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)

ACE-inhibitors improve symptoms and prognosis in patients with heart failure. The V-Heft II trial has demonstrated that the beneficial effect of these agents is superior to unspecific vasodilators. Besides sustained arterial and venous vasodilation the inhibition of the neurohumoral axis is thought to play an important role. Angiotensin II and catecholamines not only exert vasoconstrictor effects, but might also contribute to vascular and myocardial growth. Thus, it may not be surprising that the beneficial effects of ACE inhibitors in heart failure only emerge during long-term therapy rather than after short-term administration. It has been shown that these agents improve blood flow to skeletal muscle during exercise after chronic therapy (not acutely), and there is some preliminary evidence that improvement of endothelial function might be involved in this effect, i.e., by reducing the degradation of bradykinin, an endothelial vasodilator. ACE inhibitors reduce LV hypertrophy, an important risk factor for cardiovascular disease and prognosis. Moreover, there is experimental evidence that ACE inhibitors can prevent and even reverse interstitial fibrosis in the left ventricle. Although the plasma renin activity may be normal in patients with chronic heart failure, recent data using polymerase chain reaction indicate that the tissue cardiac renin angiotensin system is activated in the failing human heart as assessed by measurements of angiotensin converting enzyme mRNA and angiotensinogen mRNA which may be an important target for ACE-inhibition.
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PMID:[The value of ACE inhibitors in heart failure (mechanism of action)]. 129 Mar 8

Karyotypic and phenotypic changes were found in human adult endothelial cells (EC) during aging in vitro. A trisomy of chromosome 11 was found in 11 out of 12 EC cultures examined, derived from 9 cell lines from 8 donors. The incidence of this trisomy in some cell lines increased over time from 0% to as much as 100% near the end of their in vitro life span. A number of oncogenes and other important genes are on chromosome 11. These genes might play a role in the changes observed. An increase in the percentage of polyploid cells was also found near the end of the in vitro life span in 6 lines. The cellular levels of two gene products characteristic of the EC, von Willebrand factor (vWF) or Factor VIII, and angiotensin converting enzyme (ACE) were also monitored. vWf was studied in 2 lines and was decreased in both with serial passage. ACE decreased in three out of the four lines examined. These chromosomal and phenotypic changes which occur with increasing age in vitro make the endothelial cell a suitable model to study in vitro culture-related changes, senescence, cardiovascular disease, and tumorigenesis.
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PMID:Karyotypic and phenotypic changes during in vitro aging of human endothelial cells. 130 25

Inhibitors of metallopeptidases may represent new alternatives in the treatment of cardiovascular disease. Recent investigations have linked the hypotensive properties of the metalloendopeptidase 3.4.24.15 (MEP 24.15) inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-para-aminobenzoate (cFP-A-A-F-pAB) to the attenuation of bradykinin metabolism. However, since angiotensin converting enzyme (ACE) is widely recognized to contribute to the metabolic clearance of bradykinin, we characterized the specificity of cFP-A-A-F-pAB towards ACE. We also determined whether cFP-A-A-F-pAB inhibits the conversion of angiotensin I (Ang I) to Ang II by pulmonary ACE. The ACE activity toward the synthetic substrate hippuryl-histidine-leucine (Hip-His-Leu) was measured in vitro using both a purified lung preparation and pooled rat serum. The ACE activity was inhibited at increasing concentrations of the MEP 24.15 inhibitor. Kinetic analysis revealed that cFP-A-A-F-pAB competitively inhibited pulmonary ACE with a Ki of 0.19 microM. In rat serum, cFP-A-A-F-pAB also competitively inhibited ACE. The hydrolysis of Ang I into Ang II by pulmonary ACE was inhibited to a similar extent by both cFP-A-A-F-pAB and the ACE inhibitor MK 422. These findings are the first to show that the MEP 24.15 inhibitor cFP-A-A-F-pAB also inhibits ACE. We suggest that the reported hypotensive actions of cFP-A-A-F-pAB may be due to the reduction in both bradykinin metabolism and Ang II generation arising from the blockade of ACE.
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PMID:Inhibition of angiotensin converting enzyme by the metalloendopeptidase 3.4.24.15 inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-p-aminobenzoate. 133 90

Left ventricular hypertrophy (LVH) is an independent risk indicator of cardiovascular disease. Obtaining reversal of hypertension-induced cardiac hypertrophy seems to be a desirable objective of antihypertensive treatment. A total of 2,357 patients were included in a meta-analysis on the effect of antihypertensive pharmacological therapy on LVH. Overall left ventricular mass (LVM) was reduced by 11.9% (95% confidence interval (CI) 10.1-13.7) in parallel with a reduction of mean arterial pressure of 14.9% (CI 14.0 to 15.8). When evaluating the effect of first-line therapies on calculated LVM using the same formula for all studies, the absolute reductions in g were 44.7 (ACE-inhibitors), 22.8 (beta-blockers), 26.9 (calcium antagonists) and 21.4 (diuretics) when adjusted for differences between studies (ANCOVA). It can be concluded that effective antihypertensive therapy reduces LVM. ACE-inhibitors, beta-blockers and calcium antagonists reduce LVM by reducing wall hypertrophy, the effect of ACE-inhibitors being the most pronounced. Diuretics reduce LVM mainly through an effect on left ventricular inner diameter. How these effects affect prognosis is still an open question.
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PMID:Regression of left ventricular hypertrophy--a meta-analysis. 134 56

