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)

ACE inhibition may be useful in several manifestations of ischaemic heart disease, such as heart failure due to ischaemic cardiomyopathy. Recent evidence suggests that these effects may also be present in normotensive patients with ischaemic heart disease without heart failure. Theoretically, converting-enzyme inhibition, through coronary and systemic vasodilating effects and negative inotropic properties, should have a favourable effect on the myocardial oxygen supply/demand ratio and, hence, affect the incidence and severity of myocardial ischaemia. It is doubtful, however, whether these cardiac and extracardiac properties of ACE inhibitors really underlie its potential antiischaemic effects, at least in the average patient with ischaemic heart disease without concomitant heart failure and hypertension. Recent animal and human studies indicate that converting-enzyme inhibitors may modulate myocardial ischaemia by reducing ischaemia-induced circulating neurohumoral activation. It has been shown that, depending on the severity of ischaemia, the circulating renin-angiotensin system may become activated together with an increase in circulating catecholamine levels. ACE inhibition suppresses this neuroendocrine stimulation during ischaemia and modulates subsequent systemic and, presumably, also coronary vasoconstriction. In addition to these effects on circulating neurohormones, ACE inhibition could affect myocardial ischaemia through a number of local actions, e.g. modulation of tissue (cardiac) angiotensin II formation and bradykinin breakdown, stimulation of prostaglandin synthesis and, in the use of sulphydryl compounds, by affecting EDRF formation. Whether ACE inhibitors have clear antiischaemic effects in all clinical conditions is uncertain. Their efficacy to limit exercise-induced ischaemia has been questioned. In contrast, pacing-induced ischaemia in patients at rest is clearly prevented by ACE inhibition. This differential effect may be related to a more pronounced difference in circulating neurohormones during exercise per se. It also suggests that ACE inhibitors may be particularly useful as (additional) antiischaemic therapy in patients with angina at rest, e.g. unstable angina and the acute phase of myocardial infarction.
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PMID:Neurohumoral activation during acute myocardial ischaemia. Effects of ACE inhibition. 197 98

Marked neointima formation occurs after balloon injury to the intima of rat arteries. Angiotensin II has been implicated as a growth factor in this process, since angiotensin converting enzyme (ACE) inhibitors block neointima formation after injury. However, ACE is an important kininase, and its inhibitors may act in part by a kinin-mediated mechanism. Kinins are also known to stimulate synthesis of endothelium-derived relaxing factor/nitric oxide (EDRF/NO) and prostacyclin, both of which have antigrowth effects. To determine whether the effect of ACE inhibitors on neointima formation is due to blockade of angiotensin II synthesis alone and/or inhibition of kinin inactivation, we followed two approaches. First, we compared the inhibition of neointima formation induced by the AT1-type angiotensin II receptor antagonist losartan with that caused by the ACE inhibitor ramipril. We also studied whether a kinin receptor antagonist, Hoe 140, blocks the effect of two different ACE inhibitors, ramipril and enalapril, on neointima formation. In addition, we studied whether the effect of ramipril is blocked by an NO synthesis inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME). Although both ramipril and losartan significantly reduced neointima formation, ramipril had a more marked effect (p < 0.05 for ramipril versus losartan). The kinin antagonist Hoe 140 reduced the inhibitory effect of ramipril and enalapril by 73% and 62%, respectively. The remaining effect of the ACE inhibitors was now similar to that of losartan. Inhibition of neointima formation by ramipril was also blocked by the NO synthesis inhibitor L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. 768 31

Endothelial function of epicardial arteries and coronary resistance vessels, as well as endothelial dysfunction and clinical symptoms of coronary artery disease and their therapeutic implications are reviewed including the presentation of the author's own results. Coronary endothelial vasodilator dysfunction represents a fundamental functional disturbance in vascular biology with the development of atherosclerosis. This functional alteration in coronary vascular reactivity appears to play an important integral part in the clinical presentation of coronary artery disease. Humoral and neuronal factors in favour of vasoconstrictor influences affect the balance between myocardial oxygen supply and demand, thus, facilitating the manifestation of myocardial ischemia. In order to identify more selective therapies the potential mechanisms underlying an impaired release or activity of EDRF/NO must be considered. Dysfunction of the endothelial L-arginine/NO pathway may involve decreased activity of NO synthase, increased inactivation of NO formed from its precursor L-arginine, impaired signal transduction mechanisms and reduced intracellular availability of L-arginine. Currently, initial therapeutic strategies include the supplementation of L-arginine, the use of antioxidants, as well as ACE-inhibitors. ACE-inhibitors have been shown not only to reduce vascular tone (and hypertrophy) by inhibition of angiotensin II formation, but also by increasing the endothelial production of NO and prostacyclin most likely due to the local accumulation of endothelium-derived bradykinin. Thus, ACE-inhibition appears to provide the potential to improve endothelial NO synthesis. Indeed, study results demonstrate that chronic ACE-inhibition is associated with an increased coronary blood flow response to acetylcholine suggesting an improvement in endothelial vasodilator functioning of coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coronary endothelial vasodilator dysfunction: clinical relevance and therapeutic implications. 785 84

