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.
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.
Angiotensin (Ang) II increases proximal tubular reabsorption by binding to receptors on the luminal and basolateral membranes and stimulating Na+/H+ antiporter, Na+/HCO3 cotransport, and Na+/K+ adenosine triphosphatase (ATPase) activity. Ang II also increases reabsorption by increasing interstitial fluid colloid osmotic pressure and decreasing interstitial fluid hydrostatic pressure. AT1, angiotensin II receptor, type 1. Reproduced with permission from Hall JE, Brands MW, Henegar JR: Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol. 1999 Apr;10 Suppl 12:S258-S265.
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
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 (ETA) receptors in the kidneys or an antihypertensive effect via ET type B (ETB) 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.
Summary of the pro- and antihypertensive actions of endothelin-1 (ET-1). The ability of ET-1 to influence blood pressure (BP) regulation and renal pressure natriuresis is highly dependent on where ET-1 is produced and which renal ET receptor type is activated. ET-1 can elicit a prohypertensive antinatriuretic effect by activating ETA receptors in the kidneys. Activation of renal ETA receptors increases renal vascular resistance (RVR), which decreases renal plasma flow (RPF) and glomerular filtration rate (GFR), and enhances sodium reabsorption by decreasing peritubular capillary hydrostatic pressure (Pc). The net effect of renal ETA receptor activation is decreased sodium excretion and increased BP. Conversely, ET-1 can elicit an antihypertensive natriuretic effect via ETB receptor activation. Activation of the renal ETB receptor leads to enhanced synthesis of nitric oxide (NO) and prostaglandin (PG) E2 and suppression of the renin–angiotensin system. The net effect of renal ETB receptor activation is increased sodium excretion and decreased BP.
ET-1 produces vasoconstriction, impairs renal pressure natriuresis, and increases BP via ETA receptor activation. ETA 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 ETA 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 ETB receptors are located on multiple cell types throughout the body, including endothelial cells and renal epithelial cells. ETB activation causes vasodilation, enhances pressure natriuresis, and decreases BP. Although much attention has been given to ETA receptor activation in the pathophysiology of cardiovascular and renal disease, several studies indicate an important antihypertensive role for the ETB receptor. The most compelling evidence for a major role of ETB receptors in regulating BP comes from reports that transgenic mice deficient in ETB receptors develop severe salt-sensitive hypertension and that pharmacologic antagonism of ETB receptors produces significant hypertension in rats.85,86,87
Bagnall et al reported that ablation of ETB receptors exclusively from endothelial cells produced endothelial dysfunction but did not cause hypertension.88 In contrast to models of total ETB receptor ablation, the BP response to a high-salt diet was unchanged in endothelial cell-specific ETB receptor knockouts compared with control mice. These findings suggest that ETB receptors in nonendothelial cells are important for BP regulation. Supporting this concept is the finding that collecting duct ETB 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 ETB 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 ETA 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 ETA-ETB 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 ETA 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 ETA 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 ETA 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 ETA-ETB 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 ETA and ETB receptors, and antagonism of antihypertensive ETB receptors may have masked an important role of ET on BP via ETA receptor activation.
In another study, 6 weeks of darusentan, a selective ETA 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 ETA/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 ETA/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.
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
Renal mechanisms whereby reduced nitric oxide (NO) synthesis decreases pressure natriuresis and increases blood pressure. Decreased endothelial-derived nitric oxide (EDNO) synthesis impairs renal sodium excretory function by increasing basal renal vascular resistance, enhancing the renal vascular responsiveness to vasoconstrictors such as Ang II or norepinephrine, or activating the renin–angiotensin system. Reductions in NO synthesis also impair sodium excretory function either by directly increasing tubular reabsorption or by altering intrarenal physical factors, such as renal interstitial hydrostatic pressure or medullary blood flow.
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.
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
Renal mechanisms whereby reactive oxygen species impair pressure natriuresis and increase blood pressure. An increase in renal oxidative stress impairs renal pressure natriuresis by increasing renal vascular resistance or enhancing tubuloglomerular feedback, both of which decrease the glomerular filtration rate. Renal oxidative stress also reduces sodium excretion by direct effects to increase renal tubular reabsorption.
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
Potential mechanisms whereby inhibitors of vascular endothelial growth factor (VEGF) receptor signaling raise blood pressure (BP). Blockade of VEGF receptors results in endothelial dysfunction, leading to decreased production of endothelium-derived relaxing such as nitric oxide (NO) and prostaglandin or enhanced production of vasoconstrictor factors such as thromboxane and endothelin. Inhibitors of VEGF signaling may also result in alterations in glomerular structure and function. These changes may elevate BP by reducing renal blood flow and glomerular filtration rate (GFR) and impairing the kidney’s ability to excrete sodium and water (depicted by a decrease in the pressure natriuresis relationship).
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 ETA 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.