Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
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Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans. 128 Jul 13

The "Peripheral Arterial Vasodilation" hypothesis most completely explains the clinical spectrum of cirrhosis ranging from compensated to decompensated to the hepatorenal syndrome (Figure 15-1). As the systemic peripheral vasodilation increases, the neurohumoral responses to arterial underfilling are stimulated with resultant renal vasoconstriction, sodium and water retention. Hypoalbuminemia and portal hypertension, as well as local effects of vasodilation at the capillary level, also contribute to ascites formation and peripheral edema. The suppressed plasma renin activity and aldosterone concentrations and exaggerated natriuresis, which are observed in some patients with early cirrhosis during HWI and the supine position, probably indicate greater central translocation of splanchnic fluid in these volume expanded cirrhotic patients when compared with normal subjects. This interpretation is supported by the greater increases in ANF during HWI in these patients when compared with controls. The neurohumoral responses to arterial vasodilation in cirrhosis combine to decrease distal sodium and water delivery, an event which impairs escape from the sodium retaining effects of aldosterone and causes resistance to the distal tubular effect of ANF (Figure 15-3). As discussed, the peripheral arterial vasodilation of cirrhosis is no doubt multifactorial in nature and the resultant arterial underfilling may be worsened by events that could impair the cardiac response to afterload reduction, including bile salt accumulation, alcoholic cardiomyopathy, and tense ascites decreasing cardiac preload. This pathogenetic schema of cirrhosis is compatible with the unifying body fluid volume hypothesis (Figure 15-3), which we have recently proposed.
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PMID:Pathogenesis of sodium and water retention in liver disease. 129 35

With RIA/HPLC and immunohistochemistry, the presence of angiotensin(A) and atrial natriuretic factor-like materials (ANF-LMs) was demonstrated in the pericardium of human and rats; the distributions of AII and ANF-LMs were found to be identical; AI was more than AII; renin activity was detected in the pericardium. There were three molecular forms of ANF-LMs in the pericardium. Mesothelial cells were the principal endocrine-secreting cells. AII and ANF-LMs of the pericardium were significantly increased in rheumatic heart disease. There were no correlations between plasma AII, ANF, urine AII, ANF and pericardial AII, ANF (P > 0.05). The data reported showed that the pericardium may have endocrine function under normal and abnormal conditions (heart failure) of the heart, in addition to its known mechanical properties.
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PMID:[A study of immunocompetence of peptide hormones in human pericardium]. 130 98

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

Pathophysiological mechanisms are reviewed concerning the onset and the perpetuation of the clinical features of congestive heart failure. This syndrome is a severe condition of poor prognosis and bad life quality which in the last decades has reached, in the western industrial countries, the highest levels of general mortality, mainly due to the high prevalence of hypertensive and ischaemic myocardiopathies in the last years. To the clinical features of heart failure mainly contributes a deregulation of the physiological compensatory mechanisms contemporarily and concurrently activated following the primary deficiency of the heart pump function. In physiological conditions, following the myogenic adapting mechanisms reflex mechanisms intervene, activated by intracardiac and aortic and carotid-sinus mechanoreceptors following the variations in intracardiac and intravascular pressure and generally evoking negative feed-back effects. In patients with heart failure arterial high pressure mechanoreceptors respond to the reduction in effective arterial pressure thus provoking a deactivation of the tonic inhibition on the sympathetic cardiovascular drive. This leads to an activation of peripheral and renal vasoconstrictor tone, to a raised medullary catecholamine incretion, to heart rate and inotropism stimulation, and to an increase in pituitary gland ADH production as well as to an activation of renin-angiotensin-aldosterone system (RAAS). Analogous vasoconstrictive, and sodium and water retentive effects can be elicited by endothelin produced by endothelial cells and found in high plasma levels in CHF. These excitatory effects, leading to a rise in systemic vascular resistance and to hydro-electrolytic retention with volume expansion, are not efficiently counteracted by the opposite effects triggered by cardiopulmonary vagally mediated mechanoreceptors activated by the raised cardiac filling pressure and leading to sympathetic nervous inhibition, peripheral and renal vasodilation, ADH and RAAS inhibition. Analogous effects should be provoked by the raised production, due to enhanced heart wall distension, of atrial natriuretic factor leading to vasodilation, natriuresis and diuresis. Reduced sensitivity of cardiopulmonary baroreceptors and lowered production of ANF due to structural cardiac changes could represent, according to most opinions, the main factors responsible for the prevailing sympathetic activation and hydro-saline retention in CHF. The activation of cardiopulmonary sympathetic positive-feed back afferents, could be also involved in the characteristic alteration of the vago-sympathetic balance in heart failure. The persistent reduction in heart pump function could lead to the instauration of vicious circles among the various regulatory systems and create an overcompensation condition.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[The physiopathological aspects and new therapeutic approaches in cardiac-circulatory failure]. 149 59

The effect of chronic cyclosporine administration on volume regulation was studied in mongrel dogs. Dogs received either cyclosporine (20 mg/kg/day p.o.; N = 7) or vehicle (N = 6) while being maintained on a constant sodium diet. Dogs had measurement of baseline vasoactive hormones. Daily sodium excretion was determined. Following eight days of drug administration, dogs were anesthetized, pre-volume expansion data was collected, and dogs underwent a one hour, 10% body weight 0.9% saline volume expansion. Daily sodium balance was +8.6 +/- 2.2 mEq in the cyclosporine group versus 0.4 +/- 1.8 mEq (P less than 0.05) in the control group after 8 days. Prior to acute volume expansion, aldosterone was 22.5 +/- 7.1 ng% in the cyclosporine group versus 4.7 +/- 0.7 ng% in controls (P less than 0.05). ANF was suppressed in the animals receiving cyclosporine. In response to volume expansion, the cyclosporine group demonstrated an attenuation of maximum urine flow by 56%, fractional excretion of sodium by 52%, and electrolyte free water clearance by 75% when compared to controls (P less than 0.05). We demonstrate that chronic cyclosporine administration activates the renin-angiotensin-aldosterone system, suppresses circulating ANF, and results in chronic sodium retention. Additionally, cyclosporine attenuates the natriuretic and diuretic response to acute volume expansion.
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PMID:The sodium retaining effects of cyclosporine. 150 15

