness of RAAS blockers in obese and lean hypertensive patients, although small clinical trials have shown that both ARBs and ACE inhibitors are effective in lowering BP in obese hypertensive patients.^202,203

Antagonism of MR also provides an important therapeutic tool for lowering BP and attenuating target organ injury in obesity hypertension. Antagonism of MR in obese dogs, for example, markedly attenuated sodium retention, hypertension, and glomerular hyperfiltration.⁶⁷ Moreover, this protection against hypertension occurred despite marked increases in plasma renin activity, suggesting that combined blockade of MR and Ang II might be especially effective in treating patients with obesity hypertension. The observation that MR antagonism attenuated glomerular hyperfiltration may also have important implications for renal protection in obesity, although studies in obese humans are limited. Administration of the MR antagonists also provides significant antihypertensive benefit in resistant obese patients, although there was no correlation between plasma aldosterone levels and BP responses to MR blockade.^65,204 The reductions in BP caused by MR antagonism in obese patients with resistant hypertension occurred despite concurrent therapy with ACE inhibitors or ARBs, calcium channel blockers, and thiazide diuretics, suggesting that MR activation in obesity may occur independently of Ang II–mediated stimulation of aldosterone secretion.²⁰⁵

Renal Compression Caused by Visceral Obesity

Visceral obesity initiates several changes that lead to compression of the kidneys, increased intrarenal pressures, impaired renal pressure natriuresis, and hypertension.⁵⁰ For example, intra-abdominal pressure increases in proportion to abdominal diameter, reaching levels as high as 35 to 40 mm Hg in some individuals.²⁰⁶ In addition, retroperitoneal adipose tissue often encapsulates the kidney and penetrates the renal hilum into the renal medullary sinuses, causing additional compression and increased intrarenal pressures.^191,207 Obesity also causes changes in renal medullary histology and increased extracellular matrix that could exacerbate intrarenal compression and hypertension.²⁰⁸ Although these physical changes in the kidneys cannot account for the initial increase in BP that occurs with rapid weight gain, they may help to explain why visceral obesity is much more closely associated with hypertension than subcutaneous obesity.

Glomerular Injury and Nephron Loss in Obesity Hypertension

Obese patients often develop proteinuria, frequently in the nephrotic range, followed by progressive loss of kidney function.^191,207 The most common types of renal lesions observed in renal biopsies are of obese subjects are focal and segmental glomerular sclerosis and glomerulomegaly.²⁰⁹

Animals placed on a high-fat diet for only a few weeks have significant structural changes in the kidneys, including enlargement of the Bowman space, glomerular cell proliferation, increased mesangial matrix, and increased expression of glomerular transforming growth factor (TGF)-β.²¹⁰ These early changes, which occur with only modest hypertension, no evidence of diabetes, and only mild metabolic abnormalities, may be the precursors of more severe renal injury as obesity is sustained.

Population studies indicate that obesity increases the risk of chronic kidney disease even after adjustment for hypertension, diabetes, or preexisting renal disease.^211,212 Obesity also exacerbates the deleterious effects of other kidney insults, including unilateral nephrectomy, kidney transplantation, unilateral renal agenesis, and IgA nephropathy.^207,213 Thus, obesity exacerbates the loss of kidney function in patients with preexisting glomerulopathies and weight loss may lessen the impact of renal injury from other causes.

Gradual loss of kidney function, as well as hypertension and diabetes that commonly coexist with obesity, may lead to progressive impairment of kidney function, increases in salt sensitivity, and progressive increases in BP (Fig. 24–18). Thus, renal injury in obese subjects not only makes the hypertension more severe but also more difficult to control with antihypertensive drugs. Early control of hypertension and effective weight management are crucial in preventing injury to the kidneys in obese patients.

What is the Role of Metabolic Syndrome or Insulin Resistance in Primary Hypertension?

