Integration of Cardiorenal Function

The integration of cardiorenal function is illustrated by the response of a normal person to standing. Upon standing, there is an abrupt fall in venous return and hence in cardiac output; this elicits a baroreflex response, as resistance vessels contract to buffer the immediate fall in BP, and capacitance vessels contract to restore venous return. The end result is only a small drop in the systolic BP, with a modest rise in diastolic BP and heart rate. During prolonged standing, increased renal sympathetic nerve activity enhances the reabsorption of sodium chloride (NaCl) by the renal tubules, as well as the release of renin from the juxtaglomerular apparatus. Renin release results in the subsequent generation of angiotensin II and aldosterone, which maintain systemic BP and circulating volume. In contrast, the BP of patients with autonomic insufficiency declines progressively upon standing, sometimes to the point of syncope. Patients with autonomic failure vividly illustrate the crucial importance of a stable BP for efficient function of the brain, heart, and kidneys. Therefore it is no surprise that evolution has provided multiple, coordinated BP-regulatory processes. The understanding of the cause of a sustained change in BP, such as hypertension, requires knowledge of a number of interrelated pathophysiologic processes. The most important and best understood of these are discussed in this chapter.

Kidney Mechanisms and Salt Balance

The kidney has a unique role in BP regulation. Renal salt and water retention sufficient to increase the extracellular fluid (ECF) volume, blood volume, and mean circulatory filling pressure enhances venous return, cardiac output, and BP. The kidney is so effective in excreting excess fluid during periods of surfeit, or retaining fluid and electrolytes during periods of deficit, that the ECF volume and, specifically, the blood volume normally vary less than 10% with changes in salt intake. Consequently, the role of body fluids in hypertension is subtle. For example, a 10-fold increase in daily NaCl intake in normal subjects increases ECF volume by only about 1 L (about 6%) and normally produces no change, or only a small increase, in BP. Conversely, a diet with no salt content leads to the loss of approximately 1 L of body fluid over 3 to 5 days and only a trivial fall in BP. Different effects can be seen in patients with chronic kidney disease (CKD), whose BP often increases with the level of salt intake. This “salt-sensitive” component to BP increases progressively with loss of kidney function. Among normotensive subjects, a salt-sensitive component to BP is apparent in about 30% and appears to have a genetic component. Salt sensitivity is almost twice as frequent in patients with hypertension and is particularly common among blacks, the elderly, and those with CKD. It is generally associated with a lower level of plasma renin activity (PRA).

What underlies salt sensitivity? Normal kidneys are exquisitely sensitive to BP. A rise in mean arterial pressure (MAP) of as little as 1 to 3 mm Hg elicits a subtle increase in renal NaCl and fluid elimination. This “pressure natriuresis” also works in reverse and conserves NaCl and fluid during decreases in BP. It is rapid, quantitative, and fundamental for normal homeostasis. It is primarily a result of changes in tubular NaCl reabsorption rather than total renal blood flow (RBF) or glomerular filtration rate (GFR). Indeed, renal autoregulation maintains RBF and GFR remarkably constant during modest changes in BP. The pressure natriuresis mechanism accurately adjusts salt excretion and body fluids in persons with healthy kidneys across a range of BPs. Two primary mechanisms of pressure natriuresis have been identified.

First, a rise in kidney perfusion pressure increases blood flow selectively through the medulla, based on data in salt-loaded rats. Medullary blood flow is not as tightly autoregulated as cortical blood flow. These increases in pressure and flow enhance renal interstitial hydrostatic pressure throughout the kidney, which is an encapsulated organ. This rise in interstitial pressure reduces proximal tubule reabsorption and impairs fluid return to the bloodstream. Therefore net NaCl and fluid reabsorption is diminished. Second, the degree of stretch of the afferent arteriole regulates the secretion of renin into the bloodstream and hence the generation of angiotensin II. Thus an increase in BP that is transmitted to this site reduces renin secretion. Angiotensin II coordinates the body’s salt and fluid retention mechanisms by stimulating thirst and enhancing NaCl and fluid reabsorption in the proximal and distal nephron segments. By stimulating secretion of aldosterone and arginine vasopressin, and inhibiting atrial natriuretic peptide (ANP), angiotensin II further enhances reabsorption in the distal tubules and collecting ducts. Thus, during normal homeostasis, an increase in BP is matched by a decrease in PRA. It follows that a normal or elevated value for PRA in hypertension is effectively “inappropriate” for the level of BP, and is thereby contributing to the maintenance of hypertension.

