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)

The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in heart failure appear to be independent, at least in part, of their effect on blood pressure. The existence of a local cardiac renin angiotensin system is often suggested as an explanation. It has been known for some time that a substantial proportion of arterially delivered angiotensin I is converted to angiotensin II by ACE of the coronary vascular endothelium. The levels of angiotensin II in cardiac tissue are several times the levels of angiotensin II in circulating blood. Recent evidence suggests that most of the angiotensin II in the heart is not derived from angiotensin I in the circulation, and that most of the angiotensin I in cardiac tissue is generated in the tissue itself. On the other hand, renin mRNA levels are very low or undetectable in the normal heart. In addition, studies on the effects of bilateral nephrectomy on the cardiac tissue levels of renin, angiotensin I, and angiotensin II in pigs have indicated that cardiac renin originates from the kidney and that cardiac generation of angiotensin I and angiotensin II depends on renin from the kidney. Intracardiac synthesis of renin may occur under pathological conditions and during fetal development. The fact that angiotensins are generated by the heart raises the possibility of local mechanisms to regulate the concentrations of these peptides at certain tissue sites. For example, preliminary evidence suggests that binding of renin to cardiac membranes is a mechanism by which renin is taken up by the heart. A specific renin binding protein has been identified in cardiac tissue. Cardiac ACE levels may also influence local angiotensin II formation and are, in part, determined by the so called insertion/deletion ACE gene polymorphism. More detailed knowledge on the site of angiotensin generation and on its regulation will improve our understanding of the role of the renin-angiotensin system in cardiac function, hypertrophy, and postinfarction remodelling.
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PMID:Is there an internal cardiac renin-angiotensin system? 898 64

Previous observations on the heterogeneous distribution of von Willebrand factor in the vascular endothelium led us to examine the expression of angiotensin I-converting enzyme (ACE) in function of the vascular origin of endothelial cells (EC). EC from pig thoracic aorta, pulmonary artery, inferior vena cava and brain capillaries were cultured and assayed for ACE by enzymatic radiochemical determination and by western-blot and immunofluorescence using an antiACE polyclonal antibody. EC from the various vascular levels secreted ACE in the culture medium; western-blot analysis showed its presence at cellular level and immunofluorescence confirmed its location on the plasma membrane. But quantification revealed that EC from pulmonary artery contain more ACE than EC from the other vessels, especially from brain capillaries; immunofluorescence correlated well with the functional data. In contrast, secretion of ACE by brain capillaries EC was faster than that of arteries and of vena cava, the latter being the less effective. This differential ACE expression along the vascular tree could have a pharmacological implication since ACE inhibitors, used in the treatment of arterial hypertension, may act more at the vascular level than on the plasma renin-angiotensin system. On the other hand, endothelial distribution of ACE was different from that of von Willebrand factor; in particular we showed that EC cultured from vessels of pigs homozygous for the von Willebrand disease, in which von Willebrand factor synthesis was completely abolished, normally express ACE.
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PMID:Vascular origin determines angiotensin I-converting enzyme expression in endothelial cells. 914 23

Bradykinin exerts important influences on renal hemodynamics and tubular function by acting on renal bradykinin B2 receptors. However, the precise sites and mechanisms of its actions on the kidney are not known. To help elucidate the mechanisms of renal actions of bradykinin in vivo, we have employed high resolution electron microscopic autoradiography to localize bradykinin B2 binding sites in the rat kidney following intravenous administration of a radiolabeled ligand, 125I-HPP-Hoe140 (3-4-Hydroxyphenyl-propionyl-DArg0-[Hyp3-Thi5-D-Tic 7-Oic8]-bradykinin), a derivative of the highly selective bradykinin B2 receptor antagonist, Hoe140. In non-treated rats, bradykinin B2 binding sites were localized to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex. In the medulla (except for the outer stripe of the outer medulla), binding occurred in the distal tubules, thin limbs of the loop of Henle, collecting ducts, peritubular capillary endothelium and renomedullary interstitial cells. To exclude the possibility that the radioligand may bind to angiotensin converting enzyme, rats were pretreated with the angiotensin converting enzyme inhibitor, perindopril. In these rats, binding to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex was completely abolished, while binding remained unaltered in the medulla. Further studies using high performance liquid chromatography revealed that while the radioligand was degraded following systemic administration in nontreated rats, the degradation was significantly reduced in the rats pretreated chronically with perindopril. These results indicate that binding detected in the proximal tubules in the normal rats is due primarily to the tubular uptake of the degraded radioligand, and that bradykinin B2 binding sites occur predominantly in the renal tubules, vascular endothelium, and renomedullary interstitial cells of the renal medulla.
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PMID:Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment. 935 Jun 49

