Renal Hemodynamic Changes in Heart Failure

Heart Failure Clin 4 (2008) 411–423 Renal Hemodynamic Changes in Heart Failure Ron Blankstein, MDa, George L. Bakris, MDb,c,* a Massachusetts General Hospital, Boston, MA, USA The University of Chicago Medical Center, Chicago, IL, USA c University of Chicago, Pritzker School of Medicine, Chicago, IL, USA b Approximately 5 million people in the United States have heart failure, and over 550,000 patients are diagnosed with this condition each year. Consequently, heart failure is the most common Medicare diagnosis, and more Medicare dollars are spent on the diagnosis and treatment of this condition than for any other ailment [1]. Although there are many etiologies for the clinical syndrome of heart failure, regardless of the primary disease process, a common characteristic of this clinical syndrome is reduced cardiac output that results in the activation of numerous neurohormonal reflexes which attempt to compensate for the effects of arterial underfilling by stimulating the retention of salt and water. Such reflexes have a profound effect on cardiac and renal hemodynamics and function. The homeostatic association between the heart and kidneys has been appreciated from ancient times, from which medical texts reported the ‘‘heart ruling over the kidney’’ [2,3]. The importance of adequate perfusion of vital organs by the heart is exemplified by so-called ‘‘dropsical’’ patients with congestive heart failure. Withering noted a brisk diuresis in such patients following improved myocardial function with administration of foxglove [4]. Reduced tissue perfusion by the heart results in numerous compensatory reflexes that maintain circulatory and body fluid homeostasis and consequently result in edema formation. One of the accompanying events of cardiac failure is reduced renal excretion of sodium and water. This reduced * Corresponding author. University of Chicago Medical Center, Hypertensive Diseases Unit, 5841 S. Maryland Avenue, MC 1027, Chicago, IL 60637. E-mail address: gbakris@earthlink.net (G.L. Bakris). excretion is due, in part, to an increase in vasoconstrictor peptides secondary to a decrease in cardiac output. These events subsequently lead to enhanced sodium reabsorption by the kidney. The inability of the kidney to excrete sodium ultimately leads to edema formation in congestive heart failure. As this pathophysiologic process advances and the myocardium is further compromised, hyponatremia, azotemia, and further deterioration of cardiac function ensue. The numerous compensatory mechanisms that ensue with cardiac pump failure led one investigator to refer to these changes as a ‘‘neurohumoral storm’’ [5]. The changes that occur in the kidneys are not only due to neurohumoral alterations associated with the failing heart but are also associated with hemodynamic changes that ensue (Fig. 1). Specifically, in biventricular failure, there is a reduction in renal blood flow to a greater extent than a reduction in the glomerular filtration rate; therefore, the filtration fraction, that is, the ratio of the glomerular filtration rate to renal blood flow, is maintained. The reasons for this rise in the filtration fraction may be accounted for, in part, by an increase in efferent arteriolar tone secondary to angiotensin II, arginine vasopressin (AVP), norepinephrine (NE), and atrial natriuretic peptide (ANP) [6–11]. These vasoconstrictor peptides, by constricting the efferent arteriole, elevate intraglomerular capillary pressures and maintain the glomerular filtration rate in congestive heart failure (Fig. 2). This article presents an overview of the renal as well as neurohumoral adaptive mechanisms seen in the clinical presentation of congestive heart failure. Through a better appreciation of these mechanisms, clinicians and scientists may gain a better understanding of the rationale for many 1551-7136/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.hfc.2008.03.006 heartfailure.theclinics.com 412 BLANKSTEIN & BAKRIS Central Venous Pressure Cardiac Output Effective Circulating Blood Volume LA volume / pressure Humoral ANP ADH ET RAS AII Free H2O clearance Aldosterone Renal PGE2:PGI2 Vasodilation Vasoconstriction Tubular Na Reabsorption Neural SANS Afferent and Efferent Arteriolar Tone Baroreceptor firing Renal Nerve NE Renal Blood Flow Proximal Tubular Na Reabsorption Fig. 1. Neurohumoral factors involved in modulation of renal function in heart failure. commonly used heart failure therapies. The article that follows this discussion builds upon these principals and