Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that angiotensin converting enzyme (ACE) inhibitors not only prevent the formation of angiotensin II, but also potentiate the activity of bradykinin. We investigated the effects of the ACE-inhibitor ramipril in two models of cardiac ischemia. In anesthetized dogs with a coronary occlusion of 6-h duration, both ramiprilat and bradykinin significantly reduced infarct-size. This effect was prevented by the co-administration of the bradykinin antagonist HOE 140. In rats with a coronary occlusion of 6-weeks duration, ramipril administration significantly reduced infarct-size and prevented the development of left ventricular hypertrophy. Thus, ramipril showed a cardioprotective activity in models of acute as well as of chronic myocardial ischemia. These effects are probably mediated by the potentiation of bradykinin.
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PMID:[Reduction of infarct size and remodeling after ramipril]. 785 82

Cardiac anaphylaxis, an acute ischemic dysfunction comprising coronary vasoconstriction and arrhythmias, is a model of clinically recognized immediate hypersensitivity reactions affecting the heart. Bradykinin, a mediator of hypersensitivity, is also a potent coronary vasodilator, acting via nitric oxide and prostacyclin production. Because ischemia increases bradykinin outflow from the heart, we questioned whether bradykinin might mitigate anaphylactic coronary vasoconstriction. Antigen challenge of hearts isolated from presensitized guinea pigs was associated with an approximately 30% increase in bradykinin overflow. Furthermore, (1) when the half-life of bradykinin was prolonged with the kininase II/angiotensin-converting enzyme inhibitors captopril and enalaprilat, anaphylactic coronary vasoconstriction was attenuated and reversed, and arrhythmias were alleviated; (2) the bradykinin B2-receptor antagonist HOE 140 prevented these effects; and (3) HOE 140 exacerbated both anaphylactic coronary vasoconstriction and arrhythmias. During cardiac anaphylaxis, the coronary overflow of cGMP, a marker of nitric oxide production, and 6-ketoprostaglandin F1 alpha, a stable prostacyclin metabolite, increased two-fold and fourfold, respectively. Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F1 alpha is likely to reflect the actions of other hypersensitivity mediators (eg, histamine and leukotrienes). We postulate that bradykinin plays a protective role in cardiac anaphylaxis by accumulating at the luminal surface of the coronary endothelium and promoting, in an autocrine mode, a B2-receptor-mediated production of nitric oxide and prostacyclin in concentrations sufficient to elicit a paracrine effect on coronary vascular smooth muscle, thus opposing the vasoconstricting effects of other anaphylactic mediators.
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PMID:Protective role of bradykinin in cardiac anaphylaxis. Coronary-vasodilating and antiarrhythmic activities mediated by autocrine/paracrine mechanisms. 785 89

Aortic surgery results in ischemia/reperfusion of the lower body. This may liberate inflammatory mediators that activate neutrophils, and may result in lung microvascular changes with increased permeability and respiratory failure. We studied circulating inflammatory mediators and the pulmonary leak index (PLI) of 67Ga, a measure of transvascular transferrin transport and permeability, in patients scheduled for elective aortic and peripheral vascular surgery, before and after surgery. Aortic surgery patients in Groups 1 (n = 10) and 2 (n = 7) were studied before and at a median of 2.5 and 21.0 h after surgery, respectively. A control Group 3 (n = 6) was studied before and at a median of 2.9 h after peripheral vascular surgery. The PLI (median) increased from a median of 9.1 (range, 6.6 to 14.7) before to a median of 23.4 (range, 18.7 to 86.4) x 10(-3)/min after surgery in Group 1 but not in the other groups (p < 0.001). The postoperative increase in circulating neutrophils and elastase-alpha 1-antitrypsin, a marker of neutrophil activation, was similar among the groups. Plasma levels of activated complement 3a and tumor necrosis factor (TNF-alpha) did not change in any of the groups. In contrast, plasma levels of interleukin-8 (IL-8) increased in Group 1 from < 3 (range, < 3 to 37) before to 324 (range, 36 to 868) pg/ml after surgery, but did not change in the other groups (p < 0.005). The decrease in plasma levels of angiotensin converting enzyme (ACE) was greater in Group 1 than in the other groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transient increase in interleukin-8 and pulmonary microvascular permeability following aortic surgery. 788 59

Long-term management of patients following myocardial infarction requires assessment of both residual ischemia and left ventricular function, since these are the primary factors in determining the patient's prognosis. Most patients with uncomplicated hospital courses should undergo exercise testing and assessment of the ejection fraction. Aspirin and beta-adrenergic receptor blocking agents should be prescribed to most patients, and angiotensin converting enzyme inhibitors and cholesterol-lowering drugs should be administered when indicated. Psychologic issues unique to myocardial infarction must be addressed, and an appropriate exercise program should be prescribed. The goal is to help patients achieve the functional status they had before the infarction.
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PMID:Managing patients with myocardial infarction after hospital discharge. 781 77

