Mediators Which Stimulate Renal Salt and Water Retention and Constrict Blood Vessels

The major neurohormonal responses which increase renal salt and water retention and cause vasoconstriction are portrayed in Fig. 1.

Adrenergic Activation

The low EABV associated with heart failure activates sympathetic adrenergic nerves and elevates systemic catecholamine levels which produce both systemic and cardiac effects. Systemic arteriolar constriction mitigates the fall in

Heart Failure Cycle
FIGURE 1. The pathophysiology of salt and water retention and edema formation in patients with heart failure. Only the vasoconstricting and salt retaining mediators are shown. ADH, antidiuretic hormone; FF, filtration fraction; ECF, extracellular fluid; EABV, effective arterial blood volume.

blood pressure owing to a low cardiac output. However, the intensity of vasoconstriction is not identical in all arterioles or organs. Selectivity between organs and within organs characterizes the vascular response (Fig. 2). Vessels supplying organs and tissues which are relatively tolerant of ischemia, such as skeletal muscles, abdominal viscera, and the skin, constrict markedly. In contrast, the arterioles of the brain and heart do not constrict, and indeed may dilate despite a high level of systemic vasoconstricting forces. Selective vasoconstriction causes a greater fraction of the reduced cardiac output to be delivered to certain vital organs [29]. Consequently, cerebral and cardiac blood flow remain relatively protected despite the systemic vasoconstriction characteristic of heart failure [29]. The organ-specific vascular response is due to the differences in densities and subtypes of both adrenergic nerves and neuroreceptors which exist in various vascular beds, as well as differences in local generation and response to 02, C02, lactate, and vasoactive molecules including nitric oxide, prostaglandins, C-natruretic peptides, etc.

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FIGURE 2. (A) The regional distribution of cardiac output at rest (R) and during submaximal (submax) and maximal (max) exercise (EX) in normal subjects and patients with congestive heart failure. (B) Distribution of blood flow to vascular beds other than skeletal muscle in normal subjects during rest and exercise. E, early; L, late. (C) Distribution of blood flow to vascular beds other than skeletal muscle in patients with severe CHF during rest and exercise. (Adapted from Zelis, R., and Flaim, S. F. (1982). "Alterations in vasomotor tone in congestive heart failure." Prog Cardiovasc Dis. 24, p. 440.

Heart failure decreases total renal blood flow, but selective intrarenal vasoconstriction develops and stabilizes the glomerular filtration rate (GFR). Post-glomerular efferent arterioles constrict more vigorously than the preglomerular afferent arterioles. This pattern of constriction will maintain or increase hydrostatic pressure within the glomerular capillaries despite the fall in EABV. The renal hemodynamic response to congestive heart failure (CHF) is more fully described under Renal Function in Heart Failure, below.

The catecholamines released from sympathetic nerves impinging on the heart combine with those present in blood plasma to activate cardiac adrenergic receptors. Both cardiac contractility and heart rate increase. However, the response of the failing heart to these sympathetic stimuli is blunted as a result of reduced cardiac ^-adrenergic receptor density (especially the f3, receptors), partial uncoupling of these receptors from cyclic AMP generation, and reduced intracardiac norepinephrine synthesis [11]. Therefore, although sympathetic cardiac stimulation improves the failing heart's performance, contractility does not increase to the extent that it would in a normal subject's heart.

In general, adrenergic activation is beneficial for most patients with heart failure. The increment in cardiac output and contractility, higher peripheral vascular resistance, and the selective vascular response stabilize blood pressure and divert a greater fraction of the cardiac output to critical vital organs. However, excessive adrenergic stimulation may become maladaptive and produce adverse effects. For example: (i) Intense constriction of skeletal muscle arterioles prevents the usual dilation response to exercise. This contributes to the profound fatigue experienced by these patients and partially accounts for their susceptibility to exertion-induced lactic acidosis, (ii) The failing heart is very sensitive to increased levels of afterload which reduces cardiac output sharply (see Factors Which Increase Cardiac Contractility and Output, below, and Fig. 3). (iii) Increasing afterload raises cardiac oxygen requirements, (iv) High catecholamine levels can produce direct cardiotoxicity.

Consequently, although seemingly counterintuitive, (3 blockers have recently been effectively utilized to reduce the morbidity and mortality of certain subsets of patients with heart failure [21]. Arterial vasodilators, such as hydralazine, and drugs which reduce angiotensin II induced vasoconstriction, such as angiotensin-converting enzyme inhibitors, or angiotensin II receptor (ATI) blockers also reduce afterload and may improve cardiac output, ameliorate symptoms, and prolong the life of patients with congestive heart failure.