describes how medical therapies used in the treatment of heart failure affect renal hemodynamics and function. Neurohumoral volume sensors Neural mechanisms Baroreceptors The human body has numerous pressure receptors (baroreceptors, mechanoreceptors) throughout the arterial and venous as well as cardiopulmonary bed [12–14]. These volume receptors are located in critical areas throughout the circulatory tree (eg, the carotid sinus, aortic arch, afferent glomerular arterioles of the kidney, and the superior and inferior vena cava). In general, the purpose of baroreceptors is to detect alterations in volume (sodium) and hence relay appropriate signals, which ultimately serve to regulate renal and cardiovascular function. Because pressure and volume are usually directly related, these receptors generally react to changes in stretch of the vessel wall. In volume-depleted states where stretch is decreased, there is a subsequent loss of tonic inhibition of the sympathetic nervous system which results in increased sympathetic neuronal tone. The atria also possess baroreceptors of two types: (1) type A, located primarily at the entrance of the pulmonary veins, which discharge at the onset of systole and are not affected by volume; and (2) type B, which demonstrate increased activity with atrial filling and increased atrial size [15,16]. The neuronal inputs of the cardiac atria and the carotid body are transmitted to the medulla and hypothalamus through cranial nerves IX and X [12]. The baroreceptors of the carotid body and aortic arch are potential mediators of the antinatriuretic response seen in congestive heart failure. Studies have demonstrated a significant reduction in urinary output and sodium excretion following volume expansion in the presence of carotid sinus excitation at constant arterial pressures [17,18]. Conversely, stimulation of stellate sympathetic ganglia with electrical impulses is known to increase renal blood flow and natriuresis. Atrial transmural pressure also has a significant influence on renal function. Experiments simulating atrial tamponade in dogs (ie, decreasing atrial wall distention) result in a decrease in renal sodium excretion and urine flow rate. In addition, the normal diuretic response to volume expansion was attenuated by atrial tamponade. Other studies have also examined the relationship between atrial distensibility and neuronal control of sodium homeostasis [15,19]. These studies demonstrated RENAL HEMODYNAMIC CHANGES IN HEART FAILURE 413 Fig. 2. Renal hemodynamics in heart failure. Top diagram illustrates normal conditions for a glomerulus. In heart failure, there is decreased cardiac output which results in decreased renal blood flow. In addition, increased levels of catecholamines (NE) and neurohormones (AII, AVP, ET) result in efferent arteriole vasoconstriction. As a result, glomerular capillary pressure is maintained. AA, afferent arteriole; AII, angiotensin II; AVP, arginine vasopressin; EA, efferent arteriole; ET, endothelin; NE, norepinephrine; Press (GC), glomerular capillary pressure; RBF, renal blood flow. increased activity of neural tracts to the hypothalamus and medulla following infusion of hypertonic saline into the carotid artery below the carotid body. Conversely, increased left atrial stretch decreased activity of these neural tracts and increased urine flow rate and sodium excretion while decreasing plasma AVP levels. Plasma concentrations of ANP were increased and plasma renin activity remained unchanged in these studies [15,16,20]. In addition to neuronal inputs for maintenance of volume homeostasis, the atria also possess granules that release ANP under certain circumstances. Acute atrial distention results in release of ANP, which ultimately increases sodium excretion as much as tenfold [19]. Atrial distention yields the opposite effect on sodium excretion to that of atrial tamponade. Further discussion regarding ANP is found later in this article. The ventricles also have baroreceptors that influence body fluid homeostasis and contribute to maintenance of volume homeostasis. ANP has been localized in the right and left ventricles in different animal models of heart failure [21]. In addition, brain (b-type) natriuretic peptide (BNP) is synthesized in the ventricular myocardium, where its levels increase in patients with congestive heart failure. Because secretion of BNP and ANP from the left ventricle increases in proportion to the severity of the left ventricular dysfunction, plasma levels of these hormones may be used as a marker of the degree