Search

Antihypertensive treatment in the diabetic patient is a critical issue because hypertension has an impact on all of the vascular complications of diabetes, including nephropathy, retinopathy, atherosclerosis, and left ventricular hypertrophy. These complications are a consequence of altered endothelial-vascular smooth muscle interrelations that ultimately enhance vasoconstriction and alter the remodeling processes in the vascular wall. Several observations suggest that the renin-angiotensin system (RAS) may be an important contributor to these processes in diabetes mellitus. In both animal and human studies, angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to slow the progression of glomerulosclerosis, prevent abnormal remodeling processes in the heart following injury, and slow the progression of atherosclerosis. In particular, ACE inhibitors appear to protect the kidney more than would be expected from simply the lowering of blood pressure and decreasing of intraglomerular pressure, possibly because angiotensin II has both hemodynamic and direct effects on the glomerulus. Paradoxically, however, the activity of the circulating RAS is low in diabetic patients. Part of these seemingly inconsistent observations may be due to (1) potential activity of tissue RASs, (2) increased sensitivity to angiotensin II in diabetes, or (3) an effect of ACE inhibition on other systems in addition to the RAS. Investigation of these mechanisms will be important in determining the therapeutic role of inhibition of the RAS in diabetes mellitus.

Despite substantial progress in cardiovascular disease prevention, stroke and myocardial infarction remain the leading causes of death throughout the industrialized world. Treatment of high blood pressure, while contributing importantly to this progress, remains inefficient and less than optimally effective, particularly in regard to coronary artery disease events. Therapeutic intervention in the renin--angiotensin system offers promise of progress on bath these fronts. Renin--sodium profiles have been shown to permit prognostic stratification of otherwise indistinguishable hypertensive patients. Indeed, low renin subjects, without other cardiovascular risk factors, have a particularly favorable prognosis. Now, the pharmacologic ability to mute the pathologic effects of angiotensin II also offers the genuine possibility that the cardioprotective value of antihypertensive therapy may be significantly improved. (Am J Cardiol 1992;70:21D-26D)

In addition to the classic circulating renin-angiotensin system, increasing evidence supports the existence of local tissue renin-angiotensin systems (vascular, cardiac, kidney, and brain) that appear to participate in cardiovascular homeostasis and in the pathogenesis of cardiovascular disorders via multiple autocrine and paracrine functions. Components of local systems have been detected in cardiovascular tissues. Studies with angiotensin-converting enzyme (ACE) inhibitors provide further evidence of the existence and importance of tissue renin-angiotensin systems. The blood pressure-lowering effect of quinapril, for example, correlated better with inhibition of tissue ACE (aorta) than with inhibition of plasma ACE. The effects of ACE inhibitors on local tissue renin-angiotensin systems (vascular in particular) may be the crucial determinant of response to treatment. Newer ACE inhibitors, such as quinapril, have favorable side effect profiles as well as apparent tissue specificity for the vascular renin-angiotensin system (and possibly other relevant cardiovascular tissue). Differentiation among ACE inhibitors should play an even more important role in the future for individualization of therapy. (Am J Cardiol 1991;69:59C-64C)