Atrial natriuretic factor is the main natriuretic hormone. It is a peptide secreted by the atria in response to an increase of the central blood volume. Its effects are opposed to those of the renin angiotensin system and all result in the decrease of volemia. The main of them are an increase in renal sodium excretion, decrease in vascular resistance, increase in capillary permeability, and inhibition of renin and aldosterone secretions. ANF stimulates, via its B receptors, the production of cyclic GMP which is its second messenger. ANF is catabolized by clearance receptors which internalize it and ectoenzymes, mainly neutral endoproteinase. Plasma ANF increases in various conditions for three essential reasons: increase of its secretion from the usual sources, increase of its secretion from supplementary sites, decrease of its catabolism. Since ANF is implied in the maintenance of homeostasis in several diseases, treatment by neutral endoproteinase inhibitors which increases plasma ANF has been considered. Another natriuretic factor structurally close to digitalin and inhibiting Na(+)-K+ ATPase has been described but not identified.
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PMID:[Natriuretic factors]. 160 57

Experimental myocardial infarction is a model of cardiac overload due to amputation of part of the cardiac muscle. The development of cardiac failure depends on the size of the infarct and the time factor. This model of overload is associated with changes of the phenotype of the remaining healthy muscle and with peripheral vascular modifications partially dependent of the activation of pressor and/or deactivation of dilator systems. These changes are proportional to the size of the infarction at a given time after induction of the model. The degree of right ventricular hypertrophy and the decrease in blood pressure reflect the severity of infarction and the deterioration of the remaining myocardial function, affecting the haemodynamics both before and after the left ventricle. The increases in the 1/3 forms of isomyosins, the amount of subendocardial collagen, the biosynthesis, stocking and secretion of ANF are related to the infarct size and degree of overload. Similarly, the concentration of cyclic GMP is proportional to the infarct size. These parameters reflect ventricular overload, the increase of stress and energy deprivation of the remaining healthy muscle. The activation of peripheral pressor systems is also dependent on the infarct size reflects the effect of cardiac pump dysfunction on the kidney, liver, brain and endothelium. Large infarcts are associated with increased circulating renin and renal concentrations, with a decrease in angiotensinogen levels related to its consumption by the renin and to reduced hepatic synthesis and also with increased secretion and biosynthesis of vasopressin by the hypothalamus. In this model, Perindopril is beneficial by decreasing the cardiac load. It reduces the blood pressure, causes regression of bi-auricular and right ventricular hypertrophy. Changes in myosin isoenzyme configuration regress and subendocardial fibrosis and ANF concentrations are normalised. The effects of ACE inhibitors in this context, though very beneficial, are limited by the impossibility of normalising cardiac load and stress when the initial amputation of cardiac contractile mass exceeds 40%.
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PMID:[Experimental myocardial infarction in the rat. Effect of perindopril]. 166 27

During the last six years 13 patients suffering from congestive heart failure (CHF), refractory to conventional medical treatment and classified class IV as defined by the New York Heart Association (NYHA), were treated with continuous ambulatory peritoneal dialysis (CAPD) (1) at Innsbruck University Hospital, Department of Internal Medicine. All patients required intensive care and were end-stage. The minimum observation period was six weeks, maximum 67 months. Cardiac recompensation was effected in all patients, who were stabilized in class II after NYHA. The patient with the shortest observation period of six weeks received an orthotopic heart transplant. None of the patients died of a CAPD-associated complication. All patients were restored to a normal life style without major dependence on outside help. The occurrence and treatment of the prerenal kidney failure that causes life-threatening problems in end-stage CHF should be subject to further study with regard to its clinical course and the determination of plasma-ANF, plasma-renin and plasma-aldosterone concentration.
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PMID:CAPD: a successful treatment in patients suffering from therapy-resistant congestive heart failure. 168 Apr 67

The hemodynamic and neurohumoral effects of a single oral dose (0.4 mg) of the novel centrally acting antihypertensive agent moxonidine were investigated over 4 hours in ten patients with essential hypertension (WHO I-II). Pulmonary pressure indices and cardiac output were determined both at rest and during ergometric exercise by means of Swan-Ganz catheterization. Blood pressure was measured by sphygmomanometry and in the brachial artery. Moxonidine induced a significant fall in blood pressure over the 4-hour observation period from 176/105 mmHg to 158/95 mmHg (p less than 0.01), accompanied by a decrease in systemic vascular resistance from 1695 to 1427 dyn.sec/cm5 (p less than 0.01). Cardiac output remained unchanged, while heart rate increased slightly from 69 to 75 beats/min (p less than 0.01). No significant changes were recorded for either pulmonary artery pressure or pulmonary vascular resistance. Plasma levels of noradrenaline (337 vs. 224 pg/ml) and renin (2.6 vs 2.0 ng/ml/hr) activity fell significantly after moxonidine (p less than 0.05), both at rest and during exercise. Although aldosterone plasma levels fell slightly, level of angiotensin II and ANF remained unchanged. Moxonidine has favorable effects on hemodynamics and the neurohumoral system in patients with essential hypertension and is well tolerated at the dose administered.
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PMID:Hemodynamic and neurohumoral effects of moxonidine in patients with essential hypertension. 168 75


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