of left ventricular dysfunction [22]. Systemic infusion of recombinant BNP (nesiritide) in patients with congestive heart failure results in arterial and venous dilatation, enhanced sodium excretion, and suppression of the renin-angiotensin-aldosterone and sympathetic nervous systems. Although clinical use of this agent has shown favorable short-term outcomes [23], reports concerning its safety have limited its widespread use [24,25]. Each chamber of the heart rather than just the atria has a function in maintaining volume homeostasis in heart failure. Intrathoracic venous baroreceptors Human studies largely performed by Epstein and colleagues [26–32] used head-out-of-water immersion, a method of evaluating central venous volume in humans, to illustrate the influence of the cardiac atria and the importance of central venous volume status in regulation of volume homeostasis. Increased central venous pressure resulted in a diuresis and natriuresis as well as a concomitant reduction in systemic vascular resistance in these studies. Translocation of the fluid from the limbs to the central circulation is the mechanism postulated to increase atrial distention in these subjects. In addition, increased central venous pressure decreases baroreceptor firing and increases tonic inhibition of the sympathetic nervous system. A variety of heart failure models in the dog have examined the importance of central venous pressure as a factor in regulating sodium homeostasis. Lifschitz and Schrier [33] studied alterations in cardiac output and renal hemodynamics following chronic thoracic vena cava 414 BLANKSTEIN & BAKRIS constriction in dogs. Hemodynamic changes in these dogs included a decrease in cardiac output as well as glomerular filtration rate and renal plasma flow. Total peripheral resistance was increased with no change in mean arterial pressure. These changes persisted despite renal denervation and no change in mean arterial pressure, hematocrit, or protein concentration. In a separate set of experiments, these investigators gave continual high-dose administration of the mineralocorticoid deoxycorticosterone acetate to these dogs without any resultant effect on sodium excretion or ascites formation. They concluded that a renal vasoactive substance mediates the renal hemodynamic changes seen during chronic caval constriction. Other studies by Migdal and colleagues [34] examined the differences in sodium excretion among three separate dog models with different cardiovascular hemodynamics, namely, caval constriction, pulmonary artery occlusion, or left ventricular infarction induced by coronary artery occlusion. Saline loading to 10% body weight was accompanied by a significant natriuresis only in the caval dogs. In contrast to Lifschitz and Schrier [33], these investigators noted no significant change in glomerular filtration rate or renal blood flow, although the filtration fraction was significantly increased in the left ventricular infarction group, a group that arguably has a hemodynamic profile similar to man. Changes in renal hemodynamics were not associated with a reduction in sodium excretion in the caval model. The divergent results of these studies may be explained in several ways. First, differences in the renal and cardiovascular hemodynamics among the animal models examined may be responsible. Specifically, the caval constriction model is known to have different renal hemodynamics when compared with the left ventricular infarction model because no pump failure is present in the caval constriction model. Secondly, the contribution of renal interstitial pressure to natriuresis may differ between models. Nevertheless, the determining factor that affects renal interstitial pressure is renal artery pressure. In a separate group of studies, acetylcholine was infused in normal dogs, subsequently reducing renal artery pressure, interstitial pressure, and urinary sodium excretion [35]. Conversely, renal vasodilation with secretin did not reduce interstitial pressure, and, consequently, sodium excretion was not affected. These studies further document the importance of renal interstitial pressure as a factor in modulating sodium homeostasis in various animal models. Volume status is also important in assessing the contribution of renal interstitial pressure to natriuresis. Studies in dog models of acute occlusion of the left anterior descending artery with long-term observation demonstrate decreased baroreceptor firing, especially in the chronic stages of heart failure [36]. This decreased firing increases the