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)

In ischemia, the heart generates and releases kinins as mediators that seem to have cardioprotective actions. Kinin-generating pathways are present in the heart. Kininogen, kininogenases, kinins, and B2 kinin receptors can be measured in cardiac tissue. Kinins are released under conditions of ischemia. In anesthetized rats and dogs with coronary artery ligation and in human patients with myocardial infarction, kinin plasma levels are increased. In isolated rat hearts, the outflow of kinins is enhanced during ischemia but markedly attenuated after deendothelialization, pointing to the coronary vascular endothelium as the main possible source. Kinins administered locally exert beneficial cardiac effects. In isolated rat hearts with ischemia-reperfusion injuries, perfusion with bradykinin (BK) reduces the duration and incidence of ventricular fibrillation, improves cardiodynamics, reduces release of cytosolic enzymes, and preserves energy-rich phosphates and glycogen stores. In anesthetized animals, intracoronary BK is followed by comparable beneficial changes and limits infarct size. Inhibition of breakdown of BK and related peptides induces beneficial cardiac effects. Treatment with ACE inhibitors such as ramipril increases cardiac kinin levels and reduces post-ischemic reperfusion injuries in isolated rat hearts and infarct size in anesthetized animals. The importance of an intact endothelium that continuously generates kinins is supported by observations that basal and ramipril-induced release of kinins and PGI2 is markedly reduced after deendothelialization of isolated hearts. Blockade of B2 kinin receptors increases ischemia-induced effects. Endothelial formation of NO and PGI2 by ACE inhibition is prevented by the specific B2 kinin receptor antagonist icatibant. In isolated hearts, ischemia-reperfusion injuries deteriorate with icatibant, which also abolishes the cardioprotective effects of ACE inhibitors and of exogenous BK. Infarct size reduction by ACE inhibitors and by BK in anesthetized animals is reversed by icatibant. Kinins contribute to the cardioprotective effects associated with ischemic preconditioning because preconditioning or BK-induced antiarrhythmic and infarct size-limiting effects are attenuated by icatibant. In conclusion, kinins may act as mediators of endogenous cardioprotective mechanisms. Kinins are generated and released during ischemia, with subsequent formation of PGI2 and NO probably derived mainly from the coronary vascular endothelium. Their cardioprotective profile resembles that of ACE inhibitors.
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PMID:Role of kinins in the pathophysiology of myocardial ischemia. In vitro and in vivo studies. 852 1

Coronary reserve plays an important role in myocardial oxygen supply. During rest, oxygen consumption is near to maximal. An increase in myocardial oxygen demand can only be covered by an increase in coronary flow by dilation of coronary vessels. The maximal achievable rise in coronary blood flow is called coronary reserve. Coronary reserve is not only enhanced in patients with coronary artery disease but also in patients with disorders of coronary microcirculation for example in arterial hypertension. The following review will deal especially with disorders of the microcirculation in arterial hypertension. The impairment of coronary reserve is a result of structural and functional alterations. Structural alterations include an increase in media wall thickness of the small coronary arteries and a reduction of coronary capillaries. Extravascular myocardial forces which determine coronary resistance include myocardial hypertrophy and qualitative changes of myocardium like interstitial and perivascular fibrosis. The role of functional alterations like endothelial related vasomotion is discussed. The renin-angiotensin system modulates the growth of the small muscle cells of the vessels and induces protooncogenes and other growth factors. Therefore the renin-angiotensin system may also play an important role in hypertensive remodeling. Hypertensive coronary microangiopathy is diagnosed by exercise stress test and ST-segment-monitoring over 24 hours to show myocardial ischemia. Also nuclear medicine technics can be used if conventional methods of showing ischemia don't work. The diagnosis is definite if the determination of coronary reserve shows that the maximal coronary blood flow is not achieved. Coronary flow can be measured by the argon-gas-method, the thermodulation-technic or by the doppler-method. Also by nuclear medicine technics (PET) the coronary flow reserve can be determined. The advantages of these methods are discussed. In experimental studies calcium-channel-blockers, ACE-inhibitors and moxonidine showed an increase in density of capillaries and also a reduction of myocardial hypertrophy, which both result in an improvement of coronary reserve. Clinical studies of our group demonstrate that coronary microangiopathy in hypertensives can be improved by calcium-channel-blockers and ACE-inhibitors after one year treatment. Beta-receptor-blockers show no clear improvement of coronary reserve. It has to be shown by further studies whether the improvement of coronary reserve is more important for prognosis than the regression of myocardial hypertrophy.
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PMID:[Coronary microangiopathy in hypertensive heart disease: pathogenesis, diagnosis and therapy]. 858 95