The relationships among long-term changes in salt intake, the renin-angiotensin-aldosterone system (RAAS), and BP are shown in Fig. 64.1 . Healthy people regulate the RAAS closely with changes in salt intake. An increase in salt intake brings about only a modest and transient rise in MAP, because the RAAS is suppressed and the highly effective pressure natriuresis mechanism rapidly increases renal NaCl and fluid elimination sufficiently to restore a near-normal blood volume and BP. Expressed quantitatively in Fig. 64.1 , the slope of the long-term increase in NaCl excretion with BP is normally almost vertical. One factor contributing to the steepness of this slope, or the gain of the pressure natriuresis relationship, is the reciprocal changes in the RAAS with BP that dictate appropriate alterations in salt handling by the kidney. Therefore, when the RAAS is artificially fixed, the slope of the pressure natriuresis relationship flattens, resulting in salt sensitivity, displacement of the set point, and a change in ambient BP. For example, an infusion of angiotensin II into a normal subject raises the BP. Because angiotensin II is being infused, the kidney cannot suppress angiotensin II levels appropriately by reducing renin secretion. Therefore the pressure natriuresis mechanism is prevented, and the BP elevation is sustained without an effective and complete kidney compensation. In contrast, normal individuals treated with an angiotensin-converting enzyme (ACE) inhibitor to block angiotensin II generation or an angiotensin receptor blocker (ARB) to block AT ₁ receptors have a fall in BP. Again, the kidney cannot stimulate an appropriate effect of angiotensin II and aldosterone that would be required to retain sufficient NaCl and fluid to buffer the fall in BP. Therefore when the RAAS is fixed, the BP changes as a function of salt intake and becomes highly “salt sensitive” (see Fig. 64.1 ). These studies demonstrate the unique role of the RAAS in long-term BP regulation and its importance in isolating BP from NaCl intake.

(A) Normal steady-state relationship between plasma concentrations of renin, angiotensin II (Ang II), and aldosterone and dietary salt intake. (B) Relationships between sodium excretion relative to intake and mean arterial blood pressure in normal subjects (solid line) , in subjects given an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB; short dashes ), and in subjects given an infusion of Ang II (long dashes) to prevent adaptive changes in Ang II levels. NaCl , Sodium chloride.

(Modified from Guyton AC, Hall JE, Coleman TG, et al. The dominant role of the kidneys in the long-term regulation of arterial pressure in normal and hypertensive states. In: Laragh JH, Brenner BM, eds. Hypertension, Pathophysiology, Diagnosis and Management. New York: Raven; 1995:1311–1326, with permission.)

Some recent findings add complexity to these simple relationships. Renin is also generated within the connecting tubule and collecting ducts. This renal renin may contribute to the very high level of angiotensin within the kidney that does not share the same relationship with dietary salt. Animal models of diabetes mellitus demonstrate an increase in local angiotensin generation and action in the kidneys that may contribute to the beneficial effects of ACE inhibitor and ARB therapy, despite low circulating renin levels. Other studies have shown that prorenin, although not itself active, becomes activated after binding to a renin receptor in the tissues, notably the kidneys, where novel signaling adds another component to the effects of the RAAS. This is important because conventional RAAS antagonists may not block these actions, nor do the novel renin inhibitors block this renin receptor.