Echocardiographically determined left ventricular mass (LVM) is currently considered to be the most powerful risk indicator for cardiovascular disease, yielding prognostic information beyond that provided by the evaluation of traditional cardiovascular risk factors, high blood pressure included. It has been considered logical to try to obtain regression of cardiac hypertrophy, even though the risk-reducing implications of such a measure remain to be fully established. Experimental and clinical studies have shown that some classes of antihypertensive compounds are less effective than others in causing reversal of left ventricular hypertrophy (LVH) in spite of being similarly efficacious in lowering blood pressure. In order to extract the maximum amount of information from clinical studies, a meta-analysis was performed. This analysis included 109 treatment studies, each conformed to strict present rules. Only studies with pharmacological antihypertensive therapy and echocardiographically determined LVM were included. An analysis of the effect of the four first-hand antihypertensive treatment principles, adjusted for differences between studies with ANCOVA, showed that the ACE inhibitors, beta-blockers and calcium antagonists all reduce LVM by reversing wall hypertrophy and that the effect is most pronounced with ACE inhibitors. Diuretics reduce LVM mainly by a reduction in left ventricular diameter. If the difference in ability to reverse LVH, between ACE inhibitors and beta-blockers/diuretics would correspond to a difference in prognosis, then the outcome of antihypertensive therapy might be expected to improve. This hypothesis is currently under investigation.
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PMID:Regression of left ventricular hypertrophy--are there differences between antihypertensive agents? 136 88

The major risk factor associated with the appearance of adverse cardiovascular events and outcome attributable to cardiovascular disease is left ventricular hypertrophy (LVH). Why this should be so resides not in the increase in myocardial mass per se, but in the disruption of myocardial structure. An abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighboring interstitial spaces represents such a distortion in structure. Furthermore, this fibrosis disrupts the electrical and mechanical behavior of the hypertrophied myocardium. Mechanisms responsible for fibrillar collagen accumulation have been examined in intact animals and cultured cardiac fibroblasts. In vivo studies indicate that myocardial fibrosis is associated with the presence of chronic mineralocorticoid excess, relative to sodium intake and excretion, not hemodynamic workload. Accordingly, fibrosis can appear in both the hypertensive, hypertrophied and nonhypertensive, nonhypertrophied ventricles. In both primary and secondary hyperaldosteronism it was possible to prevent myocardial fibrosis with an aldosterone receptor antagonist, while in unilateral renal ischemia angiotensin converting enzyme (ACE) inhibition was similarly cardioprotective. A regression in fibrous tissue and normalization of diastolic stiffness has also been possible using ACE inhibition, bringing forward the concept of cardioreparation and the notion that heart failure due to fibrosis may be reversible. In vitro studies indicate that effector hormones of the renin-angiotensin-aldosterone system stimulate fibroblast collagen synthesis. Aldosterone, in pathophysiologic concentrations, and angiotensin II, in much larger concentrations, each enhance collagen synthesis without altering the mitogenic potential of these cells. Thus, elevations in circulating aldosterone and angiotensin II, relative to sodium intake, have the potential to not only alter sodium homeostasis and vascular tonicity, but also the structure of cardiovascular tissue. Thus, myocardial fibrosis represents a structural basis for pathologic hypertrophy and ultimately accounts for the appearance of adverse cardiovascular events and outcomes.
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PMID:Pathologic hypertrophy with fibrosis: the structural basis for myocardial failure. 136 63

The renin-angiotensin system has a varied role in the regulation of cardiac function, ranging from early receptor-mediated effects such as second messenger generation, to more delayed responses such as protein synthesis and cell growth. Clinically, the importance of the RAS in cardiovascular disease is becoming increasingly evident with the use of ACE inhibitors in treating various pathological processes. With evidence for the existence of a local RAS in the heart, the molecular and biochemical regulation of this system requires investigation. Much additional work needs to be directed toward elucidating the mechanisms by which the AII-receptor couples to cardiac growth, how the local RAS is regulated, and the nature of controls that modulate cardiac production and actions of this peptide. Increased understanding of the mechanisms by which AII actions are affected in cardiac tissue will likely lead to enhanced therapeutic modalities for the treatment of pathological cardiovascular conditions in which the RAS plays an integral role.
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PMID:Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. 156 74