Hypertension after renal transplantation continues to affect 50% or more of patients, despite use of modern immunosuppressive regimens. Relationships between poor control of blood pressure and reduced chronic allograft survival have been clearly demonstrated, and are analogous to the well-known acceleration of progressive renal disease by coexisting hypertension. It is likely, although to date it has not been formally proven by prospective study, that effective blood pressure control has a beneficial effect on chronic allograft outcome, as in progressive dysfunction of native kidneys. A further key question is whether differing classes of antihypertensive therapy may have differing effects on long-term graft outcome. It has been proposed that glomerular hypertension, hyperfiltration and hypertrophy, secondary both to inadequate nephron mass and to loss of functioning nephrons, may contribute to chronic allograft failure. If this is true, then use of converting enzyme inhibitors may particularly benefit long-term graft outcome. However, post-transplant hypertension in cyclosporine-treated patients is associated with sodium retention and renin system suppression, and a relative lack of renoprotective action of ACE inhibitors might be predicted in this context. An alternative hemodynamic factor underlying chronic allograft failure is glomerular ischemia, secondary to the vascular changes associated with chronic rejection and to cyclosporine-related afferent arteriolar vasoconstriction. In this setting, calcium channel blockers which lower systemic blood pressure in combination with afferent arteriolar vasodilatation may improve long-term allograft outcome. New strategies with a similar rationale include endothelin receptor antagonists and neutral endopeptidase inhibitors such as candoxatril, which in acute experimental and clinical studies reverse cyclosporine-induced reductions in renal blood flow and glomerular filtration rate. Long-term prospective controlled comparative studies are needed to assess the effect of all these differing therapeutic approaches on chronic allograft outcome.
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PMID:Does antihypertensive therapy modify chronic allograft failure? 858 70

Treadmill exercise testing is the most important risk-stratifying technique, because of its ability to assess residual ischemia, left ventricular dysfunction, and a tendency toward arrhythmias. Cessation of smoking is the most important lifestyle change. Among prophylactic medications, aspirin can be considered for most patients, beta-blockers for many, and ACE inhibitors for some.
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PMID:Management after a first myocardial infarction. 863 43

Magnesium sulphate has antiarrhythmic and antithrombotic properties, a coronary and systemic vasodilating action, a direct myocardial protective effect in experimental and clinical models of ischemia-reperfusion injury. Two meta-analyses have pooled the results of several small studies that had analyzed the effect of controlled hypermagnesiemia in acute myocardial infarction before the advent of thrombolytic and antithrombotic therapies. The results have shown a more than 50% mortality reduction, with a minimum estimated benefit of about 30%, and a reduction in ventricular arrhythmias of about 50%. In LIMIT-2, a double-blind trial of 2,316 patients where magnesium was administered as a 8 mMol bolus followed by a 24-hour infusion of 65 mMol, a 24% reduction in mortality was observed. However, these data have not been confirmed in the more than 58,000 patients of the ISIS-4 trial. In this study magnesium, at the same dose of the LIMIT trial, did not reduce 5-week mortality, neither in the general population (7.64% versus 7.24% in control patients, p = n.s.) nor in specific subgroups. The results of ISIS-4 have excluded the routine use of magnesium sulphate in acute myocardial infarction in the era of fibrinolysis and aspirin, beta-blockers and ACE-inhibitors. Nevertheless, magnesium administration could still be considered in certain clinical situations, such as 1) the presence of contraindications to fibrinolysis and aspirin, 2) the treatment of ventricular tachyarrhythmias unresponsive (or as an alternative) to lidocaine, 3) severe hypertension when beta-blockers are not indicated.
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PMID:[Magnesium sulfate in acute myocardial infarction]. 868 39