The generation of nitric oxide by the vascular endothelium maintains a continuous vasodilator tone that is essential for the regulation of blood flow and blood pressure. Nitric oxide also contributes to the control of platelet aggregation and has important antiatherogenic effects. These properties are mediated by the action of constitutive nitric oxide synthase and subsequent activation by nitric oxide of soluble guanylate cyclase. Impaired release of nitric oxide occurs in most animal and human models of hypertension, contributing to the increased peripheral resistance and most likely to the development of cardiovascular complications. Antihypertensive medications (angiotensin-converting enzyme [ACE] inhibitors and calcium channel blockers) appear to prevent the impairment of nitric oxide-mediated vasodilation in experimental hypertension, though in humans the data are not as clear. Reduced nitric oxide release appears therefore to be a consequence rather than a cause of high blood pressure, and the reduction in blood pressure per se is most important. In hyperlipidaemia, endothelium-dependent relaxations are reduced probably due to the inhibitory action of oxidized low-density lipoproteins on endothelium-dependent relaxations. Lipid-lowering strategies and, more recently, ACE inhibition have been demonstrated to improve nitric oxide dependent coronary vasodilation in hypercholesterolaemic patients with and without atheromatous coronary disease. Nitric oxide dependent vasodilation is also impaired in insulin- and non-insulin-dependent diabetes as well as in healthy aging. Endothelial dysfunction may be improved in non-insulin-dependent diabetes by administration of the antioxidants, supporting the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.
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PMID:Impairment and restoration of nitric oxide-dependent vasodilation in cardiovascular disease. 948 1

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

The vascular endothelium plays a key role in the control of vasomotor tone, local haemostasis and vascular wall proliferation processes. These responses are mediated by a variety of substances released from the endothelium in response to physiological stimuli, including prostacyclin, endothelin, and most importantly nitric oxide (NO). NO mediates vasodilation and furthermore inhibits platelet aggregation, expression of adhesion molecules for monocytes and adhesion of neutrophils, and it impairs growth of vascular smooth muscle cells. Risk factors for coronary atherosclerosis, such as hypercholesterolaemia, impair NO bioactivity, mainly due to an oxidative stress by superoxide radicals (O2-), which are able of rapidly inactivating endothelium-derived NO. Impaired NO bioactivity leads to unopposed paradoxical vasoconstriction of epicardial conductance vessels in response to physiological stimuli such as sympathetic activation as well as impaired vasodilator function of coronary resistance vessels. Therefore, endothelial dysfunction contributes to ischaemic manifestation of coronary artery disease. In addition, enhanced paradoxical vasoconstriction and a loss of endothelial antithrombotic activities might unfavourably modulate the course of acute coronary syndromes. Thus, the aim of therapeutic interventions is to increase NO bioavailability by either increasing NO production or decreasing O2- production in the endothelium. This goal can be reached, for example by ACE inhibitors, lipid-lowering drugs, increased shear-stress by physical exercise, oestrogens, and L-arginine, which have already been shown to improve endothelial vasodilator function. Nevertheless, it has to be determined whether ameliorated endothelial function will contribute to improved patients prognosis.
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PMID:Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic options. 1035 93