Previous efforts to block the renin-angiotensin system in patients with chronic congestive heart failure (CHF) have focused on 2 distal sites in the system, the angiotensin-converting enzyme and the angiotensin II receptor. Recent work, however, has led to the development of agents that directly inhibit renin, the proximal step in the cascade. In this study, we investigated the hemodynamic effects of renin inhibition in 9 patients with chronic CHF by udng enalkiren, a primate-selective, dipeptide renin inhibitor, which has been previously shown to suppress plasma renin activity and to lower blood pressure in hypertensive patients. The acute intravenous administration of enalkiren (1.0 mg/kg) produced increases in cardiac index (2.0 [+ or -] 0.3 to 2.3 [+ or -] 0.1 liter/min/[m.sup.2]) and stroke volume index (26 [+ or -] 3 to 34 [+ or -] 4 ml/[m.sup.2]) and decreases in left ventricular filling pressure (31 [+ or -] 3 to 25 [+ or -] 3 mm Hg), mean right atrial pressure (15 [+ or -] 1 to 13 [+ or -] 2 mm Hg), heart rate (78 [+ or -] 5 to 72 [+ or -] 6 beats/min) and systemic vascular resistance (2,199 [+ or -] 594 to 1,339 [+ or -] 230 [dynes*s*cm.sup.-5]) (all p, Congestive heart failure (CHF) is a condition resulting from the inability of the left side of the heart to pump sufficient blood to the body. If untreated, this condition is fatal. Treatment strategies often seek to lower blood pressure, which reduces the load against which the heart must pump; this can be done by interfering with the biosynthesis of angiotensin, an enzyme that causes blood vessels to contract. Frequently, this is accomplished by administering angiotensin converting enzyme (ACE) inhibitors, blocking the conversion of inactive to active forms of the enzyme, or by blocking the angiotensin receptor. ACE inhibitors are known to improve the condition of CHF patients, but there are unwanted side effects resulting from nonspecificity of the drugs' actions. A less-explored alternative strategy is to block an earlier step in the biosynthetic pathway, the formation of renin (an enzyme catalyzing the formation of the inactive form of angiotensin). The effects of renin inhibition have been characterized in normal volunteers and patients with high blood pressure, but the actions of drugs of this class on patients with CHF have not been reported. Nine patients with chronic CHF were given a new primate-specific dipeptide (comprised of two amino acids) renin inhibitor, enalkiren, which previously suppressed renin activity and lowered blood pressure in hypertensive patients. Acute intravenous administration of enalkiren resulted in an improvement of a number of parameters related to cardiac function, such as cardiac index, stroke volume index, left ventricular filling pressure, right atrial pressure, systemic vascular resistance, and heart rate. Further studies will be needed to determine the relative benefits of ACE and renin inhibition in the treatment of CHF. (Consumer Summary produced by Reliance Medical Information, Inc.)

The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet, plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for [is greater than or equal to]6 hours (11.9 [+ or -] 4 to 1.0 [+ or -] 0.6 ng angiotensin l/ml/hour, p [is less than]0.05). Mean arterial blood pressure declined gradually (108 [+ or -] 5 to 84 [+ or -] 4 mm Hg, p = 0.02), as did plasma aldosterone concentration (14.4 [+ or -] 3.8 to 4.4 [+ or -] 0.8 ng/dl, p = 0.03), whereas plasma immunoreactive active renin concentration increased progressively (35 [+ or -] 14 to 160 [+ or -] 60 pg/ml, p [is greater than]0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin [F.sub.1[alpha]]) decreased slightly, but not significantly (42 [+ or -] 10 to 33 [+ or -] 11 ng/g creatinine, p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system, without significantly altering urinary prostacyclin excretion, in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension. (Am J Cardiol 1990;66:1342-1347), The renin-angiotensin-aldosterone system is part of a biochemical pathway that is tightly coupled to the regulation of blood pressure. One approach to controlling hypertension (high blood pressure) is through the administration of a class of drugs called angiotensin converting enzyme (ACE) inhibitors, which block the formation of endogenous hypertensive agents. Converting-enzyme inhibition may have numerous effects, other than just blocking the conversion of angiotensin to its biologically active form. Hence, the exact mechanism by which ACE inhibitors affect their antihypertensive actions is not known. The drug enalkiren acts at an earlier point in the biochemical pathway, and it is thought that its only biologically significant action is to interfere with the enzymatic activity of renin, thus blocking the production of hypertensive byproducts. A study was carried out in eight healthy patients with essential hypertension (high blood pressure not secondary to some other identifiable factor) who were maintained on an unrestricted sodium diet. Enalkiren was administered intravenously, and blood pressure was monitored for six hours, as were blood levels of renin, angiotensin, aldosterone, and urinary levels of prostacyclin. Within 10 minutes of drug administration, blood levels of enzymatically active renin were decreased, and remained low for six hours. Blood pressure decreased, as did blood levels of aldosterone; there was a concomitant increase in the levels of biologically inactive renin. Levels of prostacyclin (one of the possible mediators of ACE inhibitor effects) were essentially unchanged. The administration of diuretics (which cause the removal of fluids from the body) increased the magnitude of the blood pressure effects. Enalkiren caused a decrease in blood pressure in the hypertensive patients solely by renin inhibition, but had no effect on prostacyclin levels. (Consumer Summary produced by Reliance Medical Information, Inc.)

