Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Contrary to popular belief, the primary directive for the release of renin is not the preservation of circulatory homeostasis, since activation of this hormonal system in patients with chronic heart failure results in deleterious rather than beneficial effects on cardiac performance. Instead, renin appears to be released by the kidneys to maintain glomerular filtration rate when renal perfusion pressure is reduced. The renin-angiotensin system carries out this beneficial action by exerting a constrictor action on the efferent arteriole. In doing so, renal blood flow declines, but filtration fraction increases and thus, glomerular hydraulic filtration pressure (and renal function) is preserved, despite severe renal hypoperfusion. When the formation of angiotensin II is inhibited during converting-enzyme inhibition, the beneficial action of this hormone on the efferent arteriole is lost, and renal function may deteriorate. This sequence of events is most likely to be seen when four risk factors are present: hyponatremia; high-dose diuretic therapy; diabetes mellitus; and the use of long-acting converting-enzyme inhibitors. In randomized studies, renal insufficiency developed more frequently with enalapril and lisinopril than with captopril. This risk of worsening azotemia is particularly high in patients with the most severe (class IV) heart failure.
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PMID:Identification of risk factors predisposing to the development of functional renal insufficiency during treatment with converting-enzyme inhibitors in chronic heart failure. 267 Feb 21

A number of theoretical and practical aspects of acute myocardial infarction suggest a potential role for ACE inhibition in enhancing coronary blood flow and limitation of infarct size. Indeed, the use of ACE inhibitors in acute myocardial infarction could be viewed as a logical intervention in the face of the neuroendocrine response which accompanies the acute phase. During the first 24 h post-infarction, very high plasma concentrations of arginine-vasopressin and catecholamines occur. This is followed by a sharp rise in the concentration of angiotensin II (ANG II) over the next few days. The neuroendocrine response is most marked in those patients with larger infarcts, who frequently develop left ventricular failure. The extent to which these factors influence coronary flow in acute myocardial infarction is unknown, although in chronic heart failure ACE inhibition does not reduce coronary blood flow despite a reduction in rate-pressure product, suggesting a coronary vasodilator effect. However, in the presence of fixed coronary stenoses, the fall in blood pressure and, therefore, of coronary perfusion pressure must be taken into account. Whether or not the use of ACE inhibitors can limit infarct size in man also remains to be determined, although it has been clearly demonstrated that concentrations of ANG II similar to those observed in the early phase of myocardial infarction can cause myocardial cell damage in experimental animals. Post-infarction ventricular enlargement can be reduced by ACE inhibitors. Additionally, ACE inhibitors, through their balanced vasodilator effect, maintain cardiac output whilst reducing filling pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of angiotensin-converting enzyme inhibition on coronary blood flow and infarct size limitation. 267 35

1. The identification of a vascular wall renin angiotensin system and of angiotensin converting enzyme on the luminal surface of the endothelium in many tissues, including the brain, has stimulated research on the influence of the renin angiotensin system on regional blood flows. 2. In experimental studies inhibition of the angiotensin converting enzyme shifts the limits of cerebral blood flow autoregulation towards lower blood pressure values. 3. In patients with chronic arterial hypertension and in patients with chronic heart failure cerebral blood flow is not changed by acute or chronic angiotensin converting enzyme inhibition, despite in some cases pronounced reductions in the mean arterial blood pressure. Angiotensin converting enzyme inhibition does not change ischaemic regional cerebral blood flow in acute stroke. 4. It is concluded that following angiotensin converting inhibition cerebral blood flow is maintained at an unchanged level. The mechanism may include inhibition of locally produced angiotensin II leading to a selective dilation of larger cerebral arteries with a compensatory constriction of the smaller cerebral arteries.
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PMID:Angiotensin converting enzyme inhibition and cerebral circulation--a review. 269 Sep 8