Myocardial infarction represents a crossroads in the natural history of coronary artery disease. The prognosis is determined by the severity of coronary artery disease, infarct size (and hence ejection fraction), and age of the patient. After infarction, patients may remain symptomless, or suffer angina, silent ischemia, reinfarction, heart failure or sudden death. Hence patient management after infarction includes (1) estimation of risk, (2) the use of stress tests to detect ischemia and rhythm disorders, (3) PTCA or bypass if required and (4) medical therapy. Cardiac catheterization is indicated in patients with angina or silent ischemia, non-Q wave infarction or large infarctus; its use is less well established in patients without ischemia and left ventricular dysfunction, but this indication is nevertheless increasingly accepted. PTCA is primarily utilized in patients with single or two vessel disease, while coronary bypass surgery is indicated in patients with left main or three vessel disease. All these measures are designed to improve symptoms and prognosis. For secondary prevention medical therapy should be used to treat cardiovascular risk factors (antihypertensive drugs, lipid-lowering drugs etc.), to inhibit platelets (aspirin, ticlopidine) or coagulation (coumarins), to block neurohumoral activation (betablocker, ACE-inhibitors), for vasoconstriction (calcium channel blockers, nitrates) and to suppress arrhythmias. The large number of drugs requires reasoned use depending on the risk profile of the individual patient. Cardiovascular risk factors should be treated appropriately. Platelet inhibitors should be given to all patients except those with atrial fibrillation or large ventricles (coumarins). Betablockers reduce mortality, reinfarction and sudden death after infarction and hence should be used if no contraindications exist. ACE-inhibitors are particularly effective in improving symptoms and prognosis in patients with impaired left ventricular function. Calcium antagonists should be used with caution and only in patients with normal left ventricular function. Nitrates are primarily effective in improving symptoms in patients with angina or heart failure. Antiarrhythmic drugs (amiodarone) are only useful in patients with complex arrhythmias. Digitalis has been shown to improve symptoms in patients with heart failure, while other inotropic drugs are virtually no longer used. These guidelines allow reasoned differential therapy after myocardial infarction to the maximum benefit of the patient and at minimum cost.
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PMID:[Therapeutic measures following acute myocardial infarct: differential use of PTCA, surgery and drugs]. 868 87

Periods of ischemia followed by reperfusion of the ischemic tissue are associated with myocardial damage and ventricular arrhythmia. Angiotensin converting enzyme inhibitors limit the occurrence of these arrhythmias. The protective effects of angiotensin converting enzyme inhibitors may be due to inhibition of bradykinin (BK) degradation, rather than inhibition of angiotensin II formation. Other enzymes which catabolize BK include the endopeptidases EP24.11 and EP24.15. The purpose of this study was to determine if inhibitors of EP24.11 and EP24.15 decrease ischemia/reperfusion injury and if this protection is mediated by BK receptors. Rabbits were anesthetized and prepared for recording of cardiovascular parameters. The chest was opened and a left ventricular artery occluded for 30 min, followed by a 2-hr reperfusion period. Infarct size was determined using triphenyl tetrazolium chloride staining immediately after reperfusion. The enzyme inhibitors, ramiprilat, N-[1-(R,S)-carboxy-3-phenylpropyl]-Phe-pAB, and N[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-pAb, singly and in combinations were administered 3 min before reperfusion. Compared to saline (32.1 +/- 2.1), ramiprilat (18.3 +/- 2.8) and the EP inhibitors (14.4 +/- 1.4 for the combination) significantly decreased infarct size, with the greatest decrease occurring when all three inhibitors were combined (10.6 +/- 1.5). The protective effect of the EP inhibitors was blocked by the BK2 receptor antagonist, HOE 140 (30.1 +/- 2.6). Enzyme assays demonstrated EP24.11 and EP24.15 in the rabbit heart. We conclude that the EP inhibitors decreased ischemia/reperfusion injury by protecting BK from metabolism and that a combination of inhibitors provides superior protection to that given by a single agent.
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PMID:Endopeptidase inhibitors decrease myocardial ischemia/reperfusion injury in an in vivo rabbit model. 881 83