Acute renal failure after contrast media injection has been recognized for at least 35 years but the exact mechanism responsible for the renal injury remains an enigma. The clinical characteristics of contrast-induced nephropathy (CAN) are well-known although more recently the nonoliguric presentation has occurred at an increased frequency--in 70 to 90% of cases. For nonoliguric presentation of CAN, one can expect an asymptomatic increase in serum creatinine, the mean peak occurring at 4.2 days. If oliguric, the fractional excretion of sodium will be A popular scheme has been proposed to describe the possible sequence by which ischemia or nephrotoxins, or both, induce acute renal failure. In particular, a vascular mechanism (i.e., ischemia), is an appealing explanation for CAN since acute changes in renal hemodynamics after contrast media injection have been confirmed by several animal experiments. Unlike other vascular beds in which contrast media induce acute vasoconstriction followed by vasodilatation, the initial effect on the renal circulation is acute vasodilation, followed by progressive vasoconstriction, increasing renal vascular resistance and a concomitant decrease in both renal blood flow and glomerular filtration rate. The intensity of the vasoconstrictive phase is reduced by either simultaneous volume repletion or pretreatment with a high-salt diet. However, these renal hemodynamic changes are short-lived, with complete return to normal within 1 to 2 hours after the procedure. Since clinically significant CAN involves continued deterioration of renal function for 3 to 10 days after the procedure, a more severe experimental renal insult is needed to mimic the clinical state. Examination of patients at risk for CAN (i.e., chronic renal insufficiency, diabetic nephropathy, congestive heart failure and hypertension) reveals that preexisting renal ischemia is a common association. Under these circumstances, renal ischemia will include stimulation of both endogenous vasoconstrictors (angiotensin II, norepinephrine and vasopressin) and vasodilator substances (prostaglandin [I.sub.2] [[PGI.sub.2]] and prostaglandin [E.sub.2] [[PGE.sub.2]]. A disturbance of this balanced vasoconstrictor/vasodilator action on renal circulation will cause acute deterioration of renal function. Animal experiments suggest that contrast agents act in a manner similar to nonsteroidal anti-inflammatory agents by selectively inhibiting the vasodilation caused by prostaglandins and inducing renal dysfunction. Circulating angiotensin II causes both renal vasoconstriction, principally in the efferent arterioles, and de novo synthesis of vasodilator prostaglandins. In the unstimulated state, circulating angiotensin II induces a balanced state between constriction and dilatation resulting in normal renal vascular resistance. When renin release is stimulated, the associated increase in angiotensin II results in increased vasoconstrictive and vasodilatory actions, with the final effect on renal vascular resistance being either unchanged or modestly increased. However, selective interference with the prostaglandin limb of the stimulation causes a reduction in renal blood flow, and the possibility of a reduction in glomerular filtration rate. From animal studies one of the effects of contrast media is to interfere with [PGI.sub.2] production, thus resembling nonsteroidal antiinflammatory drugs with regard to the pathophysiologic process leading to acute renal failure. (Am J Cardiol 1990;66:18F-22F), Renal (kidney) failure is an uncommon but potentially fatal complication of the injection of contrast agents for the visualization of blood vessels by X-ray. Although the association between contrast agents and renal failure has been recognized for almost four decades, the precise mechanisms remains unclear. While the first cases to be noted involved oliguria, or reduced urine production, it is now recognized that perhaps as many as 90 percent of the cases of renal toxicity are asymptomatic and may be detected as an increase in the levels of creatinine in the blood. Fortunately, most such patients will recover, and fewer than 10 percent will require dialysis. The function of the kidney may be conveniently thought of as two contributing processes, the filtration of the blood, which relies on adequate perfusion of the kidney, and the resorption and secretion processes of the kidney tubules, which reclaim water and important ions and nutrients. The use of contrast media may affect both these processes. Most of the body's blood vessels react to the injection of contrast agents with an acute constriction followed by prolonged relaxation. However, the blood vessels of the kidneys seem to respond in the opposite manner; an initial dilation is followed by a progressive constriction. This, of course, reduces the flow of blood through the kidneys and thus the glomerular filtration. These effects are only important for a few hours, however, while contrast-associated nephropathy involves continued deterioration for 3 to 10 days. The ischemia resulting from inadequate blood flow may also cause tubule damage. Experiments with animals, however, have indicated that the progressive kidney dysfunction may result from upsetting the normal working of the renin-angiotensin system, which moderates blood pressure. In the normally functioning kidney, the vasoconstricting effects of angiotensin II are balanced by prostaglandins. The authors suggest that the contrast media interfere with the production of prostaglandins, and therefore the action of the angiotensin II proceeds unopposed. According to this hypothesis, the nephropathy caused by contrast media would be directly comparable to that caused by nonsteroidal anti-inflammatory drugs. (Consumer Summary produced by Reliance Medical Information, Inc.)