Four compelling lines of evidence implicate the kidney and RAAS in long-term BP regulation. First, kidney transplant studies in rats showed that a normotensive animal that received a kidney from a hypertensive animal becomes hypertensive, and vice versa. Similarly, human kidney transplant recipients frequently become hypertensive if they receive a kidney from a hypertensive donor. Apparently, the kidney in hypertension is programmed to retain salt and water inappropriately for a normal level of BP, thereby resetting the pressure natriuresis to a higher level of BP and dictating the appearance of hypertension in the recipient, even if the neurohumoral environment is that of normotension. Nevertheless, recent studies in gene-deleted or transgenic mice subjected to kidney transplantation concluded that the increase in BP during prolonged infusion of angiotensin II was mediated by the combined effects within the kidney and the systemic circulation, most likely involving the renal afferent arterioles and the brain. A second observation was that the BP was normally reduced 5% to 20% by an ACE inhibitor, an ARB, an aldos­terone receptor antagonist, or a renin inhibitor. The fall in BP was greatest in those with elevated PRA values, and it was enhanced by dietary salt restriction or concurrent use of diuretic drugs (see Fig. 64.1 ). Third, almost 90% of patients approaching end-stage renal disease (ESRD) have hypertension. Fourth, the major monogenetic causes of human hypertension involve genes that activate RAAS signaling (such as glucocorticoid-remediable hypertension) or renal sodium transport (such as Liddle syndrome).

Total-Body Autoregulation

An increase in cardiac output necessarily increases peripheral blood flow. However, each organ has intrinsic mechanisms that adapt its blood flow to its metabolic needs. Therefore, over time, an increase in cardiac output is translated into an increase in TPR. The outcome is that organ blood flow is maintained, but hypertension becomes sustained. This total-body autoregulation is demonstrated in human subjects who are given salt-retaining mineralocorticosteroid hormones. An initial rise in cardiac output is translated in most individuals into sustained hypertension and an elevated TPR over 5 to 15 days.

Structural Components to Hypertension

Hypertension causes not only hypertrophic or eutrophic remodeling in the distributing and resistance vessels and the heart, but also fibrotic and sclerotic changes in the glomeruli and interstitium of the kidney. Hypertrophy of resistance vessels limits the ratio of lumen to wall and dictates a fixed component to TPR. This is evidenced by a higher TPR in hypertensive versus normotensive individuals during maximal vasodilatation. Moreover, thickened and hypertrophied resistance vessels have greater reductions in vessel diameter during vasoconstrictor stimulation. This is apparent as an increase in vascular reactivity to pressor agents. Remodeling of resistance arterioles diminishes their response to changes in perfusion pressure. This manifests as a blunted myogenic response contributing to incomplete autoregulation of RBF, thereby adding a component of barotrauma to hypertensive kidney damage. Sclerotic and fibrotic changes in the glomeruli and kidney interstitium, combined with hypertrophy of the afferent arterioles, limit the sensing of BP in the juxtaglomerular apparatus and kidney parenchyma. This blunts renin release and pressure natriuresis, thereby contributing to salt sensitivity and sustained hypertension. Rats receiving intermittent weak electrical stimulation of the hypothalamus initially had an abrupt increase in BP followed by a sudden fall after the cessation of the stimulus. However, eventually the baseline BP increased in parallel with the appearance of hypertrophy of the resistance vessels. These structural components may explain why it often takes weeks or months to achieve maximal antihypertensive action from a drug, a reduction in salt intake, or correction of a renal artery stenosis or hyperaldosteronism. Vascular and left ventricular hypertrophy is largely, but usually not completely, reversible during treatment of hypertension, whereas fibrotic and sclerotic changes are not.