Several risk factors for cardiovascular disease are discussed, including blood pressure, left ventricular hypertrophy, stress and smoking. Beta-blockers have a modest effect in reversing increased left ventricular mass, compared with angiotensin converting enzyme (ACE) inhibitors, although beta-blockers are as effective as ACE inhibitors in reducing posterior wall and interventricular septal thickness. Coronary events and many risk factors show a circadian rhythm. Beta-blockers can reduce the mid-morning (0700-1000 h) risk of ischaemic events and myocardial infarction. Catecholamine levels peak at 0700-1000 h, and catecholamine-induced myocardial necrosis can be significantly reduced by beta-blockade. Beta-blockers appear to be more effective than calcium antagonists in modifying the mid-morning vulnerable period and reducing the duration of ischaemia. However, the problems of using surrogate endpoints are discussed. In young to middle-aged hypertensives, beta-blockers are more effective in primary prevention of myocardial events than diuretics, though this is not the case for the elderly. Beta-blockers are also more effective than calcium antagonists in reducing morbidity and mortality after a myocardial infarction (i.e. secondary prevention). Patients with hypertension associated with ischaemic heart disease are most likely to get maximal benefit from treatment with beta-blockers.
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PMID:Identification of patients at risk from ischaemic complications. 168 61

Hypertension is one of the primary risk factors for cardiovascular disease, especially coronary artery disease (CAD), cerebrovascular disease, and congestive heart failure. Recent analysis of the numerous prospective clinical trials of the efficacy of antihypertensive therapy performed during the past quarter century has shown that active treatment reduces mortality and cerebrovascular disease but has not prevented CAD. The reason for this paradox--that lowering blood pressure does not reduce CAD mortality or morbidity--is uncertain. During the past several years, it has become clear that hyperinsulinemia and peripheral insulin resistance constitute the link between hypertension, obesity, and non-insulin-dependent diabetes mellitus, three conditions in which the rate of CAD is very high. Other studies have shown that hyperinsulinemia is a potent cardiovascular risk factor. Epidemiologic surveys and retrospective reviews of clinical experience have pointed out the surprising fact that when hypertension and non-insulin-dependent diabetes mellitus occur in the same patient, hypertension is likely to be diagnosed first and the risk of developing diabetes is much higher if antihypertensive drugs (thiazide diuretics or beta-adrenoreceptor blockers) were given. Recently, careful studies have shown that both thiazide diuretic and beta-adrenoreceptor blockers worsen insulin sensitivity, whereas angiotensin converting enzyme inhibitors (captopril) and peripheral alpha 1-blockers (prazosin) improve it and also favorably affect the levels of other atherogenic risk factors. Although it is too early to be certain, this information suggests that, pending the results of long-term clinical trials that measure clinical events, treatment of hypertension might be better able to reduce CAD if it were directed at improving insulin sensitivity. Nonpharmacologic measures that reduce hyperinsulinemia, weight loss, and exercise should be vigorously recommended, and pharmacologic therapy should be aimed at avoiding drugs that worsen insulin sensitivity, as long as blood pressure is successfully reduced.
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PMID:The coronary artery disease paradox: the role of hyperinsulinemia and insulin resistance and implications for therapy. 169 28

Atenolol is a selective beta 1-adrenoceptor antagonist with a duration of activity of at least 24 hours. The scope of therapeutic use of the drug has been expanded and become better defined since it was first reviewed in the Journal in 1979. Atenolol is effective and generally well tolerated in patients with all grades of hypertension. Data from comparative studies show that when administered orally, atenolol reduces blood pressure to a similar extent, and in a similar proportion of patients, as usual therapeutic doses of other beta-adrenoceptor antagonists (such as acebutolol, celiprolol, betaxolol, indenolol, metoprolol, nadolol, pindolol, propranolol, tertatolol), angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril and lisinopril), calcium antagonists (e.g. amlodipine, diltiazem, felodipine, isradipine, nitrendipine, nifedipine, verapamil), doxazosin, ketanserin and alpha-methyldopa. Atenolol effectively lowers blood pressure in elderly patients with hypertension and in women with hypertension associated with pregnancy, and improves objective and subjective indices in patients with stable angina pectoris. Oral atenolol is used for preventing recurrence of supraventricular arrhythmias once control is achieved by intravenous administration of atenolol. Early intervention with intravenous atenolol followed by oral maintenance therapy reduces infarct recurrence and cardiovascular mortality in patients with known or suspected myocardial infarction. There is also encouraging evidence of reduced mortality from cardiovascular disease during long term therapy with atenolol in patients with hypertension. Atenolol is well tolerated in most patients. Increases in plasma levels of both total triglycerides and very low density lipoprotein (VLDL) triglycerides have accompanied atenolol therapy although the clinical relevance, if any, of longer term metabolic effects has yet to be determined. Its low lipid solubility and limited brain penetration results in a lower incidence of central nervous system effects than that associated with propranolol. After many years of clinical usage atenolol is a well established treatment option in several areas of cardiovascular medicine such as mild to moderate hypertension and stable angina pectoris. Furthermore, it has also shown potential in the treatment of some cardiac arrhythmias and has been associated with reduced cardiovascular mortality in patients with hypertension and in patients with myocardial infarction.
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PMID:Atenolol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders. 172 Mar 83


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