Endothelium-dependent vasodilation is impaired in patients with congestive heart failure. For vascular endothelium, hepatocyte growth factor (HGF) is one of the most potent and specific growth factors, which acts protectively against endothelial dysfunction. HGF production is downregulated by angiotensin II (Ang II) in vitro. We hypothesized that HGF production is impaired as the result of increased Ang II in patients with congestive heart failure, and that if so, the impaired production should be restored with angiotensin-converting enzyme inhibitors (ACE-I). We studied 16 patients with congestive heart failure caused by previous anterior myocardial infarction in whom left ventricular ejection fraction was 35+/-8% (mean+/-SD). Before and approximately 4 weeks after the treatment with ACE-I, blood samples were collected to measure the levels of HGF, Ang II, and brain natriuretic peptide as a biochemical marker for severity of heart failure. We also studied 5 control subjects, in whom heparin increased HGF production to 48+/-5-fold. However, in patients with heart failure, HGF response to heparin was significantly attenuated (24+/-5-fold, P<0.05 vs control). Therapy with ACE-I decreased the levels of Ang II and brain natriuretic peptide and restored HGF production in response to heparin by 43+/-7-fold, comparable to the control response. In conclusion, impaired HGF production was restored after the treatment with ACE-I probably by the mechanism of Ang II suppression. This novel effect of ACE-I may contribute to the clinical improvement in patients with heart failure and thereby may have an important therapeutic implication.
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PMID:Angiotensin-converting enzyme inhibition restores hepatocyte growth factor production in patients with congestive heart failure. 1037 19

There is recent evidence that the membrane potential of vascular endothelium regulates not only nitric oxide (NO) synthesis, but also superoxide generation, such that hyperpolarization stimulates NO production while suppressing that of superoxide. Given that NO works in a variety of ways to inhibit atherothrombotic disease and hypertension, whereas superoxide not only vetoes the benefits of NO but also disrupts endothelial metabolism and promotes LDL oxidation through its oxidant activity, it is thus evident that endothelium membrane potential is a crucial determinant of cardiovascular risk. Membrane polarization can be enhanced by measures which increase the synthesis or availability of the Na+-K+-ATPase, moderately enhance serum K+ and increase the conductance of membrane K+ channels. Such measures may include high-K+/low-Na+ natural diets, insulin sensitizing modalities, 'euthyroid replacement therapy' and ACE inhibitors. Epidemiological correlations of insulin resistance with hypertension and cardiovascular risk may reflect the low membrane potential of insulin-resistant vascular endothelium. Adjunctive measures for suppressing the generation or half-life of endothelial superoxide are suggested.
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PMID:Endothelial membrane potential regulates production of both nitric oxide and superoxide--a fundamental determinant of vascular health. 1060 62

Endothelin (ET) is a potent vasoconstrictor associated with various cardiovascular diseases. ET mediates its effects through ET receptors on vascular smooth muscle cells as well as on the vascular endothelium. Furthermore, a neurotransmitter role for ET has been suggested on the basis of experimental and human in vivo studies. ET antagonists are potent tools for studying the effects of ET and its receptors. They have been widely used in vitro and in experimental models of cardiovascular disease, where ET levels are elevated and reactivity to ET is altered. Promising clinical trials in hypertension, coronary artery disease, and congestive heart failure are discussed in this review. Different forms of renal failure are associated with markedly increased ET levels, and ET antagonists experimentally improve renal function in these models. Extrapolating from experimental and first clinical experience, ET antagonists could be useful in the treatment of hypertension, coronary artery disease, congestive heart failure, and renal failure, especially in combination with other drugs, ie, angiotensin converting enzyme inhibitors. The inhibition of ET-induced stimulation of nociception allows for speculation that ET antagonists might even have analgesic properties.
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PMID:Endothelin in cardiovascular control: the role of endothelin antagonists. 1098 Oct 46

The development of new antihypertensive agents is becoming even more important. We need better blood pressure control and also agents that treat hypertension as a disease of the vascular endothelium. Recently, it has been shown that blocking the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors reduces blood pressure and decreases the incidence of vascular disease. Another peptide system, the natriuretic peptide system, has also been shown to be important in blood pressure control and volume homeostasis. Because ACE and neutral endopeptidase, the enzyme responsible for the degradation of the natriuretic peptides, are both zinc metalloproteases, new pharmaceuticals that inhibit both enzymes have been developed. The first of these, omapatrilat, has been shown to be an effective antihypertensive agent and to have great potential for treating congestive heart failure.
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PMID:Vasopeptidase inhibition: a new direction in cardiovascular treatment. 1098 Nov 74


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