Physiology and Pathophysiology of Hypertension


Normal blood pressure (BP) regulation involves the integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems. Chronic hypertension is a disorder of long-term BP regulation, although short-term BP control systems may also be affected. Abnormal kidney function, as reflected by resetting of renal-pressure natriuresis to higher BP, is present in all forms of chronic hypertension. However, impaired renal-pressure natriuresis and chronic hypertension can be caused by extrarenal as well as intrarenal factors that reduce glomerular filtration rate (GFR) or increase renal tubular salt and water reabsorption; some of these factors include excess activation of the renin–angiotensin–aldosterone and sympathetic nervous systems, increased reactive oxygen species, endothelin, and inflammatory cytokines, or decreased synthesis of nitric oxide and various natriuretic factors. Although the precise causes of impaired kidney function in human primary hypertension are not completely understood, excessive weight gain and dietary factors appear to play a major role since hypertension is rare in non-obese hunter-gathers living in non-industrialized societies. Recent advances in genetics promise opportunities to discover gene-environment interactions that may contribute to hypertension, although success thus far has been limited mainly to identification of rare monogenic forms of hypertension.


obesity; sympathetic; renin–angiotensin system; aldosterone; blood pressure; hormones; nervous system; endothelial factors


Hypertension is the leading risk factor for cardiovascular deaths, causing approximately 7.6 million premature deaths per year worldwide. Over 1 billion people including more than 50 million Americans have hypertension, making it the most common chronic disease. Blood pressure (BP) typically rises with age and in the United States, approximately 50% of people 60–69 years old and 75% of people 70 years and older have hypertension. In non-industrialized populations, however, BP does not rise with aging and only a small fraction of the population develops hypertension. This suggests that environmental factors play a major role in causing hypertension, and that a rise in BP with aging is not inevitable when these conditions 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. Observational studies indicate that death from CVD increases progressively as BP rises above 115 mmHg systolic and 75 mmHg diastolic pressure. For every 20 mmHg systolic or 10 mmHg diastolic increase in BP there is a doubling of mortality from ischemic heart disease and stroke in all age groups from 40 to 89 years old.

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 is still poorly-controlled in most countries, including the United States, and continues to be the most important modifiable risk factor for CVD.

Blood Pressure Classification for Hypertension Treatment

BP is a variable, quantitative trait with a normal distribution slightly skewed toward higher BPs. Although there is no clear level of BP where cardiovascular or renal disease begins to occur, a definition of hypertension is useful for treatment decisions. A commonly used BP classification was proposed in 2003 by the Seventh Report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP JNC 7 and is now widely used.

According to these criteria, normal BP is defined as a systolic BP<120 mmHg and a diastolic BP<80 mmHg. Persons with a systolic BP between 120–139 mmHg or diastolic BP between 80–89 mmHg are designated as having prehypertension . Hypertension is further characterized by two stages: Stage 1, the milder (systolic 140–159 mmHg and/or diastolic 90–99 mmHg) and most common form of hypertension, accounts for approximately 80% of hypertension. Stage 2 hypertension includes those with systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg. Isolated systolic hypertension is defined as systolic BP of ≥140 mmHg and diastolic BP<90 mmHg.

Using these definitions, and including those taking antihypertensive medications, approximately 24% of the adult population in the United States has hypertension. This percentage varies with: 1) race, being higher in blacks 32% and lower in whites 23% and Mexican Americans 23%; 2) age, because systolic BP rises throughout life in the United States, as well as in most industrialized countries, whereas diastolic BP rises until age 55–60 years; 3) gender, with hypertension being more prevalent in men than in premenopausal women, after menopause women have BPs that are nearly the same as in men; 4) geographic patterns, with hypertension being more prevalent in the Southeastern United States; and 5) socioeconomic status, which is inversely related to the prevalence of hypertension.

Primary hypertension accounts for about 95% of all cases of hypertension, and is usually defined as elevated BP for which an obvious secondary cause (e.g., renovascular disease, aldosteronism, pheochromocytoma or gene mutations) cannot be determined. Although primary hypertension is a heterogeneous disorder, some of the main risk factors are known. For example, overweight and obesity may account for as much as 65–75% of the risk for primary hypertension. Other factors, such as sedentary lifestyle, excess consumption of alcohol or sodium chloride, and low potassium intake are also thought to contribute to increased BP in many patients. This review discusses basic concepts of BP control and pathophysiological changes that may cause primary hypertension, as well as selected forms of genetic and secondary hypertension.

Basic Physiology of Blood Pressure Regulation

BP regulation depends on integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems. Although hypertension is usually considered as a disorder of the average level at which BP is regulated, there is increasing interest in other measures of BP, including peak arterial pressure, BP variability, nighttime and daytime BP, and responses of BP to stress, which may affect cardiovascular risk.

The complex local control, hormonal, neural, and renal systems that regulate BP are often discussed in terms of how they influence cardiac function or vascular resistance because of the well-known formula: mean arterial pressure=cardiac output × total peripheral resistance . This conceptual framework, with the addition of factors that influence vascular capacity and transcapillary fluid exchange, is adequate to explain short-term BP regulation, but not chronic hypertension. Two additional concepts are useful when considering chronic BP regulation: 1) BP control mechanisms are time-dependent; and 2) renal excretion of water and electrolytes play a key role in long-term BP regulation.

Blood Pressure Control Systems are Time-Dependent

Figure 39.1 shows the maximum feedback gains of major BP controllers following a sudden disturbance, as might occur with rapid blood loss. Three important neural control systems begin to function powerfully within a few 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, which responds within a few seconds to ischemia of the vasomotor centers in the medulla, especially when BP falls below about 50 mmHg. Each of these nervous control mechanisms works rapidly and has potent effects on BP. Also note, however, that the feedback gains of these systems decrease with time, as disturbances of BP are maintained.