Congestive heart failure (CHF) is a condition characterized by a failure of the heart to pump sufficient blood to supply blood-borne oxygen and nutrients to the body. The renin-angiotensin-aldosterone system, which has an important role in contractility of blood vessels and fluid balance, is thought to be a key factor in the development and expression of CHF. Consequently, the blockade of this pathway, most notably by means of angiotensin-converting enzyme inhibition therapy in the treatment of (ACE) inhibitors, is an important therapeutic tool in the treatment of CHF. The pharmacokinetics (the time course of absorption, action, metabolism, and excretion) of ACE inhibitors have been difficult to ascertain in humans for several reasons. The production of angiotensin II (the biologically active vasoconstrictor form) is part of an enzymatic pathway for which the rate-limiting enzyme (renin) is not directly affected by ACE inhibition. Also, ACE inhibitors cause a buildup of intermediary compounds prior to angiotensin II in the biosynthetic pathway (renin and angiotensin I); changing the dose during a course of therapy might cause rapid, unpredictable (potentially dangerous) shifts in the levels of angiotensin II. The metabolism and effectiveness of ACE inhibition is partly a function of the action of a variety of organ systems on the drug; varying levels of compromised functioning of these organ systems in CHF patients makes extrapolation from healthy patients problematic. Because of the difficulties in experimentally determining the metabolism of ACE inhibitors resulting from these factors, determination of dosage with ACE inhibitors has been guided by careful titration of the dose, while monitoring the effect on patients' clinical characteristics. (Consumer Summary produced by Reliance Medical Information, Inc.)

The renin-angiotensin system (RAS) is an enzyme-mediated cascade of biochemical steps that results in the production of a biologically active end product, angiotensin II, that plays an important functional role in maintaining physiological equilibrium in states such as hemorrhage and sodium restriction. It has long been recognized that the components of this system circulate in the blood and interact with receptors on tissues to which they gain access via the bloodstream. Recent demonstrations have shown that there are also RAS subpopulations localized in individual target tissues such as the heart, brain, blood vessels, and kidneys. It is thought that the control mechanisms and physiological implications the two systems (circulating and tissue-bound) may differ. An important therapeutic strategy in treating various cardiovascular dysfunctions, such as hypertension and congestive heart failure, is the administration of angiotensin-converting enzyme inhibition therapy in the treatment of (ACE) inhibitors, which block the conversion from inactive to active forms of angiotensin. The short-term therapeutic response to ACE inhibition seems to be a direct function of plasma levels of RAS constituents, whereas long-term effects seem not to be related to these levels. A possible explanation for this seeming inconsistency is that only the short-term effects are mediated by circulating RAS; the chronic, long-term effects may be mediated by the less-easily measured tissue RAS. The development of drugs that can selectively target tissue and circulating RAS would represent a major step in the pharmacological treatment of cardiovascular disorders. (Consumer Summary produced by Reliance Medical Information, Inc.)

When the heart is unable to pump sufficient blood to supply blood-borne oxygen and nutrients to the body, the condition is known as congestive heart failure (CHF). As cardiac output (the amount of blood pumped by the heart) decreases, so does blood pressure. The body mobilizes a number of compensatory responses to try and overcome the cardiac insufficiency, including activation of neuroendocrine systems (such as the sympathetic nervous system, the renin-angiotensin system, vasopressin, neuropeptide Y, and others) that attempt to maintain blood pressure at normal levels. The fact that this increase in blood pressure is accomplished by constricting the blood vessels, exacerbating one of the pathological conditions responsible for the CHF in the first place, makes this neuroendocrine activation a self-defeating exercise. In addition, chronic elevation of some of the neuroendocrine hormones may cause permanent detrimental alterations in the anatomy of the heart by interfering with gene expression (the transfer of genetic information from the DNA). One of the recently accepted treatments for CHF, angiotensin-converting enzyme inhibition therapy in the treatment of (ACE) inhibitors, which block the conversion of inactive to the biologically active form of angiotensin, may retard or reverse these permanent anatomical changes in the heart; this may be one of the ways in which long-term ACE inhibitor treatment ameliorates the effects of CHF. (Consumer Summary produced by Reliance Medical Information, Inc.)