influence of the sympathetic nervous system and results in decreased sodium excretion. This effect may not be true in the caval constriction model in which there may be increased baroreceptor firing. Conclusions regarding sodium homeostasis from animal models should be viewed in the context of the animal model being studied. Renal baroreceptors The juxtaglomerular apparatus of the kidney is composed of four basic elements: the terminal portion of the afferent glomerular arteriole, the macula densa (a specialized segment of the distal tubule), the extraglomerular mesangial region, and the efferent arteriole at the glomerulus [37]. The juxtaglomerular apparatus, because of its location in the nephron, is very sensitive to changes in volume homeostasis as well as renal perfusion pressure. It is known to be adrenergically innervated and responds to changes in volume and arterial pressure by activation of the renin-angiotensin system and altered neural tone [38]. The response of the juxtaglomerular apparatus to a decrease in perfusion pressure is to enhance the release of renin into the afferent arteriole, which eventually generates angiotensin II (Ang II) to raise arterial pressure and aldosterone to enhance distal tubular sodium reabsorption [39]. The b1-adrenoreceptors stimulated in the juxtaglomerular apparatus are, in part, the effectors of sympathetically mediated renin release [39]. Other factors that stimulate the renin-angiotensin system are noted in Box 1. Agents that antagonize b-receptors, which are occasionally used in the management of hypertension with mild heart failure, can cause several renal hemodynamic alterations, including a decline in renal blood flow and glomerular filtration rate with a subsequent anti-natriuretic response, most prominently with upright posture [40]. The juxtaglomerular apparatus may be thought of as the endocrine organ of the nephron because it possesses the components of a hormonal system (eg, renin, adenosine, endothelial-derived relaxing RENAL HEMODYNAMIC CHANGES IN HEART FAILURE Box 1. Factors that stimulate the reninangiotensin-aldosterone system Stimulate activity Prostaglandins E and I series Activation of renal sympathetic nerves Baroreceptor stimulation Catecholamines Upright posture Hypotension Hypoperfusion Hypovolemia Inhibit activity Arginine vasopressin Potassium (Low) calcium Angiotensin II b-adrenoreceptor antagonists Adenosine Saline loading Histamine factor) that modulate the extrarenal and circulatory signals of the nephron. Renal sympathetic nerves Although initially thought to have little influence on salt and water balance, renal sympathetic nerve activity has been found to be intimately related to body fluid homeostasis. Renal nerves have been demonstrated by immunofluorescent electron microscopic and histochemical techniques to have adrenergic receptors in the afferent and efferent arterioles, proximal and distal tubules, ascending limb of the loop of Henle, and the juxtaglomerular apparatus [41]. In addition to adrenergic receptors, dopaminergic receptors are present in the tubules and renal nerves [42,43]. Increasing frequency of renal sympathetic nerve activity is associated with decreases in renal blood flow and a reduction in urinary sodium excretion. These effects are mediated, in part, by a1-adrenoreceptors [42–44]. Renal sympathetic nerve activity is modulated by salt intake, that is, low salt diets increase and high salt diets decrease nerve activity [41]. Increased renal sympathetic nerve activity is documented in states of volume (salt) depletion (ie, heart failure, cirrhosis) and contributes to the associated elevation of plasma renin activity, reduction in renal blood 415 flow, and the subsequent anti-natriuretic state [45]. In a study of patients who had congestive heart failure, dibenzylchloroethamine, an a-adrenergic receptor antagonist, was administered intravenously [46]. Despite slight decreases in mean arterial pressure and no significant change in cardiac output, the fractional excretion of sodium was increased without significant changes in renal blood flow or glomerular filtration rate. Additional studies in heart failure patients during spinal anesthesia demonstrated a failure to correct renal hypoperfusion [47]. These findings suggest that renal nerves, although having a role in the maintenance of volume homeostasis, are not the sole modulating force of renal hemodynamics in models of heart failure. Hormonal changes and angiotensin volume homeostasis Renin-aldosterone system The renin-angiotensin-aldosterone system