Figure 39.1

Time-dependency of blood pressure control mechanisms.

Approximate maximum feedback gains of various blood pressure control mechanisms at different time intervals after the onset of a disturbance to arterial pressure.

Within a few minutes or hours after a BP disturbance, additional control systems 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 renin–angiotensin–aldosterone system RAAS which is activated when BP falls too low and is suppressed when BP increases above normal; 3) multiple vasodilator systems not shown in the figure that are suppressed when BP decreases and stimulated when BP rises above normal.

Most of the BP regulators are proportional control systems. This means that they can correct a BP abnormality only part of the way back toward the normal level, but never all the way back. The arterial baroreceptor reflex system, for example, has a feedback gain of approximately 2.0 during acute changes in BP, and therefore buffers about two-thirds of a sudden change in the BP. The renal–body fluid feedback system, however, is the one BP control system with near infinite feedback gain if it is given enough time to operate.

The Renal–Body Fluid Feedback Mechanism for Long-Term BP Regulation

Figure 39.2 shows the basic components of the renal–body fluid feedback mechanism. Extracellular fluid volume is determined by the balance between intake and excretion of salt and water by the kidneys. Even a temporary imbalance between intake and output can lead to a change in extracellular volume, and potentially a change in BP. Under steady-state conditions there must be a precise balance between intake and output of salt and water; otherwise, there would be continued accumulation or loss of fluid leading to circulatory collapse within a few days. A key component of this mechanism for regulating salt and water balance is pressure natriuresis –the effects of increased BP to raise sodium excretion. Under many conditions this mechanism stabilizes BP. For example, when BP is increased above the renal set-point, because of increased TPR or increased cardiac pumping ability, this also tends to increase sodium excretion, via pressure natriuresis, if the effectiveness of pressure natriuresis is not impaired ( Figure 39.3 ). As long as fluid excretion exceeds intake, extracellular fluid volume will continue to decrease, reducing venous return and cardiac output, until BP returns to normal and fluid balance is re-established.

Figure 39.2

Block diagram showing the basic elements of the renal–body fluid feedback mechanism for long-term regulation of arterial pressure.

Figure 39.3

Long-term effects of increased total peripheral resistance (TPR), such as that caused by closure of a large arteriovenous fistula, with no change in the renal pressure natriuresis relationship.

BP is initially increased from point A to point B, but elevated BP cannot be sustained because sodium excretion exceeds intake, reducing extracellular fluid volume until BP returns to normal and sodium balance is re-established.

An important feature of pressure natriuresis is that it continues to operate until BP returns to the original set-point. Another key aspect of pressure natriuresis is that various neurohumoral systems can amplify or blunt the pressure natriuresis mechanism. For example, increases in sodium intake are associated with only small changes in BP in many people. One reason for this insensitivity of BP to changes in salt intake is decreased formation of antinatriuretic hormones such as angiotensin II and aldosterone, which enhance the effectiveness of pressure natriuresis and allow sodium balance to be maintained with minimal increases in BP. On the other hand, excessive activation of these antinatriuretic systems reduces the effectiveness of pressure natriuresis, necessitating greater increases in BP to maintain sodium balance.

In all forms of human or experimental hypertension studied thus far, there is a shift of pressure natriuresis toward higher BPs. In some cases, impaired pressure natriuresis is caused by intrarenal disturbances that reduce glomerular filtration rate GFR or increase tubular reabsorption. In other instances, impaired pressure natriuresis is caused by extrarenal factors, such as increased activity of the SNS or antinatriuretic hormones that reduce the kidney’s ability to excrete sodium and eventually raise BP.

Vasoconstrictors May Decrease Extracellular Volume Despite Impairing Renal-Pressure Natriuresis

Some forms of hypertension, especially those associated with increased levels of vasoconstrictors such as norepinephrine, are associated with reduced rather than increased extracellular fluid volume. How can the hypertension in these instances be attributed to impaired renal pressure natriuresis when there is no evidence of sodium retention? Consider the physiological changes caused by infusion of a powerful vasoconstrictor such as norepinephrine. Chronic iv infusion of norepinephrine causes mild hypertension associated with an initial increase in sodium excretion as BP rises. After several days, sodium excretion returns to normal but extracellular fluid volume is reduced. On the other hand, if norepinephrine is infused directly into the renal artery at a low dose so that its effect on other vascular beds is minimal or if renal perfusion pressure is servo-controlled and prevented from increasing during iv norepinephrine infusion there is significant sodium retention, demonstrating a direct antinatriuretic effect on the kidneys, as well as development of hypertension.

Figure 39.4 shows the relationship between BP and sodium excretion caused by a powerful vasoconstrictor, such as norepinephrine, which has a relatively weak antinatriuretic action. The antinatriuretic effect shifts pressure natriuresis to higher BPs, but because norepinephrine has a weak antinatriuretic effect, compared to its peripheral vasoconstrictor effect, BP initially increases above the renal set-point for sodium balance and causes transient natriuresis. After a few days, extracellular fluid volume decreases and BP stabilizes at a point where sodium intake and output are balanced. The sodium retaining actions are obscured by peripheral vasoconstriction which raises BP above the renal set-point at which sodium balance is maintained, causing increased renal excretion and decreased extracellular fluid volume. However, the maintenance of high BP chronically depends on the changes in renal function that shift pressure natriuresis to higher BPs.

Figure 39.4

Long-term effects of norepinephrine, a vasoconstrictor that has a relatively weak effect to impair pressure natriuresis.