Based on the foregoing data it is not unreasonable to hypothesize that restoration of flow in the infarct-related artery at a later date might decrease mortality. If that is the case, then a strong argument can be made for coronary angiography in patients surviving acute myocardial infarction. Of course, the ideal way to investigate this problem is to perform a large-scale prospective trial in which patients who have an occluded infarct-related artery are randomized to a revascularization procedure or continued on nonsurgical therapy. The specific management strategy for the patient with an occluded infarct-related artery after myocardial infarction depends on several features that the patient exhibits. For example, the presence or absence of LV dilatation, arrhythmias, recurrent ischemia, or clinical heart failure may dictate one form of therapy or another. There is no generic postinfarction patient with an infarct-related artery occlusion. Choices of drugs to use in these patients include the vasodilators, such as nitrates and ACE inhibitors, as well as aspirin and beta blockers. The use of calcium antagonists, chronic anticoagulants, and antiarrhythmics should have specific indications. Antithrombin agents are still experimental.
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PMID:Management of myocardial infarction patients with an occluded infarct-related artery. 791 May 40

Nitrates are commonly used in the therapy of congestive heart failure (CHF). They exert beneficial hemodynamic effects by decreasing left ventricular filling pressure and systemic vascular resistance while modestly improving cardiac output. The improvement in left ventricular function caused by nitrates is the result of combined reduction in outflow resistance and mitral regurgitation, while decreased pericardial constraint and subendocardial ischemia may also contribute to the process. With continuous nitrate administration, complete arterial tolerance develops, while venous tolerance appears to be only partial. The major mechanism of tolerance is loss of vascular smooth muscle sensitivity to nitrates. An increase in total blood volume occurring during the first few hours of an acute administration may partly contribute to tolerance. The importance of reflex neurohumoral activation is controversial; although it may contribute to tolerance in CHF, its role does not appear to be major. Chronic continuous nitrate therapy in CHF improves submaximal and maximal exercise tolerance. In combination therapy with hydralazine, isosorbide dinitrate reduces mortality, although to a lesser extent than the angiotensin converting enzyme inhibitor enalapril. Intravenous or sublingual nitrates are first-line agents in the therapy of acute pulmonary edema. In severe CHF, refractory to standard medical therapy, a short course of intravenous nitroglycerin, with or without inotropic agents, can help break the vicious spiral of CHF. Because tolerance occurs without nitrate-free intervals and until an optimal schedule of administration is determined, it makes good sense to include a nightly nitrate-free interval when prescribing nitrates for CHF in order to maintain maximal benefit during the hours of activity.
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PMID:Nitrates in congestive heart failure. 794 67

Both the hibernating and the stunned myocardium are characterized by reversible contractile dysfunction. In hibernating myocardium ischemia is still ongoing, whereas in stunned myocardium blood flow is fully or almost fully restored. Both the hibernating and the stunned myocardium retain an inotropic reserve. In hibernating myocardium the increase in contractile function is at the expense of metabolic recovery whereas in stunned myocardium no metabolic deterioration occurs during inotropic stimulation. Therefore, inotropic stimulation in combination with metabolic imaging may help not only to identify viable, dysfunction myocardium but also to distinguish hibernating and stunned myocardium. The only causal therapy of hibernating myocardium is to restore blood flow to the hypoperfused tissue. Myocardial stunning per se requires no therapy at all, since by definition blood flow is normal and contractile function will recover spontaneously. If, however, myocardial stunning involves large parts of the left ventricle and thus impairs global left ventricular function, the extent of myocardial stunning can be reduced by inotropic stimulation, without inducing further damage to the myocardium. In the experimental setting, antioxidant agents, calcium antagonists and ACE inhibitors attenuate stunning, most effectively when administered before ischemia.
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PMID:Characterization of hibernating and stunned myocardium. 795 33

