Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Widely distributed throughout the heart is a network of fibers connected to the medullary cardiovascular centers by nonmedullated vagal afferent fibers. When the traffic in these fibers is interrupted by vagal cooling, and the input from the arterial baroreceptors is prevented, the arterial blood pressure increases. Thus, these receptors act to inhibit tonically the vasomotor center. The receptors in the atria alter their rate of discharge with changes in atrial transmural pressure and contractility and are most active during end-inspiration and early expiration when the transmural pressure is maximal. The receptors in the ventricles respond to changes in ventricular end-diastolic pressure (preload), to the pressure generated during systole (afterload) and to changes in ventricular contractility. The cardiac mechanoreceptors have an equal or greater effect on the renal bed than the arterial mechanoreceptors and this effect is enhanced by hypercapnia. In animals, the cardiac mechanoreceptors have less control of the muscle vessels than the arterial mechanoreceptors, but the reverse is true in man. Both the cardiac and arterial mechanoreceptors can modulate the output of renin from the kidney, but the cardiac mechanoreceptors are more sensitive to small changes in blood volume. During coronary occlusion, in association with the bulging of the ischemic myocardium, the rate of discharge of these cardiac receptors is greatly increased.
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PMID:Cardiac receptors: normal and disturbed function. 38 68

The effects of early reperfusion were studied in closed-chest pigs subjected to either 45 min or 3 hr of regional ischemia. Myocardial enzyme release during early reperfusion and electrophysiological stability after two weeks were assessed. Coronary artery occlusion durations of 3 hr and early reperfusion after 45 min were compared. The creatine phosphokinase levels in the coronary effluent were lower after early reperfusion (p less than 0.001). Moreover, in the early reperfusion group, the coronary sinus catecholamine and purine levels rose to higher values than in the 3 hr group. The plasma levels of catecholamines and the plasma renin activity increased rapidly but transiently at reperfusion in the 45 min group. Both the rate-pressure product and the heart rate were elevated at the end of the reperfusion period (p less than 0.001) in the 45 min group. Survival for two weeks was 3 out of 6 animals in the 3 hr group and 5 out of 8 in the 45 min group. In all but one surviving animal, sustained ventricular tachycardias were inducible by programmed stimulation. Abnormally low QRS amplitudes and delayed potentials were found in the signal-averaged electrocardiogram in the early reperfusion group only. In conclusion, early reperfusion causes a reduction of myocardial tissue damage, but simultaneously, neurohumoral parameters showed a greater activation of the sympathetic nervous system and the renin-angiotensin system apparently causing a deleterious increase in oxygen consumption. Therefore, this injurious component of early reperfusion might prevent the potentially beneficial effects of a reduced tissue damage on survival or late arrhythmias.
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PMID:Neurohumoral changes and the inducibility of ventricular tachycardias: effect of early reperfusion on the ischemic porcine myocardium. 135 23

Acute myocardial ischemia results from an increased cardiac workload in presence of a critical coronary stenosis (demand ischemia), coronary occlusion (supply ischemia) or a combination of both. It is complicated by cardiac arrhythmias and deterioration of function of ischemic myocardium and results in an increased load and dilatation of non-ischemic myocardium. Cardiac protection in acute myocardial ischemia can be related to preservation of coronary blood flow, function of ischemic and non-ischemic myocardium or prevention of cardiac arrhythmias. In control animals and humans, ACE-inhibitors have no major effect on coronary blood flow. Myocardial ischemia raises plasma-renin-activity, angiotensin I-conversion by passage through coronary circulation, and plasma-angiotensin-II-concentrations. ACE-inhibitors and angiotensin-II-receptor blockers increase coronary blood flow during myocardial ischemia. Other mechanisms (bradykinin potentiation) may be involved. We found a potentiation of the coronary dilatory effect of the neuropeptide neurotensin (which is probably mediated by prostaglandins) by ACE-inhibitor. ACE-inhibitor may delay infarct development in animal experiments and improve function of ischemic myocardium. The importance of early dilatation of non-ischemic myocardium is unknown and it is unclear whether it may be prevented by an ACE-inhibitor as was shown for late dilatation. Studies on the effect of ACE-inhibitors in exercise-induced angina pectoris are controversial. An antiischemic and coronary dilatory effect has been shown by invasive studies in patients. A preliminary study in unstable angina pectoris was positive. Beneficial hemodynamic and antiarrhythmic effects (as well as excessive hypotension, however) have been shown in patients with acute myocardial infarction.
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PMID:[Possibilities of ACE inhibitor therapy in acute myocardial ischemia]. 186 31