Growing evidence points to the existence of the components of the kallikrein-kinin-system (KKS) in cardiac and vascular tissue forming systemic and local KKS pathways involving different cell types like endothelial cells, cardiomyocytes and vascular smooth muscle cells. Kinins may contribute to the regulation of the cardiovascular system in health and disease and to the pharmacological effects of cardiovascular agents via autocrine-paracrine mechanisms. Based on observations from experimental models of hypertension, hypertrophy, ischemia, remodelling and preconditioning one can assume that modulation of local KKS pathways is instrumental for endogenous cardio- and vasculoprotective mechanisms. The role of kinins as possible mediators of such protective mechanisms is not only based on the existence of their generating pathways and their release, but also on observations that kinins, when given locally or being increased by inhibition of their breakdown, exert beneficial cardiovascular effects, whereas antagonism of their receptors worsens these effects. Indispensable pharmacological tools like ACE inhibitors and kinin receptor antagonists have helped to clarify these assumptions, which are now further elucidated by molecular biology and by clinical research. Especially the wealth of experimental and clinical findings with ACE inhibitors present a continuous challenge to investigate the role of kinins in the cardiovascular system and to have a closer look at the interdependence of KKS and the Renin-Angiotensin-System (RAS). Within our decade one might not only reach a clearer molecular perception of kinins in the cardiovascular system, and their role in human health and disease, but might also come to improved innovative treatment by modulation of the KKS pathways.
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PMID:Kinins in the cardiovascular system. 885 52

The aim of this study was to evaluate the prevalence of renal artery stenosis in patients with clinical signs of peripheral vascular disease and hypertension. One hundred patients, mean age 69 years (range 45-88) with symptoms and clinical signs of severe peripheral ischemia, underwent aortography to determine the degree of peripheral vascular disease and possible renal artery stenosis. History of claudication, and measurement of systolic distal blood pressure (BP) and calculation of the Ankle Brachial Index was used to define the severity of peripheral vascular disease. A total of 31% had renal artery stenosis (14% greater than 50% reduction in luminal diameter). In a subgroup of patients with hypertension and peripheral vascular disease (n = 74), 34% had renal artery stenosis. In the subgroup of patients with renal artery stenosis, 81% have hypertension. Patients with renal artery stenosis and lumen reduction of more than 50%, 93% have hypertension (P < or = 0.001). In conclusion this study shows that the combination of peripheral vascular disease and hypertension is an important clinical clue for renovascular disease. Examination for reno-vascular disease in this population should be considered, since the prevalence of the condition is high. Furthermore examination for renal vascular disease in this population is mandatory, before treatment with angiotensin converting enzyme (ACE) inhibitors is initiated, since treatment might lead to serious renal function impairment.
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PMID:Prevalence of renal artery stenosis in patients with peripheral vascular disease and hypertension. 886 60

We studied the effects of angiotensin-converting enzyme (ACE)/kininase II inhibition selectively in the ischemic zone on reperfusion arrhythmias, and the role of bradykinin versus angiotensin II (produced locally in this zone) in modulating the severity of such arrhythmias. Isolated rat hearts (n = 12 per group) were subjected to independent perfusion of left and right coronary beds. The left coronary bed received the ACE/kininase II inhibitor ramiprilat, alone or in combination with either HOE140 (bradykinin B2 receptor antagonist) or angiotensin II, before induction of regional ischemia (10 min) by discontinuation of flow to the bed. Ramiprilat (1, 10, or 100 nM) did not significantly alter the incidence of reperfusion-induced ventricular tachycardia (VT) or fibrillation (VF), but reduced the incidence of sustained VF from 83% in controls to 75, 50, and 25% (p < 0.05). The protective effects of 100 nM ramiprilat were abolished by coinfusion of HOE140 (10 or 100 nM) but not affected by coinfusion of angiotensin II (1 nM). HOE140 (10 nM), when infused alone into the left coronary bed before 7-min ischemia, increased the incidence of sustained VF from 42 to 100% (p < 0.05). Although HOE140 caused vasoconstriction in the left coronary bed when given alone or in combination with ramiprilat, its proarrhythmic effects were not due to a reduction of flow to the bed. We conclude that selective inhibition of ACE/kininase II in the ischemic zone moderately attenuates reperfusion arrhythmias and that enhanced bradykinin availability rather than reduced angiotensin II in synthesis contributes to such an effect.
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PMID:Attenuation of reperfusion arrhythmias by selective inhibition of angiotensin-converting enzyme/kininase II in the ischemic zone: mediated by endogenous bradykinin? 890 6


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