Renin-Angiotensin Activation

Normal Physiology

The renin-angiotensin systems (RAS) exist in both systemic and local hor-mone/autocrine/paracrine forms. The systemic RAS was described first. Its c c

Local Renin Angiotensin Systems Heart

Afterload figure 3. Frank-Starling relationships between stroke volume and left ventricular end-diastolic pressure (LVEDP) and between stroke volume and afterload in normal and failing hearts. The normal heart functions on the sharply rising portion of the Frank-Starling curve where small changes in filling pressure produce large changes in stroke volume. Note that large changes in afterload have only minor stroke volume effects in the normal heart. The Frank-Starling curve of the failing heart is shifted to the right and downward. Higher LVEDP is required to produce acceptable, though still reduced, stroke volume. When the LVEDP exceeds 20 mm Hg pulmonary congestion becomes likely. Cardiac performance may move from curve C to curve D if cardiac contractility increases due to catecholamines or the administration of an inotropic agent. Note, the stroke volume of the failing heart is markedly affected by the level of afterload. (Adapted from Sonnenblick, E. H. (1994). Pathophysiology of heart failure. In "The Heart: Arteries and Veins" (J. W. Hurst, R. C. Schlant, et al., eds.) p. 398, McGraw Hill, New York.

Afterload figure 3. Frank-Starling relationships between stroke volume and left ventricular end-diastolic pressure (LVEDP) and between stroke volume and afterload in normal and failing hearts. The normal heart functions on the sharply rising portion of the Frank-Starling curve where small changes in filling pressure produce large changes in stroke volume. Note that large changes in afterload have only minor stroke volume effects in the normal heart. The Frank-Starling curve of the failing heart is shifted to the right and downward. Higher LVEDP is required to produce acceptable, though still reduced, stroke volume. When the LVEDP exceeds 20 mm Hg pulmonary congestion becomes likely. Cardiac performance may move from curve C to curve D if cardiac contractility increases due to catecholamines or the administration of an inotropic agent. Note, the stroke volume of the failing heart is markedly affected by the level of afterload. (Adapted from Sonnenblick, E. H. (1994). Pathophysiology of heart failure. In "The Heart: Arteries and Veins" (J. W. Hurst, R. C. Schlant, et al., eds.) p. 398, McGraw Hill, New York.

components include renin released from the kidneys, angiotensinogen released from the liver, angiotensin-converting enzyme present in vascular tissue (especially in the lungs), and angiotensin II receptors in vessels, the adrenal gland, kidneys, brain, heart, and many other organs. The juxtaglomerular apparatus (JGA), located between the afferent renal arteriole and the distal tubule, is the principal renal site of renin synthesis and storage. Renin released by the juxtaglomerular apparatus is delivered to the systemic circulation via the renal veins (and also acts locally within the kidney—see below). The major activating stimulus for the systemic RAS is a reduction in systemic blood pressure and/or a low EABV. This reduces renal arteriole perfusion pressures and activates renal baroreceptors, thereby triggering the release of renin. Sympathetic adrenergic nervous activation also causes renal renin release and participates in the response to hypotension. Prostaglandins are also involved in the renal renin response mechanism and drugs which inhibit prostaglandins may reduce systemic renin levels.

Renin is a proteolytic enzyme which catalyzes the cleavage of the decapep-tide angiotensin I from its protein substrate angiotensinogen. The angiotensin I is then converted to the potent vasoactive octapeptide, angiotensin II, by angiotensin-converting enzyme (ACE). ACE exists in high concentration in the endothelium of pulmonary vessels and is also present at lower concentrations in vessels and tissues throughout the body. Systemic effects of angiotensin II include arteriolar vasoconstriction, stimulation of adrenal aldosterone synthesis and release, increased thirst, and others. Angiotensin II also increases renal salt reabsorption through several mechanisms: (i) direct stimulation of renal epithelial sodium transport, (ii) renal hemodynamic effects which enhance renal tubule salt reabsorption, (iii) stimulation of adrenal aldosterone synthesis and release which increases distal tubule sodium reabsorption. These multiple effects of high angiotensin II levels oppose the fall in blood pressure and/or EABV which is the physiologic trigger for the cascade. If the blood pressure improves and/or EABV normalizes, then renin levels decrease. This defines a classic closed loop endocrine system.

The RAS also has major paracrine effects in the kidney, heart, blood vessels, and probably many other organs and tissues. The entire array of enzymes and substrates required to generate and respond to angiotensin II exists as a self-contained system within many tissues including the kidney. The local RAS in the kidney regulates the distribution of intrarenal blood flow and the rate of glomerular filtration. Renal underperfusion increases local renin and angiotensin II generation which causes more intense constriction of postglomerular efferent arterioles than the afferent arterioles. This pattern of selective vasoconstriction mitigates the reduction in glomerular hydrostatic pressure associated with underperfusion and thereby stabilizes the GFR (see Renal Function in Heart Failure, below).