Dyslipidemia, hyperinsulinemia, and hyperglycemia often occur concurrently with hypertension, leading to the proposal of a unique pathophysiologic condition that is often called the metabolic syndrome. Definitions of the metabolic syndrome generally include disordered glucose homeostasis or measures of insulin resistance, dyslipidemia, hypertension, and obesity.²¹⁴

Some researchers suggest that a defect in insulin action (ie, insulin resistance) is the main cause of all the CVD risk factors that constitute the different versions of the metabolic syndrome.²¹⁵ Broadly defined, insulin resistance refers to a subnormal tissue response to a given concentration of insulin or an impairment of insulin’s action of overall glucose homeostasis.²¹⁶ Other analyses of the metabolic syndrome, however, have questioned whether insulin resistance and hyperinsulinemia are, in fact, the underlying causes of this complex cluster of cardiovascular risk factors.^217,218

Hyperinsulinemia Does Not Cause Hypertension in Humans

Evidence supporting a role for hyperinsulinemia in hypertension comes mainly from epidemiologic studies showing correlations between insulin resistance, hyperinsulinemia, and BP and from short-term studies indicating that insulin has sympathetic effects that, if sustained, could theoretically increase BP.²¹⁹ However, chronic hyperinsulinemia, in the absence of obesity, does not raise BP in dogs or humans (see Hall et al^220,221,222 for reviews). For example, chronic insulin infusions did not increase BP even when there was preexisting impairment of renal function caused by a 70% reduction of kidney mass²²² and did not enhance the hypertensive effects of other pressor substances such as norepinephrine or Ang II.^220,223 Chronic hyperinsulinemia also did not increase BP in insulin-resistant obese dogs that were resistant to the vasodilator effects of insulin.²²³ Multiple studies in humans have also shown that chronic insulin treatment does not raise BP, and patients with severe hyperinsulinemia as a result of insulinoma are not hypertensive.^220,224 These observations suggest that hyperinsulinemia per se is insufficient to cause chronic hypertension.

Does Insulin Resistance Cause Hypertension Independent of Hyperinsulinemia?

Insulin resistance has also been suggested to cause hypertension by increasing TPR through mechanisms that are independent of hyperinsulinemia. However, several disorders associated with severe insulin resistance in humans and experimental animal models are not associated with hypertension. For example, experimental models of obesity caused by mutations of the leptin gene or the leptin receptor, or by mutations of the MC4R, have severe insulin resistance and many of the characteristics of the metabolic syndrome but do not have increased BP compared to WT control subjects.^50,198 Likewise, humans with leptin gene mutations have severe insulin resistance but no indication of SNS activation or hypertension.¹⁹⁶

Several reports indicate that antihyperglycemic agents that increase insulin sensitivity, such as the thiazolidinediones, also lower BP. However, these drugs also influence the expression of multiple genes by binding to the peroxisome proliferator-activated receptor-γ, a nuclear receptor. Thiazolidinediones also inhibit L-type calcium channels and reduce BP in renovascular hypertension that is not associated with insulin resistance or hyperinsulinemia.²²⁵ Therefore, the BP-lowering effects of these drugs are likely related to other actions besides improvement of insulin sensitivity.

Although a direct causal relationship between insulin resistance and hypertension has not been established, abnormalities of glucose and lipid metabolism associated with insulin resistance may, over many years, lead to vascular and renal injury and contribute indirectly to increased BP. However, the importance of these effects in the absence of diabetes is still unclear.

Does Hypertension Cause Insulin Resistance?

It also has been suggested that insulin resistance is secondary to peripheral vascular changes that occur in hypertension.²²⁶ However, most models of secondary hypertension, such as renovascular hypertension, are characterized by increased peripheral vascular resistance and vascular rarefaction but are not associated with development of insulin resistance (see Hall et al^216,221 for reviews). These observations indicate that hypertension per se is not a primary cause of insulin resistance.

Although insulin resistance and hypertension are often closely correlated, much of the available evidence suggests that this association is largely a consequence of obesity that causes both insulin resistance and high BP through parallel mechanisms. There is little doubt that obesity, especially visceral obesity, is a major cause of the entire cluster of CVD risk factors associated with the metabolic syndrome. Importantly, all of the disorders associated with the metabolic syndrome can be reversed in most patients with weight loss.

Until more effective antiobesity drugs are developed, the impact of obesity on hypertension and related cardiovascular, renal, and metabolic disorders is likely to become even more important as the prevalence of obesity continues to increase. In the meantime, effective BP control is essential in treating patients with metabolic syndrome and preventing CVD. Weight reduction is an essential first step in the effective management of most patients with metabolic syndrome and hypertension, and more emphasis should be placed on lifestyle modifications that help patients to maintain a healthier weight and prevent CVD.

The authors’ research was supported grants from the National Heart, Lung and Blood Institute (PO1 HL51971) and the National Institute of General Medical Sciences (P20 GM104357 and U54 GM115428). We thank Stephanie Lucas for expert assistance in preparing this chapter.