has an important role in the initiation and maintenance of edema generation and volume homeostasis associated with cardiac pump failure. Fig. 2 lists the factors that stimulate the renin-angiotensin-aldosterone system. Elevated renin secretion occurs early in the course of biventricular heart failure [48,49]. Circulating levels of renin act as an enzyme on the renin substrate angiotensinogen, a protein synthesized by the liver. Enzymatic cleavage of the 10 terminal amino acids of angiotensinogen forms the decapeptide angiotensin I (Ang I), which is physiologically inert. Removal of the two carboxy terminal amino acids by converting enzyme, primarily in the endothelial cells of the lung, results in generation of the octapeptide Ang II, one of the most potent vasoconstrictors in the human body. Angiotensin II is later converted to Ang III, which then directly stimulates the zona glomerulosa of the adrenal to produce aldosterone. Elevations of renin in congestive heart failure states are associated with high levels of Ang II generation as well as increased aldosterone. The physiologic effects of Ang II are many and varied. They include stimulation of central neural centers associated with increased thirst mechanisms as well as a heightened activity of ganglionic nerves via its effects on the autonomic nervous system [50]. The inotropic effect of Ang II on the heart has been well characterized by Peach [51]. 416 BLANKSTEIN & BAKRIS Elevation of this vasoconstrictor peptide serves to overcome the initial decrease in stroke volume associated with early biventricular heart failure; however, this elevation is only one of a myriad of factors that serve to increase peripheral vasoconstriction in an attempt to restore arterial pressure and improve cardiac output in this setting. Other vasoconstrictor peptides, such as AVP and catecholamines, are elevated [50–53]. Ang II also serves to increase aldosterone synthesis, increasing sodium reabsorption by the kidney, which ultimately may raise arterial pressure and worsen sodium retention, if present. Nevertheless, normal subjects usually exhibit an escape from the salt-retaining effects of aldosterone [50,54–56]. This escape usually occurs after a 3-day period in humans. In heart failure, this escape phenomenon is not achieved [57,58]. Subjects with biventricular failure may also have poor hepatic perfusion and decreased clearance of aldosterone; therefore, they are known to have elevated plasma aldosterone levels [59]. Despite this fact, spironolactone, the aldosterone antagonist, does not consistently affect sodium or potassium excretion in patients with congestive heart failure [60]. As renal perfusion declines in concert with decreased cardiac function, loop diuretics are the only effective agents that may be used to achieve a diuresis. Catecholamines Catecholamines have a vital role in heart failure. Studies in cardiomyopathic hamsters have demonstrated that, as cardiac sympathetic tone increases, there is a decrease in cardiac NE [61]. This decrease in cardiac NE content is the result of maximal turnover of myocardial NE. The failing heart cannot respond adequately to stimulation of its sympathetic nerves because its NE turnover rate has already been maximized. Studies by Chidsey and colleagues [62] documented high plasma NE levels in patients with congestive heart failure. These findings were corroborated by later studies, which showed that plasma NE levels correlate with activation of the sympathetic nervous system as well as mortality [63,64]. Intrarenal circulation is altered when effective circulating volume is reduced and sympathetic tone is increased. Blood flow to the kidney is reduced, and the circulation to the cortical nephrons versus juxtamedullary nephrons is likewise attenuated [65]. Enhanced sympathetic tone contributes to sodium avidity in several ways. Increased baroreceptor activity causes direct enhancement of proximal tubule sodium reabsorption in the proximal tubule and loop of Henle [41,66,67]. Postglomerular capillary pressure falls and oncotic pressure rises, further enhancing proximal tubular reabsorption [41]. The contribution of dopamine to improvement of cardiac function and maintenance of renal hemodynamics has received much attention. Dopamine may be released from intrarenal nerve endings or possibly synthesized from plasma [68–70]. Dopamine- induced vasodilation is mediated via the effects on afferent and efferent arterioles and the intralobular arteries [69,70]. Afferent and efferent vasodilation is the mechanism for enhanced renal