The normal curve (blue) is compared with the vasoconstrictor curve (red line). Initially the vasoconstrictor raises BP (from point A to point B) above the renal set point for sodium balance. Increased BP, however, causes a transient natriuresis and decreases extracellular fluid volume until BP eventually stabilizes at a level (point C) at which sodium intake and output are balanced at a reduced extracellular fluid volume. See color section at the back of the book.

Renal Mechanisms of Hypertension

Commonly used measurements of kidney function, such as GFR, renal blood flow, serum creatinine, and sodium excretion, are often within the normal range in hypertensive patients, at least prior to renal damage due to prolonged high BP. On the other hand, increased TPR is found in many hypertensive patients, leading to emphasis on peripheral vasoconstriction as a cause of increased BP. However, increased TPR may be an autoregulatory response to increased BP, and may not cause sustained hypertension in the absence of impaired pressure natriuresis.

Almost all forms of experimental hypertension and all monogenic forms of human hypertension discovered thus far are caused by insults to the kidneys that alter renal hemodynamics or tubular reabsorption. For example, constriction of the renal arteries e.g., Goldblatt hypertension, compression of the kidneys e.g., perinephritic hypertension or administration of sodium-retaining hormones (e.g., mineralocorticoids or angiotensin II) are all associated with either initial reductions in renal blood flow and GFR or increases in renal tubular reabsorption prior to development of hypertension. Likewise, in all known monogenic forms of human hypertension there is impaired renal excretory function caused by mutations that increase renal sodium reabsorption or activity of antinatriuretic hormones. As BP rises, the initial changes are obscured by compensations that restore kidney function toward normal. The rise in BP then initiates a cascade of cardiovascular changes, including increased TPR that may be more striking than the initial kidney disturbance. For this reason, the importance of renal dysfunction in causing hypertension has often been underestimated.

Although specific abnormalities of kidney function are difficult to identify in most patients with primary hypertension, one aspect of kidney function that is invariably abnormal is renal pressure natriuresis. Maintenance of a normal sodium excretion equal to sodium intake despite elevated BP, which would normally cause natriuresis and diuresis, indicates that pressure natriuresis is reset in hypertensive subjects.

Some types of renal abnormalities that cause chronic hypertension include: 1) increased preglomerular resistance; 2) decreased glomerular capillary filtration coefficient; 3) reduced numbers of functional nephrons; and 4) increased tubular reabsorption ( Figure 39.5 ). As discussed below, some of these abnormalities cause blood pressure to be more sensitive to changes in dietary salt intake (salt-sensitive), whereas other renal abnormalities may cause hypertension that is relatively insensitive to changes in salt intake (salt-insensitive).

Figure 39.5

Steady-state relationships between BP, sodium excretion, and sodium intake for subjects with normal kidneys and four general types of renal dysfunction that cause hypertension: decreased kidney mass; increased reabsorption in distal and collecting tubules; reductions in glomerular capillary filtration coefficient (K f ); and increased preglomerular resistance.

Note that increased preglomerular resistance causes salt-insensitive hypertension, whereas the other renal abnormalities cause salt-sensitive hypertension.

Generalized Increases in Preglomerular Resistance Cause Salt-Insensitive Hypertension

Examples of a generalized increase in preglomerular resistance are those caused by suprarenal aortic coarctation or constriction of one renal artery and removal of the contralateral kidney (e.g., 1-kidney, 1-clip Goldblatt hypertension). After renal artery constriction or aortic coarctation, renal blood flow, GFR, and sodium excretion are initially reduced, and there is a rapid rise in renin secretion. Renal blood flow and GFR may return to near normal if autoregulatory mechanisms are not impaired, and if constriction is not so severe that it reduces renal perfusion pressure below the autoregulatory range ~65–70 mmHg. Even if GFR is not fully autoregulated, sodium excretion returns to normal and sodium balance is re-established within a few days. If sodium and fluid intakes are 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.

Homogeneous increases in preglomerular resistance typically cause salt-insensitive rather than salt-sensitive hypertension. One of the main reasons that increased salt intake does not greatly exacerbate this form of hypertension is that after BP increases sufficiently to restore renal perfusion pressure and renin secretion to nearly normal, the RAAS is fully capable of appropriate suppression during high salt intake. As discussed later, the ability to effectively modulate RAAS activity is critical for preventing salt-sensitivity of BP.

Functional or pathologic increases in preglomerular resistance at other sites besides the main renal arteries, such as the interlobular arteries or afferent arterioles, could also increase BP through the same mechanisms activated by clipping the renal artery. For example, structural increases in afferent arteriolar resistance (e.g., nephrosclerosis or functional increases in resistance caused by excessive activation of the SNS) could also cause hypertension through the same mechanisms as constriction of the main renal artery. Some patients with primary hypertension have essentially the same characteristics seen in 1-kidney, 1-clip Goldblatt 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. Also, drug therapies that decrease preglomerular resistance, such as calcium channel blockers, cause a parallel shift of pressure natriuresis toward lower BP. 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.

Non-Homeogeneous Increases in Preglomerular Resistance Cause Salt-Sensitive Hypertension

In 2-kidney, 1-clip Goldblatt hypertension or in patients with a stenosis in only one renal artery, there is a non-homogeneous increase in preglomerular resistance, with ischemia occurring in nephrons of the clipped/stenotic kidney, while nephrons in the contralateral nonstenotic kidney have normal or increased single-nephron blood flow and GFR. The underperfused clipped kidney secretes large amounts of renin, whereas the untouched kidney secretes little renin.

In the 2-kidney, 1-clip model, the glomeruli of the untouched kidney are subject to the full effects of increased BP. With prolonged hypertension, pathologic changes in the untouched kidney may further impair renal function. At this stage, removal of the clipped kidney only partially normalizes BP. However, removal of the contralateral untouched kidney and unclipping the stenotic kidney usually normalizes BP if the underperfusion of the clipped kidney is not too severe and ischemic injury has not occurred. Thus, chronic exposure to high BP in the untouched kidney may cause pathological changes that increase the severity of hypertension.