Sympathetic Nervous System, Brain, and Baroreflexes

A rise in BP diminishes the baroreflex, thereby reducing the tone of the sympathetic nervous system and increasing the tone of the parasympathetic nervous system. Paradoxically, human hypertension is often associated with an increase in heart rate, maintained or increased plasma catecholamine levels, and an increase in directly measured sympathetic nerve discharge despite the stimulus to the baroreceptors. What is the cause of this inappropriate activation of the sympathetic nervous system in hypertension? Studies in animals show that the baroreflex “resets” to the ambient level of BP after 2 to 5 days. Thereafter, the baroreflex no longer continues to “fight” the elevated BP but defends it at the new higher level. Much of this adaptation occurs within the baroreceptors themselves. With aging and atherosclerosis, the walls of the carotid sinus and other baroreflex sensing sites become less distensible. Therefore the BP is less effective in stretching the afferent nerve endings, and the sensitivity of the baroreflex is diminished. This may contribute to the enhanced sympathetic nerve activity and increased plasma catecholamines that are characteristic of elderly hypertensive subjects. Additionally, animal models have identified central mechanisms that alter the gain of the baroreflex process, and therefore the sympathetic tone, in hypertension. The importance of central mechanisms in human hypertension is apparent from the effectiveness of drugs, such as clonidine, that act within the brain to decrease the sympathetic tone. The kidneys themselves contain barosensitive and chemosensitive nerves that can regulate the sympathetic nervous system. In one study, hemodialysis patients experienced an increased sympathetic nervous system discharge and increased BP that were not apparent after bilateral nephrectomy. This suggests that the renal nerves were maintaining enhanced sympathetic tone. Based on this pathophysiology, radiofrequency ablation of the renal nerves has successfully improved BP control in some, but not all, studies of patients with drug-resistant hypertension, further illustrating the importance of the renal nerves in setting the long-term level of BP in human subjects.

Endothelium and Oxidative Stress

Calcium-mobilizing agonists, such as bradykinin or acetylcholine, as well as shear forces produced by the flow of blood result in the release of endothelium-dependent relaxing factors, predominantly nitric oxide (NO). NO has a half-life of only a few seconds because of inactivation by oxyhemoglobin or reactive oxygen species (ROS), such as superoxide anion ( ). People with essential hypertension have defects in endothelium-dependent relaxation of peripheral vessels and also diminished NO generation. One underlying mechanism is oxidative stress, with excessive formation inactivating NO and leading to functional NO deficiency. Another mechanism is the appearance of inhibitors of nitric oxide synthase (NOS), including asymmetric dimethyl arginine (ADMA). Finally, atherosclerosis, prolonged hypertension, or the development of malignant hypertension causes structural changes in the endothelium that limit endothelial function further. NO inhibits renal NaCl reabsorption in the loop of Henle and collecting ducts of the kidney. Therefore NO deficiency not only induces endothelial dysfunction and vasoconstriction but also reduces renal pressure natriuresis. Functional NO deficiency in large blood vessels contributes to vascular inflammation and atherosclerosis.

Genetic Contributions

The heritability of human hypertension can be assessed from differences in the concordance of hypertension between identical twins (who share all genes and a similar environment) versus nonidentical twins (who share only a similar environment). These studies suggest that genetic factors contribute less than half of the risk for developing hypertension in modern humans. Studies in mice with targeted disruption of individual genes or insertions of extra copies of genes provided direct evidence of the critical regulatory roles for certain gene products in hypertension. Deletions of the gene in mice for endothelial NOS lead to salt-dependent hypertension, and the BP of mice decreases with the number of copies of the gene encoding ACE. While these are compelling examples of circumstances in which a single gene can sustain hypertension, there is increasing recognition of the complexity and importance of gene–gene interactions and the crucial effects of the genetic background on the changes in BP that accompany insertion or deletion of a gene.

Currently there is evidence that certain individual gene defects can contribute to human essential hypertension. However, the net effect on BP is small. Certain rare forms of hereditary hypertension are caused by single-gene defects. For example, dexamethasone-suppressible hyperaldosteronism is caused by a chimeric rearrangement of the gene encoding aldosterone synthase that renders the enzyme responsive to adrenocorticotropic hormone. Liddle syndrome is caused by a mutation in the gene encoding one component of the endothelial sodium channel that is expressed in the distal convoluted tubule. The mutated form has lost its normal regulation, leading to a permanent “open state” of the sodium channel that dictates inappropriate renal NaCl retention and salt-sensitive, low-renin hypertension (see Chapter 9 , Chapter 38 , Chapter 66 ).