We used the technique of high-performance liquid chromatography combined with radioimmunoassay to establish the profile of angiotensin peptides in the periphery and across the circulation of the dog's heart. Data were obtained before and after blockade of angiotensin converting enzyme, and after acute myocardial ischemia produced by occlusion of the left anterior descending coronary artery. Baseline values of plasma renin activity and immunoreactive angiotensin II were higher in the aortic root than in the coronary sinus but concentrations of angiotensin I and angiotensin-(1-7) were similar. In untreated animals, coronary occlusion produced significant increases in renin activity and arterial and venous levels of angiotensin I and angiotensin II. Inhibition of converting enzyme with benazeprilat (CGS-14,831) increased baseline circulating levels of angiotensin I, whereas angiotensin II and its carboxyl terminal fragments were reduced markedly. Baseline plasma levels of angiotensin-(1-7) and its fragments did not change. Myocardial ischemia in benazeprilat-treated dogs increased plasma renin activity and circulating levels of angiotensin I. Concentrations of angiotensin II and angiotensin-(1-7) did not change either in peripheral blood or across the coronary circulation. These results indicate that angiotensin peptides can be formed endogenously by enzymatic pathways alternate to converting enzyme. Furthermore, these data provide the basis for a further understanding of the role of the renin-angiotensin system after myocardial ischemia.
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PMID:The renin-angiotensin system during acute myocardial ischemia in dogs. 240 54

The possibility of a coexistence of coronary arteriolar constriction mediated by the renin-angiotensin system and myocardial ischemia was evaluated. Left anterior descending coronary artery was cannulated and perfused at normal (mean aortic), intermediate (50 mm Hg), and low (30-40 mm Hg) pressure in analogy to a progressive coronary stenosis. Lactate production was present at low coronary pressure indicating myocardial ischemia. In control animals (n = 18), mean coronary conductance was higher (p less than 0.005) at intermediate than at high coronary pressure consistent with autoregulation at coronary flow. Coronary conductance was lower (p less than 0.05) at low than at intermediate coronary pressure, indicating coronary constriction during myocardial ischemia. Adenosine (20 micrograms/kg per min i.c., n = 6) resulted in higher coronary conductance, suggesting coronary vasodilator reserve even at low coronary pressure. Indomethacin (5 mg/kg i.v., n = 12) resulted in low coronary conductance; however, the increase at intermediate (autoregulation) and the decrease (constriction) at low pressure was maintained. Plasma renin activity increased, and saralasin (0.1 microgram/kg per min i.c.) and captopril (0.25 mg/kg i.v.) acted as coronary vasodilators in various models of myocardial ischemia. Captopril limited myocardial infarct size at 6 hours of coronary occlusion, diminished flow repayment and prevented lactate production after 30 s of coronary occlusion, and abolished the deterioration of myocardial function during myocardial ischemia induced by coronary hypoperfusion and atrial pacing. Thus, myocardial ischemia does not generally represent a state of maximal coronary dilatation. The renin-angiotensin system is activated by myocardial ischemia and may exert a coronary constrictive tone. Captopril was beneficial in experimental myocardial ischemia.
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PMID:Coronary vasoconstriction in experimental myocardial ischemia. 244 Dec 6

An increase in plasma renin activity (PRA) following experimental coronary occlusion has previously been demonstrated in anaesthetized and conscious dogs. The purpose of the present study was to analyse the mechanism of this renin release. In two distinct models of myocardial ischaemia in anaesthetized dogs--i.e. occlusion of the left-anterior descending coronary artery (model A, n = 21) and atrial pacing in the presence of stenosis of the left-anterior descending coronary artery (model B, n = 23), an increase in arterial PRA was found from 1.68 +/- 0.43 to 3.06 +/- 0.63 ng ml-1 h-1 (model A, mean +/- SEM, P less than 0.025) and from 9.87 +/- 3.59 to 14.96 +/- 4.06 ng ml-1 h-1 (model B, P less than 0.05), respectively. The increase in PRA following coronary occlusion was not blunted by adrenergic beta-receptor blockade with propranolol (3 mg kg-1 i.v.; n = 4). Coronary sinus PRA was lower than arterial PRA and the increase in PRA did not occur in nephrectomized dogs (n = 5). The data suggest that myocardial ischaemia induces a release of renin from the kidney which is not mediated by adrenergic beta receptors.
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PMID:On the mechanism of renin release during experimental myocardial ischaemia. 300 60