Non-homogeneous increases in preglomerular resistance may also cause salt-sensitivity of BP. The main reason is that the underperfused nephrons secrete large amounts of renin, whereas the remaining nephrons are overperfused and have reduced renin secretion. In both cases, the nephrons have impaired ability to adequately suppress renin secretion during high salt intake, and BP becomes more salt-sensitive.

Some patients with essential hypertension may have non-homogenous nephrosclerosis within each kidney, providing another clinical counterpart to the 2-kidney, 1-clip Goldblatt model of hypertension. In these instances, the combined effects of hypertension and hyperfiltration in non-ischemic nephrons may eventually damage the nephrons that were not initially ischemic, leading to progressive nephron loss.

Reduced Glomerular Capillary Filtration Coefficient

Decreased glomerular capillary filtration coefficient K f initially lowers GFR and sodium excretion, while stimulating renin release and causing vasodilation of afferent arterioles via macula densa feedback. The sodium retention and increased angiotensin II formation raise BP, which helps to normalize GFR and renin release. After these compensations, the main persistent abnormalities of kidney function are reduced filtration fraction, increased glomerular hydrostatic pressure, and increased renal blood flow. Unfortunately, compensatory increases in BP and glomerular hydrostatic pressure, which offset a fall in K f and restore sodium excretion to normal, may also cause further glomerular injury, loss of glomeruli, further reductions in K f , and additional increases in 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.

Nephron Loss Increases Salt-Sensitivity

Surgical removal of large amounts of the kidney, to the point that uremia occurs, rarely cause much hypertension as long as sodium intake is normal. In this case, GFR and tubular reabsorption capability are proportionally reduced so that balance between filtration and reabsorption are maintained without major changes in BP. Reducing the number of nephrons, however, makes the kidneys susceptible to additional challenges of sodium homeostasis. For example, hypertension associated with excess mineralocorticoids is more severe after reducing kidney mass. Likewise, high sodium intake is accompanied by larger BP increases when kidney mass is reduced.

Nephron loss also initiates compensatory changes that may damage the surviving nephrons. For example, renal vasodilation and increased single nephron GFR, over long periods of time, may lead to glomerulosclerosis and reductions in K f . These pathologic changes, in addition to loss of functional nephrons, may further impair pressure natriuresis and cause hypertension. Thus, even though hypertension may not begin with nephron loss, chronic elevations in glomerular pressure and other metabolic abnormalities often associated with hypertension may cause progressive nephron loss that amplifies the hypertension and makes BP salt-sensitive.

Partial renal infarction causes high renin hypertension. In contrast to the effects of surgical removal of kidney mass, loss of nephrons because of ischemia or infarction of renal tissue usually causes marked hypertension, even with normal salt intake. The so-called 5/6 ablation model is produced by removing one kidney and obstructing two of the three branches of the renal artery of the remaining kidney. In this model, hypertension develops even without high salt intake because of ischemia of the surviving nephrons, activation of the RAAS, and immune-mediated renal injury. This hypertension model has non-homogeneous areas of renal ischemia with characteristics similar to that described for the 2-kidney, 1-clip Goldblatt model. The clinical counterpart of this model occurs with partial renal infarction caused by septic emboli, thrombus, trauma or sometimes after corrective surgery for renal artery stenosis.

Increased Renal Tubular Sodium Reabsorption

Hypertension caused by increased distal or collecting tubular reabsorption is exacerbated by increased salt intake. Increased reabsorption at sites beyond the macula densa elicits increased sodium chloride delivery to the macula densa which, in turn, suppresses renin secretion, sometimes to very low levels, which prevents further suppression of angiotensin II formation during high sodium intake, making BP salt-sensitive.

An increase in proximal or loop of Henle tubular reabsorption, however, may result in a salt-insensitive hypertension. Increased proximal tubular reabsorption tends to increase renin secretion, and elicits a compensatory renal vasodilation that raises GFR and renal plasma flow in response to reduced macula densa NaCl delivery. However, as hypertension develops, macula densa NaCl delivery and renin secretion return to nearly normal, and the RAAS may be fully capable of responding to increased salt intake. Therefore, high salt intake may be accompanied by appropriate suppression of angiotensin II formation, which permits sodium balance to be maintained with only small increases in BP. Nevertheless, pressure natriuresis is shifted to higher BP.

A feature of hypertension caused by increased tubular reabsorption is that it may initially be associated with extracellular volume-expansion. However, volume-expansion and increased cardiac output usually subside because of pressure natriuresis, and TPR increases secondarily to increased BP. When increased tubular reabsorption is also associated with marked peripheral vasoconstriction, such as occurs with very high levels of angiotensin II, the degree of volume-expansion depends on the relative effects of the vasoconstrictor on peripheral and renal blood vessels. With severe peripheral vasoconstriction and decreased vascular capacitance, relatively small amounts of volume retention can lead to substantial hypertension.

Significance of Salt-Sensitive Hypertension

Many factors are associated with salt-sensitivity of BP. Older individuals are usually more salt-sensitive than young people, and African Americans are often more salt-sensitive than whites. However, there are exceptions to these generalizations and considerable heterogeneity exists in the BP responses to increased salt intake.

Genetic factors independent of ethnicity have been linked to salt-sensitivity of BP, especially monogenic disorders that increase distal and collecting tubule sodium reabsorption or that increase secretion of sodium-retaining hormones. Also, diabetes mellitus, renal diseases that cause nephron loss, and abnormalities of the RAAS are associated with increased salt-sensitivity of BP. Many of these examples share two common pathways to salt-sensitivity: 1) loss of functional nephrons as discussed previously or 2) reduced responsiveness of the RAAS.