blood flow and no change in glomerular filtration rate; however, pure dopaminergic effects are seen at very low concentrations (w1 mg/min) of dopamine. Doses greater than 2 mg/min have both a- and b-adrenoreceptor effects [71]. Dopamine inhibits proximal tubule reabsorption of sodium [72,73]. In addition, decreased sodium reabsorption may be related, in part, to a dopamine-mediated attenuation in aldosterone secretion [74]. Numerous studies in various animal models uniformly demonstrate a reduction in urinary sodium excretion following administration of dopaminergic receptor blockade. Dopamine may be modulating the catecholamine effect in heart failure and may have a regulatory role in extracellular volume. Furthermore, it appears to provide a homeostatic effect on maintenance of volume and renal hemodynamics. Atrial natriuretic peptide The peptide ANP is stored in the perinuclear granulocytes in cardiac atria and released in response to atrial stretch mechanisms [19]. The peptide hormone is stored as a high molecular weight (126 amino acids) precursor or prohormone. The primary form isolated from plasma is low molecular weight (28 amino acids) a-ANP. Although various types of ANP receptors exist in various tissues, in the kidney two receptors have been identified, with the greatest number in the glomerulus and medulla [75]. Only one of these classes of receptors is intimately associated with activation of guanylate cyclase. Cyclic guanosine monophosphate (cGMP), the product of guanylate cyclase activation, is thought to be the messenger of the biologic activity of ANP. Infusions of cGMP can mimic the vasodilation and RENAL HEMODYNAMIC CHANGES IN HEART FAILURE inhibition of renin release seen with ANP infusions [76]. The major renal actions of ANP are summarized in Box 2. The relative increase in glomerular filtration rate versus the relatively blunted effect on renal blood flow implies that ANP dilates the afferent arteriole of the nephron while constricting the efferent arteriole [6,77]. This hemodynamic effect on the postglomerular circulation favors a natriuretic response. The effects of ANP on sodium excretion are mediated by direct and indirect tubular affects [78–80]. Nevertheless, no convincing data exist to demonstrate that ANP directly inhibits sodium or chloride transport in the proximal tubule. Furthermore, data are also lacking for an effect at the loop of Henle. ANP does inhibit angiotensin-stimulated proximal tubular salt and water reabsorption as well as vasopressin-stimulated water permeability in the inner medullary collecting duct [81,82]. Also, ANP inhibits oxygen consumption in the intermedullary collecting duct. This inhibition in oxygen consumption may result in direct inhibition of sodium reabsorption. Lastly, ANP causes a decrease in arterial pressure secondary to a decrease in cardiac output. The decrease in cardiac output is induced by a combination of a direct decrease in the strength of myocardial contraction and decreased venous return [78]. Several investigators have noted a correlation between plasma ANP levels and right atrial and pulmonary capillary wedge pressures [52,83]. Interestingly, despite the increase in circulating ANP levels, sodium retention and edema Box 2. The major renal activity of atrial natriuretic peptide Increases Renal blood flow (transient) Glomerular filtration rate Sodium excretion Potassium excretion (minimal) Phosphate excretion Tubular flow rate Calcium excretion Magnesium excretion Decreases Renin-angiotensin-aldosterone system Vasopressin (inhibits action) Angiotensin II (inhibits action) Hemodynamics Arterial pressure 417 eventually develop in heart failure. This result may be explained by several factors. First, a much higher than generated ANP plasma level may be required to achieve the desired natriuretic effect in these patients. Evidence for this contention exists in models of congestive heart failure. Activation of ventricular myocytes, which normally do not synthesize ANP, has clearly been shown to lead to synthesis and release of ANP in heart failure [21,84]. Furthermore, studies by Awazu and colleagues [85] strongly suggest that the increased levels of plasma ANP seen in congestive heart failure are associated with a relative increase in sodium excretion. A second possibility for the relative lack of natriuresis by ANP may be downregulation of ANP receptors. This effect would result in decreased effectiveness of ANP in heart failure patients. This down-regulation is clearly documented with NE cardiac receptors [61]. Numerous studies