Acute left anterior descending coronary artery occlusion was produced in 21 conscious, chronically instrumented dogs. Forty minutes after coronary occlusion, nine dogs were given i.v. teprotide, 25 micrograms/kg/min, followed by oral doses of captopril, 10 mg/kg every 8 hours for 24 hours. The remaining 12 dogs served as saline-infused controls. In all dogs, acute coronary occlusion increased plasma renin activity and peripheral vascular resistance and reduced cardiac output, but did not change mean aortic blood pressure significantly. Teprotide significantly (p less than 0.05) decreased peripheral vascular resistance (from 3804 +/- 1158 to 2876 +/- 816 dy-sec-cm-5) (+/- SD) and mean aortic pressure (from 117 +/- 12 to 107 +/- 15 mm Hg), and increased cardiac output (from 2.63 +/- 0.67 to 3.12 +/- 0.74 l/min). Teprotide also produced a relative increase in flow to the renal and splanchnic circulations compared with the saline-treated controls. There were, however, no differences in segmental systolic shortening, blood flow in the normal or ischemic myocardium, or infarct size. These results indicate that the renin-angiotensin system may play an important role in dogs with acute coronary occlusion and that blockade of this system lowers systemic blood pressure and improves cardiac output. However, direct effects of renin-angiotensin system blockade on the myocardium are lacking; there were no changes in myocardial blood flow, myocardial mechanics or infarct size.
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PMID:Renin-angiotensin system inhibition in acute myocardial infarction in dogs. Effects on systemic hemodynamics, myocardial blood flow, segmental myocardial function and infarct size. 618 19

Coronary artery occlusion results in the acute activation of the renin-angiotensin system and production of angiotensin II, a potent vasoconstrictor and positive inotropic agent. This has raised the possibility that angiotensin converting enzyme (ACE) inhibitors might be "cardioprotective" (that is, might attenuate myocardial injury, dysfunction and necrosis) in the setting of acute ischemia and infarction. Captopril, enalapril and ramipril have, in fact, been reported to acutely limit myocardial injury and necrosis in models of permanent coronary artery occlusion. The mechanisms responsible for this cardioprotection are complex, but include favorable alterations in myocardial oxygen supply/demand, and, in some instances, inhibition of bradykinin metabolism and/or increased prostaglandin synthesis. Other studies, however, have failed to document a reduction in infarct size with ACE inhibitor treatment. Results obtained in models of coronary occlusion/reperfusion have also been mixed. In models of brief transient ischemia not associated with necrosis, captopril and zofenopril have consistently been found to attenuate postischemic contractile dysfunction of the viable but "stunned" myocardium during the early hours following relief of ischemia. In contrast, there is no consensus on the effects of enalapril on the stunned myocardium: both positive and negative results have been obtained. Similar disparity has been reported in models of more prolonged ischemia/reperfusion resulting in subendocardial necrosis: some studies have reported myocardial salvage, while others have provided disturbing evidence of apparent exacerbation of myocardial necrosis with captopril and enalapril therapy. Thus, after a decade of investigative effort, the question of whether ACE inhibitors are "cardioprotective" in the setting of acute myocardial ischemia and infarction remains unresolved. Nonetheless, clinical protocols are in progress to assess the effects of early ACE inhibitor treatment in patients with acute myocardial infarction.
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PMID:"Cardioprotection" by ACE-inhibitors in acute myocardial ischemia and infarction? 835 29