Congestive heart failure (CHF) is a condition in which the heart is unable to pump sufficient blood to supply oxygen and nutrients to the body. One way that the body seeks to compensate for the insufficient blood supply is by mobilizing neurohormonal responses that tend to increase blood pressure; this compensatory neurohormonal activation is actually detrimental to cardiovascular function and results in increased mortality. Drugs that block one of these neurohormonal steps (angiotensin-converting enzyme inhibition therapy in the treatment of /ACE~ inhibitors, which inhibit the production of the potent vasoconstrictor angiotensin II) are widely used as treatment for CHF. A large-scale study was carried out and has been reported on previously (the CONSENSUS Trial) in which 253 patients were randomly assigned to receive either their normal course of treatment for CHF (placebo group) or their normal course of treatment plus enalapril, an ACE inhibitor. At the end of the six-month treatment period, significantly more of the enalapril patients than placebo patients were alive. This same pattern was evident at six-month and two-year follow-ups. In the placebo group, there were significant correlations between mortality and blood levels of norepinephrine, epinephrine, angiotensin II, aldosterone, and atrial natriuretic peptide. No such relationships were seen in the group treated with enalapril. These data suggest that enalapril may act at least partially through counteracting neuroendocrine activation, particularly through activation of the renin-angiotensin system. (Consumer Summary produced by Reliance Medical Information, Inc.)

To study the relation between Plasma atrial natriuretic peptide (ANP) and cardiac pressure, and to assess the pathophysiologic significance of ANP in water and electrolyte metabolism, the changes in plasma levels of ANP and arginine vasopressin (AVP) were examined in 11 pattern with mitral stenosis who underwent permbneous transvenous mitrald valvuplasty and compared with the changes in the renin-angiotensin-aldosterone system and renal function. immediately after valvuloplasty, plasma ANP levels decreased significantly with a concomitant decrease in mean pressures in the left atrium, the pulmonary artery and the right atrium. plasma ANP levels decreased tO the normal range in 4 of the 6 patients with normal sinus rhythm, while all 5 patients with atrial fibrillation had higher levels despite a similar degree of decrease in atrial pressure. There were significant positive correlations between plasma ANP levels and the mean left atrial pressure (r = 0.61, p, Atrial natriuretic peptide (ANP) is a substance originally isolated from the human atrium (either of the chambers of the heart that receive blood from the body and lungs prior to delivering it to the ventricles), that has now been purified and synthesized. ANP has effects on sodium and water retention, as well as on blood vessels, and it is possible that it is released in response to increased pressure in the atria, such as could occur during heart failure, when blood is not pumped efficiently. If atrial stretch is significantly involved in increasing ANP levels, then reduction of atrial pressure should decrease them, and this was assessed in 11 patients with faulty mitral valves (the valve between the left atrium and left ventricle) who underwent a corrective procedure. Blood was taken before the procedure known as percutaneous transvenous mitral valvuloplasty (valve surgery or restoration), and at intervals afterward until 24 hours had passed. Blood was assayed for its levels of ANP, AVP (arginine vasopressin, a hormone apparently detected by cells in the atrium), renin, and aldosterone. These latter substances are known to control sodium and water retention, and to reflect renal (kidney) function. Results showed a decrease in the average left atrial pressure, but not the right, after valvuloplasty. ANP levels were elevated in nine patients before the procedure, and dropped to lower than control levels immediately afterward. Although lower, ANP levels remained above normal for the five patients who experienced atrial fibrillation (random, irregular contractions of the atria). Levels of ANP were correlated with left atrial pressure, right atrial pressure, and pulmonary arterial pressure (the artery through which blood flows from the right ventricle to the lungs). AVP levels increased temporarily after valvuloplasty, then returned to the same level as before surgery. Renin and aldosterone levels increased 30 minutes after valvuloplasty, as did measures of renal function. Overall, the results indicate that the heart's atrium responds to a reduction in pressure by reducing ANP secretion, which, in turn, alters water and sodium metabolism. It also appears that atrial fibrillation, or abnormal atrial contraction in itself, can stimulate ANP secretion. (Consumer Summary produced by Reliance Medical Information, Inc.)