The influential studies by Hostetter and associates [103] as well as by others in the last decade have firmly established the association between adaptive increases in renal hemodynamics as well as tubular reabsorption and the progression of renal disease. Many different vasoactive hormones may be involved in such regulatory processes. On the other hand, many investigators have observed that compensatory renal growth, although initially helping to restore functional renal tissue, may be rather harmful in the long-term for renal function, even in the absence of concomitant hemodynamic changes. These apparently separate areas of renal pathophysiology have become united by the identification of the growth regulatory properties of many vasoactive substances. Thus, a perturbation of vasoconstrictors and vasodilatory substances may not only influence vascular tone, glomerular filtration rate and renal plasma flow but also the growth regulation of distinct populations of cells along the nephron. As a generalization, it appears that vasoconstrictors stimulate growth of renal cells (mitogenesis and hypertrophy), whereas vasodilators inhibit the growth response. It can be speculated that similar effects of different hormones may depend on the activation of common second messenger pathway, e.g. the ANG-II-, AVP-, ET-induced mesangial proliferation through the phosphorylation of a common set of target proteins, or the antimitogenic effects of ANP, EDRF and PGE2 through an increase in intracellular cGMP. However, the majority of the growth regulatory effects of vasoactive substances have been studied in relatively artificial cell culture systems. Nevertheless, the well-documented protective effects of ACE inhibitors on renal function in several models include effects on renal growth. The rapid development of new vasoactive drugs like the recently introduced nonpeptide ANG II receptor antagonists may also offer an opportunity to influence renal growth [104]. The mechanisms of the progression of renal disease have become fascinatingly complex, and the next years will most likely witness major achievements in the elucidation of chronic renal pathophysiology on both cellular and molecular levels.
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PMID:Vasoactive substances as regulators of renal growth. 808 63

Many cell types in myocardial tissue, including cardiocytes, contain receptors for angiotensin-II, but the activation of these receptors requires angiotensin concentrations in the micromolar range, which do not occur in plasma in vivo. However, angiotensins formed locally in the heart can activate these receptors in a paracrine and autocrine mode. In cardiac hypertrophy due to hemodynamic overload, the myocardial angiotensin formation is enhanced due to an augmented expression of angiotensinogen and ACE. Though the mRNA for prorenin is expressed in myocardium, the formation of active renin within the heart has not yet been demonstrated and myocardial renin activity is mainly due to contamination from circulating active renin. Intracoronary application of ACE inhibitors in hypertrophied hearts in vivo and in vitro indicates that the locally formed angiotensin-II contributes to coronary constriction, impairment of diastolic relaxation and marginally to the maintenance of systolic tension development. Angiotensin-II can exert trophic effects on cardiocytes and cardiac fibroblasts, and chronic inhibition of the cardiac RAS by ACE-inhibitors or AT receptor antagonists can induce partial regression of overload hypertrophy, even without normalizing the overload. This anti-trophic action may be partially due to the impairment of the angiotensin axis, but also due to enhancement of bradykinin availability, which results in an augmented release of endothelial anti-trophic signals such as EDRF/NO and prostacyclin. Preliminary evidence is compatible with the hypothesis that an activated local RAS in elastic arteries contributes to the localization and progression of atherosclerosis by suppressing EDRF releasability. However, the anti-atherosclerotic potential of ACE inhibitors and AT receptor antagonists in humans is still unknown.
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PMID:The cardiac renin-angiotensin system: physiological relevance and pharmacological modulation. 851 37

This study was designed to evaluate the effect of chronic treatment with cilazapril on vascular reactivity of aorta and mesenteric artery from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Cilazapril (5 mg/kg), an angiotensin converting enzyme inhibitor, was injected intraperitoneally twice a day for 4 weeks. Results demonstrated that acetylcholine (ACh)-induced relaxation in aorta and mesenteric artery from SHR was significantly less than that from WKY, cilazapril-treated WKY, and SHR. The impairment of ACh-induced relaxation in SHR was significantly reversed after cilazapril treatment and there were no significant differences among WKY, cilazapril-treated WKY, and SHR. Meanwhile, both N omega-nitro-L-arginine (LNNA; 10(-4) mol/L) and methylene blue (MB; 10(-5) mol/L) completely blocked the vasodilator response to ACh in aorta but only partly inhibited in mesenteric artery from WKY, cilazapril-treated WKY, and SHR. These LNNA- and MB-resistant vasodilator responses to ACh in mesenteric artery were only slightly inhibited by TEA (10(-3) mol/L) but not by indomethacin (5 x 10(-6) mol/L). These findings suggest that there may be an unidentified endothelium-dependent relaxing factor(s) (EDRF), which exists in the endothelium and may participate in the modulation of blood pressure in SHR. Results further demonstrate that the antihypertensive effect of cilazapril may be partly mediated by the reversing function of endothelium to release EDRF and LNNA-resistant, unidentified relaxing factor(s).
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PMID:Cilazapril reverses endothelium-dependent vasodilator response to acetylcholine in mesenteric artery from spontaneously hypertensive rats. 854 Oct 9