Carperitide, a recombinant form of alpha-hANP, possesses potent diuretic, natriuretic, and vasodilatory activity, and inhibits the renin-aldosterone system and sympathetic nervous activity. However, its beneficial effects on ischemic myocardium have not been studied fully. We examined carperitide's effects on infarct size, hemodynamics, and arrhythmia frequency in anesthetized dogs (n = 20) subjected to a 90-min coronary artery occlusion/6-h reperfusion protocol. Intravenous infusion of carperitide (0.2 microg/kg/min) commenced 15 min after occlusion and continued during occlusion/reperfusion. Ventricular fibrillation developed in two of 10 control versus three of 10 treated dogs (p = NS). Hemodynamics, collateral blood flow to the ischemic wall measured 10 min after occlusion, and extent of area at risk were comparable for the two groups. Infarct size/area at risk was smaller in treated than in control dogs (4.5 +/- 2.1% vs. 27.8 +/- 7.8%, respectively; p < 0.05). During occlusion, carperitide tended to increase collateral blood flow (+39%) and significantly decreased left ventricular systolic pressure (-13%) and end-diastolic pressure (-40%) compared with baseline. In control dogs, collateral blood flow tended to decrease (-8.3%), whereas most hemodynamic parameters did not change significantly with respect to baseline. The number of arrhythmias recorded during occlusion/reperfusion was similar in the two groups. Intravenous administration of carperitide limited infarct size, but did not reduce incidence of ventricular arrhythmias after 90-min coronary occlusion/6-h reperfusion in anesthetized dogs. Although the beneficial effects of carperitide may be attributable to concomitant changes in hemodynamics and collateral blood flow, the precise mechanisms require further investigation.
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PMID:Alpha-human atrial natriuretic peptide, carperitide, reduces infarct size but not arrhythmias after coronary occlusion/reperfusion in dogs. 1089 56

Actions mediated by the renin-angiotensin system may be inhibited at various levels: renin itself may be inhibited, angiotensin-I (A-1) conversion to angiotensin-II (A-II), or binding of A-II at the A-II type 1 (A-II1) receptor. The angiotensin-converting enzyme (ACE) inhibitors and the A-II1 receptor antagonists are now clinically established. Because ACE is a relatively unspecific peptidase which catalyses the breakdown of A-I, bradykinin and neuropeptides like substance P and neurotensin, the effects of ACE inhibitors go far beyond the prevention of A-II production. On the other hand, in certain tissues like vascular and cardiac tissue, A-II is produced by other enzymes, for instance chymase, and ACE inhibitors do not consistently prevent A-II production. The action of A-II1 receptor antagonists may also not be confined to prevention of binding of A-II at the A-II1 receptor, as by rebound more A-II may bind at the A-II type 2 (A-II2) receptor and thus mediate until now not well defined effects. Thus, anti-ischemic actions of these drugs may be related to multiple mechanisms. Inhibition of A-II effects at the A-II1 receptor may prevent systemic and coronary vasoconstriction and growth effects of A-II on various cell types. In addition, A-II may potentiate, by pre- and postsynaptic mechanisms, activation of the sympathetic nervous system. Prevention of breakdown of bradykinin, substance P and neurotensin may result in direct vasodilation or release of nitrous oxide from the endothelium. Thus, growth-inhibiting effects may also be mediated. All these mechanisms seem to direct to a reduction of cardiac load by vasodilation and to a limitation of cardiovascular cell growth. While the systemic circulating renin-angiotensin system is probably responsible for control of cardiac load, local systems seem to control cell growth. Systemic effects seem to depend on activation of the renin-angiotensin system which has been shown in various ischemic syndromes. Activation of various components of the renin-angiotensin system has been demonstrated in myocardial ischemia, acute myocardial infarction and coronary occlusion and reperfusion models as well as in chronic left ventricular dysfunction post-myocardial infarction. While animal models of stress-induced myocardial ischemia have revealed predominantly positive results, clinical studies, which mostly were small and not well controlled, were equivocal. Large clinical trials with ACE inhibitors in acute myocardial infarction showed small benefits over placebo. Hypotension seems to be a critical side-effect in this situation. Experimental models show protective effects of both ACE inhibitors and A-II1 receptor antagonists in the situation of ischemia and reperfusion. New data on large clinical trials in patients at risk of cardiovascular events but normal left ventricular function demonstrate clear benefits of an ACE inhibitor. Large clinical trials in patients with chronic left ventricular dysfunction post-myocardial infarction show reduction of ischemic events.
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PMID:Anti-ischemic potential of drugs related to the renin-angiotensin system. 1139 74


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