Renin plays a major role in the control of blood pressure and water and electrolyte metabolism and it is clear that blocking of this system is particularly effective in the treatment of essential hypertension and heart failure. A large number of converting enzyme inhibitors have been synthesized. Converting enzyme inhibitors are remarkably active in heart failure and they reduce microalbuminuria and possibly maintain glomerular function. Blocking of the renin-angiotensin system by converting enzyme inhibitors is not accompanied by hypotension or reflex stimulation of the sympathetic nervous system. Converting enzyme inhibitors represent a major therapeutic advance in the field of cardiovascular and renal disease but the long-term effects of decreased angiotensin II levels are unknown. There are other ways to inhibit the renin-angiotensin system. The recent discovery of orally-active non-peptide angiotensin II antagonists opens a range of fascinating prospects. Another approach consists in inhibiting the reaction of renin on angiotensinogen, which is remarkably selective. Although it is too early to know whether these new approaches will be less active, more active or as active as current converting enzyme inhibitors, they may constitute a progress in relation to currently available treatments.
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PMID:New therapeutic prospects of renin-angiotensin system inhibition. 269 Nov 25

A fall in blood pressure occurs, in most patients, within a few hours of a single dose of an angiotensin converting enzyme (ACE) inhibitor. While a serious fall in pressure is unusual in previously untreated essential hypertension, some patients are at risk of severe first-dose hypotension. These include those with treated heart failure, severe hypertension on polypharmacy, 'renin-dependent' renovascular hypertension and the occasional elderly patient. In such groups of patients the incidence of severe, symptomatic first-dose hypotension approaches 10%. This effect is not specific for ACE inhibitor therapy and may well occur as frequently with other drugs in such patients. First-dose hypotension may not be accompanied by tachycardia, possibly as a result of a parasympathomimetic action that may contribute to the first-dose effect. It is generally not possible to predict patients at risk, although plasma renin and angiotensin II concentrations show a modest positive correlation with the initial fall in blood pressure. The maximum initial hypotensive effect of ACE inhibitors is not clearly dose related but the duration of effect may be. Therefore such drugs should be started at minimum effective dosage. High-risk patients should be observed closely for at least 6 h. Symptomatic hypotension usually responds to supine rest although infusion of angiotensin II, atropine and occasionally saline may be required.
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PMID:Angiotensin converting enzyme inhibitors in the clinic: first-dose hypotension. 282 78

The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.
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PMID:Angiotensin-converting enzyme inhibitors. Relationship between pharmacodynamics and pharmacokinetics. 284 18

A series of neurohumoral systems are activated in congestive heart failure that contribute to the increased vascular resistance and sodium retention that characterize this disorder. Abnormalities in baroreceptor function are intrinsic to the pathophysiology of heart failure and may subserve the vasoconstrictive and volume overloaded state that defines patient morbidity. Blunted baroreceptor responses to high cardiac filling pressures or depressed cardiac function reduce afferent signals that normally inhibit sympathetic efferent activity, vasopressin release, and indirectly, renin secretion. The resulting increase in neurohumoral activity mediates the redistribution of blood flow that occurs in this disorder. Limb blood flow is usually reduced and may be responsible for exercise intolerance. Decreased renal blood flow and altered intrarenal hemodynamics contribute to sodium retention. In addition, renal vasoconstriction and elevated circulating levels of angiotensin II and vasopressin may contribute to hyponatremia by influencing free water intake and excretion. Hence, baroreceptor dysfunction may be a principal mechanism that contributes to neurohumoral activation and subsequent alteration in vascular resistance and sodium and water balance in congestive heart failure. It may not be coincidental that two principal markers of an unfavorable prognosis in patients with heart failure, high plasma norepinephrine levels and hyponatremia, share baroreceptor dysfunction as a common theme.
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PMID:Baroreceptor function in congestive heart failure: effect on neurohumoral activation and regional vascular resistance. 288 66