have examined the potential beneficial effects of exogenous administration of ANP to patients with congestive heart failure [50,86]. These studies are somewhat less than satisfying in that, although they demonstrate an increase in natriuresis and diuresis, it is not of the magnitude anticipated. Nevertheless, ANP does appear to have beneficial hemodynamic effects in such patients, despite its negative inotropic effects. The benefits of ANP in heart failure patients appear to be short lived. Specifically, when the infusions of ANP are terminated, the patients eventually revert to their baseline state. Arginine vasopressin AVP, also known as antidiuretic hormone, is a peptide hormone derived from a prehormone precursor that is synthesized in the hypothalamus. It is then transported and stored in the posterior part of the pituitary gland and released in response to multiple mechanisms associated with volume depletion and increased osmolarity. In the kidney, AVP facilitates urinary concentration primarily by modulating the passage of water and urea from the collecting ducts into the medullary interstitium [51,53]. Under most pathophysiologic circumstances, AVP has no role in edema formation or maintenance of intraglomerular hemodynamics; however, as heart failure becomes more severe, AVP contributes greatly to the development of hyponatremia and maintenance of glomerular capillary pressure (see Fig. 1) [53–56]. 418 BLANKSTEIN & BAKRIS In general, both sodium and water retention by the kidney are required for edema formulation to occur. When water is retained in excess of sodium, a subsequent dilutional hyponatremia occurs [54]. This hyponatremic effect is thought to be mediated by an increase in AVP release and a decrease in ultrafiltrate delivery to the diluting segments of the nephron [57]. The mechanisms responsible for AVP release in heart failure are multiple. In a dog model of heart failure, Anderson and colleagues [58] documented that stimulation of arterial baroreceptors (carotid sinus and aortic arch) and an attendant decline of parasympathetic afferent stimuli was the mechanism of AVP release. These findings were supported by Shade and Share [55] who demonstrated that controlled hemorrhage augments AVP release, whereas vagotomy (with carotid sinus pressure held constant) attenuates its release. In addition to baroreceptors, intracardiac receptors are implicated in AVP release [59]. These receptors are thought to be located in the atrial walls and in great veins. Furthermore, an inverse correlation has been noted between left atrial pressure and AVP levels [20]. In early heart failure, there appears to be a minor imbalance between baroreceptor and parasympathetic neuronal impulses. In the final stages, there is depression of cardiopulmonary baroreceptor function, and the secretion of vasopressin remains unopposed. This effect, coupled with the intense thirst produced by Ang II, yields a scenario that ultimately culminates in hyponatremia. In the cardiovascular system, vasopressin (as the name suggests) increases systemic and peripheral vascular resistance. Although this property has made it useful in the treatment of vasodilatory shock [60], the physiologic effects of AVP have a potentially detrimental hemodynamic effect in the setting of heart failure. As a result, it has been hypothesized that the use of a vasopressin antagonist might be beneficial in this setting. Indeed, use of the oral vasopressin V2-receptor antagonist tolvaptan has been shown to increase serum sodium concentrations among patients with heart failure or cirrhosis [87]. Nevertheless, no effect on long-term morbidity or mortality was observed when used for the acute treatment of patients hospitalized with heart failure [88]. Prostaglandins The renal prostaglandin system is implicated in the regulation of renal hemodynamics and renal sodium excretion in congestive heart failure [89,90]. With the exception of PGF2 and thromboxane, the renal prostaglandins are all vasodilators. Prostaglandins (eg, PGE2 and prostacycline) are elevated in patients with congestive heart failure, especially in patients with hyponatremia [89,91]. Other factors that may stimulate prostaglandin synthesis include renal ischemia, cirrhosis, or the presence of elevated catecholamine levels. The vasodilatory effects of prostaglandins are thought to counteract, at least in part, the vasoconstrictive effects of the so-called ‘‘hypovolemic hormones’’ (ie, AVP, Ang II, NE) [92]. Prostaglandins, in turn, antagonize the water and sodium retentive as well as vasoconstrictive