Many of the electrolyte derangements seen in chronic heart failure are related to activation of the renin-angiotensin system. Activation of the system may cause the retention of both sodium and water; the former is primarily related to the release of aldosterone and the latter is related to an angiotensin-mediated increase in thirst and decrease in the excretion of free water. The interaction of these mechanisms may explain why patients with chronic heart failure have higher values for total body sodium but lower values for serum sodium concentration than hypertensive patients or normal subjects. Activation of the renin-angiotensin system may also cause potassium depletion, which is manifest clinically by a decrease in both total body potassium and serum potassium concentration. These electrolyte disturbances may play a role in the development of ventricular arrhythmias. The renin-angiotensin system may also contribute to the development of magnesium deficits. These hormone-electrolyte interactions have important implications in the treatment of patients with heart failure, especially those in whom the renin-angiotensin system is pharmacologically inhibited., The relationship between renin and plasma electrolytes is complex in patients with congestive heart failure. As heart failure progresses, the flow of blood through the kidneys declines, and renin (an enzyme produced by the kidney) is released to help maintain systemic blood pressure. However, the decreased blood flow through the kidney also interferes with the excretion of water and sodium. This water accumulates in the tissues causing edema (swelling). Ironically, the renin-angiotensin system increases thirst. When this occurs in patients with heart failure, it does not bolster blood volume, but increases the edema and causes hyponatremia (decreased sodium in the blood). Although excess sodium has been retained, the disproportionate increase in fluid volume causes the decreased concentration of sodium. However, the total body sodium is decreased in patients with congestive heart failure. The edema that develops in this manner results in the use of diuretics for the treatment of congestive heart failure. Diuretics also increase the risk of hypokalemia (potassium depletion), if the treatment is not carefully monitored. The increase in aldosterone (adrenal hormone), which results from the stimulation of the renin-angiotensin system, also increases the excretion of potassium. However, the effects of diuretic drugs remain the greatest concern of the clinician. (Consumer Summary produced by Reliance Medical Information, Inc.)

Several changes in neuroendocrine activity follow failure of cardiac function to satisfy peripheral requirements and contribute to the clinical syndromes of heart failure. Afferent pathways are poorly understood and triggers are both central and peripheral, involving attenuation of atrial and arterial baroreceptor activity. Efferent sympathetic activity is generally increased with resulting vasoconstriction, but responses are organ-specific and differ among heart, kidney, lung and skeletal muscle. Changes in cardiac sympathetic activity are inadequately understood. Enhanced cardiac norepinephrine spillover contrasts with reduced tissue concentration and impaired activity of synthetic enzymes and neuronal catecholamine uptake. Beta-receptor down-regulation further complicates overall adrenergic responsiveness and the balance between enhancement of contractile function and reduction in arrhythmia threshold. Activation of the renin-angiotensin system is potentiated by the sympathetic nervous system and may contribute to vasoconstrictor hyporesponsiveness. Angiotensin II may in turn facilitate the central and peripheral effects of sympathetic activation and the release of vasopressin from the pituitary. Our understanding of the role of vasodilator peptides in heart failure remains rudimentary. It is likely that vasoconstrictor neuro-endocrine response adversely influences optimal cardiac funtion in heart failure and may promote arrhythmogenesis. The neuroendocrine response in individual organs, however, requires intensive study., Congestive heart failure (CHF) is a condition characterized by failure of the heart to maintain adequate circulation to the body. Symptoms of weakness, breathlessness, abdominal discomfort, and edema (accumulation of fluid) in the lower body are the result of blood pooling in the veins and reduced output from the left ventricle (which pumps blood to the body). Many of the debilitating consequences of CHF can be viewed as an exaggeration of the body's compensatory mechanisms, which are initially helpful to the cardiovascular system, but ultimately act to hasten its demise. For example, a universal characteristic of CHF is activation of the sympathetic nervous system (the branch of the peripheral nervous system supplying excitatory innervation to the heart and blood vessels). In the initial stages, enhanced activity of the sympathetic nervous system results in a beneficial increase in cardiac output. However, hypertension (high blood pressure) resulting from increased sympathetic activity exacerbates pooling of blood in the venous system and makes the heart work harder to pump blood through the constricted vasculature (blood vessels); these effects result in decreased in cardiac performance. Additionally, activation of the renin-angiotensin system, a group of kidney enzymes that cause vasoconstriction, is a normal physiological response to decreased ventricular output. Under ordinary conditions, decreased output from the left ventricle would occur during hypotension (low blood pressure) caused by hemorrhage or other factors; hormonally induced increases in blood pressure would be therapeutic. In the case of CHF, in which decreased cardiac output is not the result of low blood pressure, hormonally induced blood pressure elevation merely increases the workload of the heart, leading to rapidly worsening ventricular function. (Consumer Summary produced by Reliance Medical Information, Inc.)