Figure 39.6 shows the importance of changes in angiotensin II formation in maintaining BP relatively constant during wide variations in salt intake. In dogs with a fully-functional RAAS, only small increases in BP were associated with a 100-fold increase in sodium intake. However, when angiotensin II was prevented from being suppressed as sodium intake was raised, BP became salt-sensitive. After blockade of angiotensin II formation, BP was also salt-sensitive, although maintained at lower levels. Thus, a major function of the RAAS is to permit wide variations in sodium intake and excretion without large fluctuations in BP.

Figure 39.6

Changes in mean arterial pressure during chronic changes in sodium intake in normal control dogs, after ACE inhibition, or after angiotensin II infusion (5 ng/kg/min) to prevent angiotensin II from being suppressed when sodium intake was raised ref. [ ].

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. Thus, in ischemic and overperfused nephrons, the ability to 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 (e.g., 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.

Salt-Sensitive Subjects May Have Greater Target Organ Injury

Some studies suggest that salt-sensitivity predicts hypertensive target organ injury. Salt-sensitive hypertension may be associated with glomerular hyperfiltration and increased glomerular hydrostatic pressure that is further amplified by the hypertension ; together the hypertension and renal hyperfiltration may promote glomerular injury and cause loss of nephron function. Clinical studies support this concept, and demonstrate that salt-sensitive individuals typically have increased glomerular pressure and albumin excretion when given a salt-load, whereas salt-resistant individuals have lower glomerular pressure and less urinary albumin excretion.

There is also evidence that salt-sensitive subjects may die earlier than individuals who are salt-resistant. Weinberger et al. studied individuals 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 this increased mortality was related to BP effects of salt or to other effects is still unclear. It is also not known whether long-term high salt intake may cause a person who is initially salt-insensitive to become salt-sensitive as a consequence of gradual renal injury.

Neural and Hormonal Mechanisms of Hypertension

The following sections discuss the multiple neural, hormonal, and autacoid mechanisms that alter renal pressure natriuresis, and their potential roles in hypertension.

The Sympathetic Nervous System SNS

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 a minute. Therefore, changes in SNS activity, caused by various reflex mechanisms, central nervous system 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 regulation of BP and in the pathogenesis of hypertension by activation of the renal sympathetic nerves. There is extensive innervation of the renal blood vessels, the juxtaglomerular apparatus, and the renal tubules, and overactivation of these nerves causes sodium retention, increased renin secretion, and impaired renal pressure natriuresis. Even mild increases of the renal sympathetic nerve activity (RSNA) stimulate renin secretion and sodium reabsorption in multiple segments of the nephron, including the proximal tubule, the loop of Henle, and more distal segments. Thus, the renal nerves provide a mechanism by which the various autonomic reflexes and central nervous system (CNS) centers contribute to long-term BP regulation.

Multiple studies have shown that renal denervation reduces BP in some experimental models of hypertension. For example, renal denervation attenuates hypertension in (SHR) as well as in obese hypertensive dogs. Renal denervation also delays or attenuates increased BP in other forms of experimental hypertension, although some studies have not found an important role for the renal nerves in various forms of secondary hypertension.

Human primary hypertension, especially when associated with obesity, is often associated with increased RSNA. Bilateral renal denervation in humans, using a percutaneous, catheter-based radiofrequency method to selectively ablate the nerves that run along the renal arteries, reduced BP in patients who were resistant to the usual antihypertensive drugs. Moreover, reductions in BP were sustained for up to two years of follow-up, suggesting the absence of substantial nerve fiber regrowth. However, longer follow-up periods will be needed to determine if the renal nerves eventually regrow and reinitiate increased BP, as observed in experimental animal models of renal denervation.

Although the mechanisms that activate renal sympathetic nerves in primary hypertension or in most experimental models are still unclear, we will briefly discuss two that have attracted the interest of many researchers.

Resetting 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 associated with normal daily activities. After baroreceptor denervation, BP increases to very high levels or falls to low levels with normal daily activities, although the average 24-hour BP is not markedly altered. However, some studies suggest that the baroreceptors are relatively unimportant in chronic regulation of BP, because they tend to reset within a few days after a change in BP. To the extent that resetting of baroreceptors occurs, this would attenuate their potency in long-term control of BP.

Other experimental studies 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. This, in turn, may attenuate the rise in BP. Thus, impairment of baroreflexes may cause increased lability of BP in hypertension, and fail to attenuate the rise in BP caused by other disturbances.

Currently, there is little evidence that primary disturbances of baroreceptor function play a major role in causing chronic hypertension. However, experimental studies in dogs indicate that chronic electrical stimulation of carotid sinus baroreceptors reduces BP in some forms of experimental hypertension. In humans with hypertension resistant to drug treatment, electrical stimulation of baroreceptors also reduced BP. These observations are consistent with the hypothesis that strong activation of baroreceptors can have long-term influences on BP. However, this finding does not necessarily imply that impaired baroreflexes actually cause chronic hypertension. The primary role of arterial baroreceptors in hypertension, as in normotension, appears to be buffering of rapid deviations in BP from the set-point determined by renal pressure natriuresis.

Obesity Causes Chronic SNS Activation

Excess weight gain appears to be a major cause of human primary hypertension, and one key mechanism that links obesity with increased BP is SNS activation. Obese persons have elevated SNS activity in various tissues, including the kidneys. Studies in experimental animals and humans indicate that combined α-and β-adrenergic blockade markedly attenuates obesity-associated hypertension. Moreover, renal sympathetic efferent nerves mediate much of the chronic effects of SNS activation on BP in obesity, as bilateral renal denervation greatly attenuates sodium retention and hypertension in obese dogs. Thus, obesity increases renal sodium reabsorption, impairs pressure natriuresis, and causes hypertension in part by increasing RSNA. The mechanisms for SNS activation in obesity have not been fully-elucidated, as discussed in more detail later in this chapter.