The intrarenal RAS also participates in tubuloglomerular feedback control mechanisms. Changes in distal tubule delivery rates are detected by the macula densa, which monitors alterations in chemical composition produced by variations in tubule flow. Signals from the macular densa regulate renin releases from the J GA. This feedback system increases the GFR when distal delivery of filtrate falls and reduces the GFR when distal sodium chloride and volume delivery increase. The macula densa-JGA interaction thus synchronizes the glomerular filtration and the tubule solute and fluid reabsorption rates. The precise role of the renal and systemic RAS in this feedback loop continues to be elucidated [4],

Heart Failure

Heart failure generally reduces the EABV and severe left ventricular dysfunction produces overt hypotension. As a result, the systemic RAS and the local renin-angiotensin systems in the kidney, heart, and blood vessels are activated. Systemic RAS activation causes generalized vasoconstriction, which mitigates the fall in blood pressure and stimulates the adrenal gland to synthesize and release aldosterone. Intrarenal RAS activation mitigates the fall in glomerular filtration by causing greater constriction of efferent arterioles than afferent ar-

terioles. High angiotensin II levels directly increase salt reabsorption by the proximal renal tubules. The renal hemodynamic effects of angiotensin II on proximal tubule salt reabsorption are discussed below under Renal Function in Heart Failure. Activation of the cardiac RAS increases myocardial contractility and contributes to hypertrophy and remodeling of the heart [7,14]. The RAS in the walls of arterial vessels also participates in the vascular hypertrophic and remodeling response [7],

Aldosterone

Angiotensin II is the principal regulator of adrenal aldosterone synthesis and release. Therefore, circulating renin (and angiotensin II) and aldosterone levels usually increase or decrease in parallel. However, these hormone levels can be dissociated by certain pathophysiologic conditions. For example, simultaneous high aldosterone and low renin levels suggest autonomous aldosterone secretion, such as primary hyperaldosteronism, while high renin and low aldosterone levels may suggest an adrenal synthetic defect. The potassium concentration can also affect aldosterone levels. Hyperkalemia stimulates aldosterone synthesis and hypokalemia inhibits its synthesis.

Aldosterone, the major endogenous mineralocorticoid, increases distal renal tubule and collecting duct sodium reabsorption and simultaneously increases the secretion of potassium and protons. Aldosterone also increases sodium absorption by the colon and reduces the sodium concentration of saliva and sweat.

Patients with congestive heart failure generally have high renin, angiotensin II, and aldosterone levels as a result of their reduced EABV. These elevated hormone levels increase further when the cardiac status decompensates. The kidneys of these patients will then retain salt and water very avidly.

Antidiuretic Hormone

Antidiuretic hormone (ADH) is normally released in response to increases in plasma tonicity. This hormone increases the hydraulic permeability of the renal distal tubules and the cortical and medullary collecting ducts where urine is concentrated and water conserved. This response serves to correct the state of hypertonicity. ADH is also released nonosmotically in response to hypotension and/or a low EABV. In this loop, the hormone has systemic vasoconstricting effects and hence its other name is vasopressin. The low EABV which exists in heart failure increases ADH levels and this hormone contributes to their state of systemic vasoconstriction. The persistent high ADH levels are a response to the hemodynamic derangements of heart failure and result in renal concentration and water retention irrespective of the patient's plasma tonicity or sodium concentration.

It should be noted that the maximal urine concentration which can be achieved by patients with heart failure is not as great as that produced by normal subjects given exogenous ADH. Patients with CHF cannot generate normal medullary osmotic gradients. Nonetheless, the urine osmolality of these patients is often inappropriately high for their plasma sodium concentration.

Patients with heart failure typically have a reduced GFR and increased proximal solute reabsorption. This decreases delivery of filtrate to the thick ascending limb of Henle (TALH), thereby reducing the kidney's capacity to generate free water. These abnormalities and the high ADH levels cause frequent development of hyposmolar hyponatremia. When progressive hyponatremia develops in patients with heart failure, their state of cardiac deterioration is usually advanced and the low sodium concentration is indicative of a poor prognosis [17].

Endothelin, Thromboxane, and Other Vasoconstrictors

Endothelin, proconstrictive prostanoids, including thromboxane, and other vasoactive mediators also contribute to the vasoconstricted state of heart failure. However, the precise roles played by of these molecules have not yet been defined.

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