At the opportunity of the 100th anniversary of S. Riva-Rocci's publications on the new sphygmomanometer the author presents a review of the main publications which made this method possible and a review of clinical and pathological studies which led to the recognition of essential hypertension (EHT). He also mentions main adopted criteria of hypertension and draws attention to the difficulties associated with a definition and classification of EHT because of the variations in pressure and differences of "normal" values in various populations. From multicentre intervention studies precise and generally valid criteria for individual treatment cannot be derived. As to recent of work on the pathogenesis of EHT the author draws attention to the importance of endothelin and NO (EDRF), which play a part in the genesis of changes in the vascular wall in atheromatosis and also in hypertension. A new discovery is the bond between NO and haemoglobin (S-nitrosohaemoglobin). In addition to proved and located genetic factors also external factors are involved, in particular psychosocial factors, diet, body weight, smoking etc. on which prevention and treatment must be focused. Medicamentous treatment markedly improves the prognosis of hypertension. Antihypertensive drugs from all main groups of drugs are used. Dosage still remains an open question which cannot be resolved completely on the basis of intervention trials. ACE-inhibitors hold an important place--they reduce the blood pressure and also prevent progression of left ventricular hypertrophy. Beta-blockers and diuretics still remain the basis of first line treatment. Among Ca-inhibitor, preparation with long-term action are preferred. Open questions include--apart from dosage--the comparison of the efficacy/side effects ratio of new effective drugs (A I, A II, renin) and older antihypertensive drugs when used on a long-term basis; furthermore the justification to administer vasodilatating drugs as monotherapy and in combinations during long-term treatment with regard to the activation of the sympathetic nerve and risk of hypotension. The author discusses the sympathetic activation to which BP should be reduced and thus also the question of doses reduction and discontinuation of the drug--in particular in old patients. And finally, the role of hypertension as the sole cause of increased mortality (EEHT per se) must be proved. In practice the problems of the detection rate, adherence, information and correct treatment are of major importance.
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PMID:[100 years of hypertension]. 951 Dec 69

The mechanism of captopril, an angiotensin converting enzyme (ACE) inhibitor with sulfhydryl group (SH) in its structure, to produce an endothelium-dependent vasorelaxation was studied. In rabbit aorta with intact endothelium and precontracted with phenylephrine, captopril and superoxide dismutase (SOD) produced dose-dependent relaxation. Lisinopril, an ACE inhibitor without a -SH group in its structure, did not produce endothelium-dependent relaxation. It was observed that captopril, like SOD, produced the relaxation by protecting the EDRF from getting inactivated by superoxide anions as pyrogallol and methylene blue inhibited both the captopril and SOD-mediated relaxation. The free radical scavenging action of captopril is further substantiated by the observation that captopril, but not lisinopril, inhibited FeCl3/ascorbic acid-induced lipid peroxidation in whole tissue homogenates of rabbit aorta to a level comparable to that of SOD. These results suggest that endothelium-dependent vasodilation produced by captopril may be due to its ability to scavenge superoxide anion and this property may be ascribed to the -SH group present in its structure.
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PMID:Possible mechanism of captopril induced endothelium-dependent relaxation in isolated rabbit aorta. 965 79

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors(s) (EDRF) under basal conditions. In addition, the endothelium can increase the release of EDRF in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions the most important stimulus to the release of EDRF is an increase in blood flow, leading to increased shear stress on endothelial cells. Recent experimental studies have raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or endothelium-derived hyperpolarizing factor. Recent studies in humans have demonstrated that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has been shown to be important in humans in both peripheral and coronary arteries. Angiotensin-converting enzyme (ACE) inhibitors not only decrease angiotensin II but also increase bradykinin levels, since ACE is identical to kininase II, which degrades bradykinin. The beneficial vascular effects of ACE inhibitors may therefore be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect is bradykinin-dependent. Our preliminary data also indicate that ACE inhibition improves endothelium-mediated vasodilation in patients with heart failure and coronary artery disease due to an enhanced availability of nitric oxide. These findings suggest that the beneficial vascular effects of ACE inhibition in heart failure may be due in part to improved endothelial function.
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PMID:Effect of ACE inhibition on endothelial dysfunction in patients with chronic heart failure. 971 56

The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.
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PMID:Endothelial dysfunction in human disease. 1007 15


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