The Renin–Angiotensin–Aldosterone System (RAAS)

The RAAS is perhaps the body’s most powerful hormone system for regulating BP, as evidenced by the effectiveness of various RAAS blockers in treating hypertension. Although the RAAS has many components, its most important effects on BP are exerted by angiotensin II, a powerful vasoconstrictor that maintains BP in conditions associated with blood volume depletion, sodium depletion or circulatory depression e.g., heart failure. The long-term effects of angiotensin II on BP, however, are closely intertwined with volume homeostasis through direct and indirect effects on the kidneys.

Blockade of the RAAS, with angiotensin II receptor blockers ARBs, angiotensin converting enzyme ACE inhibitors or mineralocorticoid receptor MR antagonists, increases renal excretory capability so that sodium balance is maintained at reduced BP. However, blockade of the RAAS also makes BP salt-sensitive. Thus, effectiveness of RAAS blockers in lowering BP is greatly diminished by high salt intake; conversely, reducing sodium intake or addition of a diuretic improves effectiveness of RAAS blockers in reducing BP.

Inappropriately high levels of angiotensin 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 angiotensin II include direct and indirect effects to increase tubular reabsorption, as well as renal hemodynamic effects.

Angiotensin II Stimulates Renal Sodium Reabsorption

Angiotensin II increases renal sodium reabsorption through stimulation of aldosterone secretion, by direct effects on epithelial transport, and by hemodynamic effects. Angiotensin 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. 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 angiotensin II on the vasa recta may also enhance reabsorption in the loop of Henle and collecting ducts.

Angiotensin II also directly stimulates tubular sodium reabsorption. This effect occurs at low angiotensin II concentrations, and is mediated by actions on the luminal and basolateral membranes. In proximal tubules, angiotensin II stimulates the Na + H + exchanger on luminal membranes and increases sodium–potassium ATPase activity, as well as sodium bicarbonate co-transport on basolateral membranes ( Figure 39.7 ). These effects are partly mediated by inhibition of adenyl cyclase and increased phospholipase C activity.

Figure 39.7

Angiotensin II increases proximal tubular reabsorption by binding to receptors on the luminal and basolateral membranes and stimulating Na + /H + antiporter, Na + /HCO 3 co-transport, and Na + /K + adenosine triphosphatase (ATPase) activity.

Angiotensin II also increases reabsorption by increasing interstitial fluid colloid osmotic pressure and decreasing interstitial fluid hydrostatic pressure.

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

Renal hemodynamic Effects of Angiotensin II

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

The relatively weak constrictor action of angiotensin II on preglomerular vessels is due partly to protection of these vessels by autacoid mechanisms, such as prostaglandins or endothelial-derived nitric oxide NO. When the ability of the kidney to produce these autacoids is impaired by treatment with nonsteroidal anti-inflammatory drugs (NSAIDS) or by chronic vascular disease (e.g., atherosclerosis) angiotensin II may reduce GFR by constricting afferent arterioles.

Angiotensin II May Contribute to Glomerular Injury in Overperfused Kidneys

Although blockade of angiotensin II vasoconstrictor of efferent arterioles may cause a further decline of GFR in ischemic nephrons, RAAS blockade may be beneficial when nephrons are hyperfiltering, especially if angiotensin II is not appropriately suppressed. For example, in diabetes mellitus and in certain forms of hypertension associated with glomerulosclerosis and nephron loss, angiotensin II blockade, by decreasing efferent arteriolar resistance and BP, lowers glomerular hydrostatic pressure and attenuates glomerular hyperfiltration. Thus, RAAS blockers are more effective than other antihypertensive agents in preventing glomerular injury, even with similar reductions in BP.

Does Angiotensin II Cause Target Organ Injury Independent of Increased Bp?

Angiotensin II has been suggested to cause injury to the kidneys and other organs through direct actions, in addition to its hemodynamic effects. Although RAAS blockers may provide greater renal protection than other antihypertensive drugs, decreases in glomerular hydrostatic pressure because of efferent arteriolar vasodilation may have contributed to these beneficial effects. In studies where BP was measured accurately, using 24-hour telemetry, the renal protective effects of angiotensin II blockade appeared to be largely a result of reduced BP.

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 angiotensin II levels. Also, the clipped kidney in 2-kidney, 1-clip Goldblatt hypertension is exposed to high angiotensin II levels, but is protected from increased BP by the clip on the renal artery and has no visible injury as long as the stenosis is not too severe. However, the nonclipped kidney, exposed to lower angiotensin II concentrations but higher BP, has marked focal segmental glomerular sclerosis, as well as tubulointerstitial changes characteristic of hypertension.

Convincing evidence in this controversial area of research comes from the observations of Coffman and colleagues who studied the effects of chronic angiotensin II infusion in normal wild-type mice, in wild-type mice that received transplanted kidneys from AT1 receptor knockout mice, and in AT1 receptor knockout mice that received transplanted kidneys from normal wild-type mice. Chronic angiotensin II infusion in normal wild-type mice increased BP and caused cardiac hypertrophy and fibrosis. However, in wild-type mice that received transplanted kidneys from AT1 receptor knockout mice (i.e., AT1 receptors were present in the heart and other organs, but not in the kidneys), angiotensin II infusion did not chronically raise BP or cause cardiac hypertrophy and fibrosis. In AT1 receptor knockout mice that received transplanted kidneys from normal wild-type mice (i.e., AT1 receptors were present only in the kidneys and not in the heart or other organs), angiotensin II infusion caused chronic hypertension, as well as cardiac hypertrophy and fibrosis. These observations indicate that: 1) the renal effects of angiotensin II, and not the peripheral vascular or other non-renal effects, mediate chronic increases in BP; and 2) in the absence of hypertension, angiotensin II does not cause cardiac hypertrophy or fibrosis. Thus, the hemodynamic effects appear to account for most of the target organ injury that occurs in angiotensin II-dependent hypertension, and the effects of angiotensin II to raise BP are due to its renal actions, not to extrarenal effects, such as peripheral vasoconstriction or central nervous system effects.