We investigated the protective effect of angiotensin II (Ang II) type 1 receptor antagonist on myocardial ischemia-reperfusion injury and the role of exogenous Ang II to this injury in perfused hearts. We orally administered TCV-116 (Ang II type 1 receptor antagonist) and delapril (angiotensin converting enzyme inhibitor) to Wistar rats for 1 week and measured the immunoreactive cardiac Ang II. Immunoreactive cardiac Ang II (pg/gm tissue) was 14.3 +/- 2.0 in control group, 11.8 +/- 0.8 in TCV-116-treated group, and 7.3 +/- 0.6 in delapril-treated group (p < 0.05 compared to TCV-116-treated group; p < 0.01 compared to control group). The 15 hearts (five rats in each group) were perfused by a langendorff method and global ischemia was maintained for 30 min. Both TCV-116 and delapril were found to improve postischemic cardiac function and decrease reperfusion creatine kinase (CK) release. Ang II injection before ischemia worsened postischemic cardiac function and increased reperfusion CK release. Only TCV-116 prevented this injury. These data indicated that TCV-116 Ang II type 1 receptor antagonist was effective against myocardial ischemia-reperfusion injury, and exogenous Ang II accelerated this injury through Ang II type 1 receptor.
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PMID:Cardioprotective effect of the angiotensin II type 1 receptor antagonist TCV-116 on ischemia-reperfusion injury. 801 62

We evaluated, firstly, the sensitivity to cardiac ischemic ATP breakdown during the development of hypertension and cardiac hypertrophy in Spontaneously Hypertensive Rats (SHR) v Wistar Kyoto (WKY) controls, and secondly, the effects of short-term (8 days) and prolonged (3 months) antihypertensive treatment with the angiotensin converting enzyme inhibitor enalapril on hypertrophy and sensitivity to global ischemia. In isolated perfused hearts, ischemia was induced by a stepwise lowering of the perfusion pressure and the appearance of the ATP breakdown products (purines) in the coronary effluent was assessed as a measure of ischemia. Hearts from 2.5- and 4-month-old SHR started to release purines at a higher perfusion pressure than hearts of WKY, associated with a higher maximum concentration in the coronary effluent. This increased ischemic ATP breakdown in 2.5- and 4-month-old SHR could be attributed to a decreased flow at a given perfusion pressure, because of a two-fold increase in coronary vascular resistance (CVR). In contrast, the maximal purine concentration in the coronary effluent in hearts of 7-month-old SHR was reduced compared to the younger SHR and only slightly higher than 7-month-old WKY, despite a persistent increase in CVR. Enalapril normalized the blood pressure, but only prolonged treatment, significantly prevented and regressed cardiac hypertrophy, and reduced CVR. Whereas enalapril did not influence ATP breakdown in WKY, in SHR both short- and long-term treatment normalized it to the pattern observed in WKY. We conclude that during the early phase of cardiac hypertrophy the hearts of SHR become more sensitive to ischemic ATP breakdown solely because of an increase in CVR, whereas during the established hypertrophic phase, the hearts appear to adapt metabolically, resulting in normalized purine release. Enalapril normalized the transient increase in sensitivity to ischemic ATP breakdown during the development of hypertension in SHR, independent of effects on cardiac hypertrophy, apparently by improving coronary flow at low perfusion pressures.
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PMID:Age-related increase in sensitivity for ischemic ATP breakdown in hypertrophic hearts of SHR normalized by enalapril. 807 19

The adjunctive use of ACE-inhibitors with thrombolytic therapy early during acute myocardial infarction offers theoretic advantages. In the acute phase, captopril may scavenge free radicals, blunt the catecholamine response, elicit coronary vasodilation and increase prostacyclin and bradykinin levels. In the chronic phase remodelling may be attenuated. At present, a large number of controlled clinical trials mainly focussing on the effects of ACE-inhibition in the chronic phase is under way. Only few studies concentrate on the effect of acute intervention with ACE-inhibitors in ischemia-reperfusion i.e. thrombolysis in myocardial infarction. In the Captopril And Thrombolysis pilot study (CAT pilot-study) 3 mg and 6.25 mg captopril was tolerated well as adjunctive therapy to intravenous streptokinase. Decrease in mean arterial blood pressure (36 +/- 11%) after 6.25 mg was comparable to the control group (30 +/- 7%). Furthermore noradrenaline levels decreased dose dependently to 47 +/- 6 and 38 +/- 7% from baseline respectively. These results prompted a large nationwide acute intervention trial with captopril in 300 patients receiving thrombolytic therapy: the Captopril And Thrombolysis Study (CATS). The primary hypothesis of CATS supposes a very early effect of converting enzyme inhibition on evolving myocardial damage due to ischemia and the consequences of early reperfusion. This will be evaluated by serial echocardiography, Holter monitoring and neurohumoral measurements immediately upon thrombolysis and during the first year after myocardial infarction. Blinded data show a favourable blood pressure response, with systolic hypotension below 100 mm Hg occurring only in 0.2% of patients.
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PMID:Angiotensin-converting enzyme inhibition during thrombolytic therapy in acute myocardial infarction: the Captopril and Thrombolysis Study (CATS). 812 21


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