effects of these pressor hormones [93,94]. Studies suggest that prostaglandins alter sodium reabsorption at the thick ascending loop of Henle and the cortical collecting tubule [95]. Animal studies in caval constricted dogs further document the importance of prostaglandins for maintenance of hemodynamics and promotion of natriuresis [96]. Investigators demonstrated a profound reduction in renal blood flow when dogs with heart failure were given a prostaglandin synthetase inhibitor. These effects can be observed in humans as well. For instance, patients with severe heart failure who are given a non-steroidal anti-inflammatory drug that blocks cyclooxygenase demonstrate a marked deterioration in renal function. The importance of prostaglandins as modulators of renal function in patients with heart failure is exemplified by a study by Dzau and colleagues [91]. They studied the relationship among activation of the renin-angiotensin system, concomitant hyponatremia, and prostaglandin levels in patients with congestive heart failure. Metabolites of PGI2 and PGE2 were observed in patients with severe congestive heart failure. The metabolites were three to ten times above levels found in normal subjects. The presence of hyponatremia also directly correlated with prostaglandin metabolites, plasma renin activity, and plasma Ang II activity. Patients were challenged with the prostaglandin synthetase inhibitor indomethacin. The subset of patients with hyponatremia had significant decreases in cardiac index with significant elevation of pulmonary capillary wedge pressure and systemic vascular resistance. The patients with normal serum sodium values had no significant hemodynamic changes. These data are consistent with the concept that prostaglandins have an important role in the maintenance of renal RENAL HEMODYNAMIC CHANGES IN HEART FAILURE Stimuli: Angiotensin II Vasopressin (AVP) Epinephrine Calcium Thrombin 419 Increased: Renin angiotensin system Atrial natriuretic peptide Endothelin Decreased: Glomerular filtration rate Renal blood flow Urinary sodium Fig. 3. Humoral factors that increase endothelin in heart failure and its consequences. hemodynamics and sodium homeostasis in patients with severe heart failure. clearance of endothelin is decreased in the setting of heart failure [102]. Endothelin Prognosis of presence of renal dysfunction in heart failure In 1985, Rubani and Vanhoutte [96] noted that hypoxia was associated with release of a vasoconstrictor substance from endothelial cells not altered by prostaglandin inhibition. Within 3 years of this initial observation, Yanagisawa and colleagues [97] isolated this vasoconstrictor peptide from porcine aortic cell cultures and characterized its amino acid sequence. Today, we know this peptide as endothelin. Autoradiographic studies have localized endothelin receptors throughout the body. Endothelin receptors are found throughout the kidney, including the renal arteries and veins, arcuate and interlobular arteries, glomeruli, renal papillae, and vascular bundle [98,99]. The hemodynamic and hormonal effects of endothelin include an elevation of arterial pressure and an increase in plasma ANP concentration, renin release, and plasma aldosterone level. Other effects of endothelin as well as neurohumoral factors that increase plasma levels are summarized in Fig. 3. Interestingly, elevations of plasma endothelin concentration correlate with the severity of adverse hemodynamic changes in heart failure patients and decline in patients who respond to therapy [100]. Plasma endothelin concentrations increase in humans with heart failure [101]; therefore, it seems appropriate to consider endothelin as having the properties of a circulating hormone in congestive heart failure. Unfortunately, limited definitive data are available concerning the effects of endothelin in congestive heart failure. Although increased endothelin production may occur in heart failure and contribute to increased plasma levels, animal studies suggest the possibility that Because the severity of renal dysfunction in patients with heart failure is often closely correlated with the degree of heart failure and the level of adverse renal hemodynamic changes that take place, it is not surprising that renal function is a strong predictor of outcomes among patients with heart failure. Among patients with advanced heart failure, in addition to worsening renal function, hyponatremia has been recognized as an important predictor of mortality [103,104]. 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