Support for the concept that neurohormonal mechanisms play an important role in determining the survival of patients with severe chronic heart failure is derived from two lines of evidence: circulating levels of neurohormones are markedly elevated in patients who have a poor long-term prognosis and the survival of high-risk patients may be favorably modified by treatment with specific neurohormonal antagonists. Plasma norepinephrine is a major prognostic factor in patients with severe chronic heart failure, the most markedly elevated levels being observed in patients with the most unfavorable long-term prognosis. Data from uncontrolled studies suggest that low-dose beta-blockade may improve the survival of patients with dilated cardiomyopathy. Similar trends were noted in the Beta-Blocker Heart Attack Trial, in which patients with congestive heart failure before or accompanying their acute myocardial infarction experienced a significant reduction in sudden death when treated with beta-blockers. In contrast, there appeared to be little selective benefit in patients without heart failure, who presumably had low circulating levels of catecholamines. Similarly, serum sodium concentration is a major prognostic factor in patients with severe chronic heart failure, the shortest survival being observed in patients with the most severe hyponatremia. The poor long-term outcome of hyponatremic patients appears to be related to the marked elevation of plasma renin activity in these individuals, since (in retrospective studies) hyponatremic patients appeared to fare significantly better when treated with converting-enzyme inhibitors than when treated with vasodilator drugs that did not interfere with angiotensin II formation. In contrast, there appeared to be no selective benefit of converting-enzyme inhibition on the survival of patients with a normal serum sodium concentration, in whom plasma renin activity was low. These data suggest that neurohormonal systems may exert a deleterious effect on the survival of some patients with severe chronic heart failure, which may be favorably modified by long-term treatment with specific neurohormonal antagonists.
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PMID:Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. 288 67

The hemodynamic and renal electrolyte/function effects of a synthetic peptide (ANF) corresponding to the sequence of the 26 amino acids contained in atrial natriuretic factor (ANF) were assessed in closed-chest dogs in which acute left ventricular failure was produced by coronary artery embolization with 50 micron plastic microspheres. Coronary embolization produced a sustained reduction in cardiac contractility (LV dP/dtmax) and cardiac output which averaged 42 and 44%, respectively. Following a 45 min equilibration period after heart failure induction, most of the hemodynamic functions stabilized. At this time, ANF infused intravenously at 100 pmol/kg per min X 30 min (n = 9) did not lower mean arterial pressure although it increased cardiac output (P less than 0.05) by 17% at only one time period. With the exception of a fall in coronary resistance and an increase in myocardial blood flow, a higher dose of ANF (200 pmol/kg per min) did not consistently alter hemodynamic function. Fractional excretion of sodium (FE Na%) increased 3.4-fold with ANF at 100 pmol/kg per min and 1.8-fold with the 200 pmol/kg per min dose. Neither dose of ANF produced significant effects on renal blood flow (RBF) or glomerular filtration rate (GFR). Plasma angiotensin II which was 91 +/- 20 fmol/ml at baseline increased to 175 +/- 25 fmol/ml (P less than 0.05) 45 min after heart failure induction. However, neither dose of ANF significantly reduced these high circulating angiotensin II levels. These results demonstrate that an infusion of a synthetic ANF stimulated saluresis without altering RBF or GFR, and improved cardiac output in dogs with acute left ventricular failure.
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PMID:Hemodynamic effects of synthetic atrial natriuretic factor (ANF) in dogs with acute left ventricular failure. 293 67

Recent findings support the existence of independently functioning, local renin-angiotensin systems in a number of tissues. The clinical importance that inhibitors of the renin-angiotensin system have gained in the treatment of hypertension and cardiac failure, as well as molecular biology data, suggest that a functional, tissue renin-angiotensin system is present in the heart. Using several experimental approaches we present evidence to support the existence and the possible physiopathological relevance of such a cardiac renin-angiotensin system. Tissue angiotensins were documented and quantified in different regions of the heart by high performance liquid chromatography combined with specific radio-immunoassay. Reduction of cardiac angiotensin after administration of converting enzyme inhibitors in nephrectomized animals indicates that these peptides are generated locally. Effects of converting enzyme inhibitors on angiotensin II-dependent facilitation of cardiac sympathetic tone further support this concept and emphasize the potential physiological role of a cardiac renin-angiotensin system. Further, direct evidence for local generation of angiotensin II in the myocardium is provided by assessment of the intracardiac conversion of angiotensin I to angiotensin II and by measurement of the activity of angiotensin converting enzyme in the heart.
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PMID:Tissue renin-angiotensin systems: focus on the heart. 295 9


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