Aldosterone is also a powerful sodium-retaining hormone, and consequently 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 epithelial membrane. These effects are termed genomic , because they are mediated by gene transcription and require 60–90 minutes to occur after aldosterone administration.

Aldosterone also exerts 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 a few minutes after application. In vascular smooth muscle cells, aldosterone stimulates sodium influx by activating the Na + H + exchanger in less than 4 minutes. Acute aldosterone administration may rapidly reduce forearm blood flow in humans, although some investigators have found no change or an increase in blood flow. The putative membrane receptor and the cell-signaling mechanisms responsible for these rapid 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 BP is still unclear.

The overall effects of aldosterone on pressure natriuresis are similar to those observed for angiotensin II. With low sodium intake, increased aldosterone helps prevent sodium loss and reductions in BP. Conversely, during high sodium intake, suppression of aldosterone prevents 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 six-to ten-fold causes marked hypertension when sodium intake is normal or elevated, but there is very little effect on BP when sodium intake is low.

The role of aldosterone and MR activation in human hypertension is a topic of renewed interest in recent years. Hyperaldosteronism may be more common than previously believed, especially in patients with hypertension that are 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.

There is also emerging evidence that MR antagonism may provide an important therapeutic tool for reducing BP and preventing target organ injury in hypertension ; for example, antagonism of MR attenuated sodium retention, hypertension, and glomerular hyperfiltration in obese dogs fed a high-fat diet even though plasma aldosterone concentration was only slightly elevated. 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, insulin-resistant 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, insulin-resistant patients.


Endothelin-1 ET-1 is derived from a 203 amino acid peptide precursor, preproendothelin, which is cleaved after translation to form proendothelin. A converting enzyme cleaves proendothelin to produce the 21 amino acid peptide, endothelin. ET-1 receptor-binding sites have been identified throughout the body, with the greatest numbers of receptors in the kidneys and lungs. ET-1 can either elicit a hypertensive effect by activating endothelin type A (ET A ) receptors or an antihypertensive effect via endothelin type B (ET B ) receptor activation in the kidneys. Thus, the ability of ET-1 to influence BP regulation is highly dependent on where ET-1 is produced, and which ET receptor type is activated ( Figure 39.8 ).

Figure 39.8

Summary of the pro- and antihypertensive actions of endothelin-1 (ET-1).

The ability of ET-1 to influence blood pressure 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 anti-natriuretic effect by activating ET A receptors in the kidneys. Activation of renal ET A 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 ET A receptor activation is decreased sodium excretion and increased BP. Conversely, ET-1 can elicit an antihypertensive natriuretic effect via ET B receptor activation. Activation of the renal ET B receptor leads to enhanced synthesis of nitric oxide (NO) and 20-HETE, and suppression of the renin–angiotensin system. The net effect of renal ET B receptor activation is increased sodium excretion and decreased BP.

ET-1 Elicits a Hypertensive Effect by Activating ET A Receptors in the Kidneys

Endothelin-1 produces renal and systemic vasoconstriction, impairs renal pressure natriuresis, and increases BP via ET A receptor activation. ET-1 exerts multiple actions via ET A receptor activation 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 kidneys include stimulation of mesangial cell proliferation and extracellular matrix deposition, as well as vascular smooth muscle hypertrophy in renal resistance vessels. 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. Treatment with endothelin receptor antagonists attenuated the hypertension and small artery morphologic changes, and improved kidney function in these models.

ET-1 Elicits an Antihypertensive Effect by Activating ET B Receptors in the Kidneys

ET B receptor activation by ET-1 causes vasodilation, enhances renal pressure natriuresis, and decreases BP. While much attention has been given to ET A receptor activation, several studies indicate an important antihypertensive role for ET B receptor. The most compelling evidence comes from reports that transgenic mice deficient in ET B receptors develop salt-sensitive hypertension, and that pharmacologic antagonism of ET B receptors produces hypertension in rats.

Because ET B receptors are located on multiple cell types throughout the body, including endothelial cells and renal epithelial cells, both intrarenal and extrarenal mechanisms could theoretically mediate the hypertension produced by chronic disruption of ET B receptors. Bagnall et al. reported that ablation of ET B receptors exclusively from endothelial cells produced endothelial dysfunction, but did not cause hypertension. 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 A / B receptor knockouts compared to control mice. These findings suggest that ET B receptors in non-endothelial cells are important for BP regulation. Supporting this concept are the findings that collecting duct ET B knockout mice on a normal-sodium diet were hypertensive and a high-sodium diet worsened the hypertension. Moreover, collecting duct ET B knockout mice on a normal-sodium diet were hypertensive, and a high-sodium diet worsened the hypertension. 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.

ET-1 Plays an Important Role in Experimental Salt-Sensitive Hypertension

Dahl salt-sensitive (DS) rats placed on a high-sodium diet have impaired pressure natriuresis and develop hypertension and progressive renal injury. ET-1, acting via an ET A receptor, may play a role in mediating renal injury in 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. 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. An important unanswered question is whether these beneficial effects of ET A blockade are mediated through lower BP or through direct renal mechanisms.

Role of Endothelin in Human Hypertension

Bosentan, a combined ET A -ET B receptor antagonist, lowered BP in a large, double-blind, clinical trial, indicating that the endothelin system helps maintain BP in human hypertension. However, the magnitude of the BP reduction by bosentan was almost the same as that observed in normotensive humans. This observation suggests that endothelin probably 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 the antihypertensive ET B receptor may have masked an important role of endothelin on BP via ET A receptor activation. In another study, six weeks of darusentan, a selective ET A receptor antagonist, lowered systolic and diastolic BP. Bakris et al. and Weber et al. also showed that darusentan reduced mean 24 hour systolic BP more than placebo in patients with treatment-resistant hypertension. 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. Moreover, clinical studies examining the effect of selective ET A receptor antagonism in humans with salt-sensitive hypertension are lacking. Therefore, the importance of ET-1 in human essential hypertension deserves further investigation.

Nitric Oxide

Release of nitric oxide NO by the vascular endothelium and renal tubular cells plays a major role in regulating renal hemodynamics and tubular function. Long-term inhibition of NO synthase causes impaired renal pressure natriuresis and sustained hypertension. The renal mechanisms whereby reduction in NO synthesis impairs pressure natriuresis can be divided into hemodynamic and tubular components, each of which may be modulated by processes that are intrinsic or extrinsic to the kidneys Figure 39.9 . For example, reduced NO synthesis may decrease renal sodium excretory function by increasing renal vascular resistance directly or by enhancing responsiveness to vasoconstrictors such as angiotensin II or norepinephrine. Reductions in NO synthesis also increase renal 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. Inhibition of NO synthesis reduces RIHP and urinary sodium excretion. Stimulation of NO production 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 BP.

Figure 39.9

Renal mechanisms whereby reduced nitric oxide (NO) synthesis decreases pressure natriuresis and increases BP.

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 angiotensin 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.

Impaired NO Production Produces Salt-Sensitive Hypertension

Increased renal NO production, as evidenced by increased urinary excretion of NO metabolites or the NO second messenger, cyclic guanosine mono-phosphate, has been reported to be essential for the maintenance of normotension during a dietary salt challenge. Prevention of this increase in renal NO production resulted in salt-sensitive hypertension.

There is also evidence that NO-induced vasodilation is impaired in many models of hypertension, and in some vascular beds in human essential hypertension. The extent to which these effects are secondary to hypertension or reflect important mechanisms for the etiology of hypertension remains unclear. NO activity does not increase with increasing dietary salt-loading in the Dahl salt-sensitive DS hypertensive rats as it does in normotensive Dahl salt-resistant DR rats; furthermore, chronic administration of L-arginine prevents hypertension during dietary salt-loading in the DS rat, but has no effect on BP in DR rats. We have shown that injections of L-arginine will prevent the development of hypertension in DS rats, even during prolonged exposure to an 8% sodium diet. This is not the case in all models of hypertension, even when individual tissues from these animals show impaired NO responses. Thus, in 2-kidney, 1-clip renovascular hypertension, inhibitors of NO synthesis result in an exaggerated increase in BP and vascular resistance compared to normotensive rats, but L-arginine does not prevent hypertension. Similarly, in the DOCA salt-hypertensive model, L-arginine administration improves agonist-induced NO release, but has no effect on BP.

Because of the central role of the kidney in sustaining changes in BP, it is reasonable to postulate that the long-term increases in BP induced by inhibition of NO synthase in normal animals, as well as the reduction in blood pressure induced by NO agonists in DS rat, should be associated with changes in the relationship between renal perfusion pressure and urinary sodium excretion. This has been confirmed in several studies. In normal animals, the acute intrarenal administration of the NO synthesis inhibitor NG nitro L-arginine methyl ester L-NAME significantly reduces the natriuresis and diuresis usually induced by increases in renal perfusion pressure. Chronic NO synthase inhibition also blunts the chronic renal function curve measured during changes in sodium intake. Stimulation of NO production by L-arginine supplementation has also been reported to alter BP and enhance renal pressure natriuresis. Chronic L-arginine supplementation in DS rats maintained on a high-sodium diet normalizes the blunted pressure natriuresis relationship which usually characterizes these hypertensive-prone animals. Thus, alterations in NO production or release can have important effects on renal pressure natriuresis.

Role of NO in Human Hypertension

There is also evidence that NO synthesis is impaired in 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. NO deficiency can occur by multiple mechanisms, including altered NOS enzyme expression, NO scavenging or NOS enzyme inhibition by endogenous inhibitors. Recent studies have implicated the endogenous NO synthase inhibitor asymmetric dimethylarginine ADMA in the pathogenesis of hypertension. While there is a strong correlation between ADMA levels and severe cardiovascular events and mortality, only a few clinical studies have shown a relationship between high BP and high plasma ADMA concentrations. However, when hypertension and renal disease are present, increased plasma ADMA is observed. Thus, it appears that the observed increase in ADMA during hypertension may be secondary to chronic kidney disease.

Oxidative Stress

Recent studies suggest that reactive oxygen species (ROS) may play a role in the initiation and progression of cardiovascular dysfunction associated with hypertension. In many 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 nitrous oxide synthase NOS by oxidants. 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. Several physical, hormonal, and local autocoid factors are known to be important stimuli for the production of ROS. For example angiotensin II, aldosterone, ET-1, and sodium intake all enhance production of ROS. Moreover, BP-induced endothelial damage is also associated with increased production of ROS. Thus, in many forms of hypertension, the elevation in ROS production may be secondary to the increased BP.

ROS produced by migrating inflammatory cells and/or vascular cells cause 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 ( Figure 39.10 ).

Jun 6, 2019 | Posted by in NEPHROLOGY | Comments Off on Physiology and Pathophysiology of Hypertension

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