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)

Organic nitrates are widely used in the treatment of ischemic heart disease. The magnitude and duration of their circulatory and ischemic effects are, however, rapidly reduced during continuous treatment. The specific mechanisms underlying this tolerance development are not clear. According to the most widely accepted theory, tolerance is due to an intracellular depletion of thiol compounds (GSH and/or cysteine) involved in the conversion of nitrates to vasoactive intermediates. This presentation deals with aspects of in vivo thiol/nitrate interactions in different experimental and clinical conditions. The major results and conclusions are: The acute hypotensive effect of NTG is decreased by lowering of intracellular GSH levels. This finding emphasizes that normal intracellular thiol levels are required for optimal conversion of nitrates. Thus, intracellular GSH plays a critical role in the metabolism of NTG. Despite development of tolerance to the hypotensive effect of NTG, arterial and venous thiol levels are similar in nitrate tolerant and non-tolerant animals, suggesting that depletion of vascular thiol compounds may not be the cause of nitrate tolerance in vivo. The effect of exogenous thiol administration on intravascular thiol levels are different in nitrate tolerant and non-tolerant conscious rats. Exogenous thiol compounds (e.g. NAC) augments the hypotensive effect of NTG by a tolerance nonspecific mechanism. This effect is most likely mediated by an extracellular and/or membrane-related nitrate/thiol interaction and formation of NO. N-acetylcysteine inhibits angiotensin converting enzyme and counteracts nitrate-induced stimulation of the renin angiotensin system in vivo. Therefore, in addition to an effect on nitrate metabolism, thiol compounds may modify tolerance development by attenuating nitrate-induced counter-regulatory mechanisms. In the clinical setting, co-administration of NAC and ISDN delays and partially prevents tolerance to the antianginal and antiischemic effects normally seen in patients with stable angina pectoris during treatment with ISDN. N-acetylcysteine treatment in humans, potentiates and preserves nitrate induced venodilation and augments the effect of nitrates on small resistance vessels without affecting the response to nitrates in larger sized arteries. Thus, administration of NAC may change the normal vasodilator profile of nitrates. In conclusion, changes in cellular thiol levels may modify the hemodynamic effect of organic nitrates and the cellular handling of thiols and/or thiol related enzymes is altered after development of nitrate tolerance. In addition, a tolerance unrelated thiol/nitrate interaction, potentiating the effect of nitrates, may occur after administration of exogenous thiol compounds. In the clinical setting administration of thiols results in a characteristic change in the vasodilator profile of nitrates and an attenuation of the nitrate-induced stimulation of the renin-angiotensin system. The combination of these effects probably contributes to the improvement in antianginal and antiischemic parameters which may be seen during continuous and prolonged treatment with nitrates and thiol compounds.
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PMID:Thiol compounds and organic nitrates. 874 3

The 4 major classes of antihypertensive drugs are diuretics, beta-blockers, ACE inhibitors and calcium antagonists. The diuretics have recently regained prominence, largely due to the results of recent controlled trials. These trials in elderly patients demonstrated that low-dose diuretics were effective not only in preventing stroke but also in greatly reducing coronary-related events. Diuretics also decrease left ventricular mass more than the other major drug classes. In addition, they are the most effective drugs for use in combination therapy. By contrast, the safety of calcium antagonists has recently been questioned because of report of increased coronary morbidity and mortality. However, these adverse events may be restricted to the short-acting preparations, especially nifedipine, which causes cardiac stimulation. ACE inhibitors, like beta-blockers, are not only effective in reducing blood pressure, particularly when combined with a diuretic, but also improve angina and decrease postinfarction mortality. They also benefit congestive heart failure, stabilise or improve renal function in hypertensive and diabetic nephropathy and reduce albuminuria. Beta-Blockers are especially effective in reducing sudden cardiac death in patients with coronary heart disease, particularly in postinfarction patients. Final proof of the relative effectiveness of these drugs in preventing morbidity and mortality must await the outcome of large comparative trials currently under way. A recent national survey in the US found that more than 75% of hypertensive patients did not have their hypertension completely controlled. Possible reasons for this disturbing statistic are discussed along with suggestions for improvement.
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PMID:Current drug treatment and treatment patterns with antihypertensive drugs. 879 81

ACE inhibitors have the potential to affect myocardial ischaemia in patients with asymptomatic ventricular dysfunction and ischaemic cardiomyopathy after long-term treatment. However, anti-ischaemic effects are virtually absent in stable effort angina during short-term therapy, which suggests different mechanisms of action in different patient subtypes. Long-term treatment in left ventricular dysfunction may lead to a reduction in myocardial oxygen demand and ischaemia as a result of ventricular remodelling, possibly supported by structural coronary vascular effects, i.e., an improved endothelial function and vasodilator capacity. An alternative mechanism by which ACE inhibitors may affect ischaemia, is through modulation of ischaemia-induced neurohormonal activation and subsequent systemic vasoconstriction. Depending on the severity of ischaemia, pronounced catecholamine activation and stimulation of the circulating renin-angiotensin system occur, accompanied by systemic vasoconstriction and an increase in afterload. These changes are marked in patients with left ventricular dysfunction. Moreover, a change from net catecholamine release to uptake in the ischaemic area is observed. Although the clinical significance of the latter observation is still unclear, sympathetic activation may lead to coronary vasoconstriction in stenotic areas where normal endothelium-dependent coronary vasodilatation has become impaired. In the resting patient, enalaprilat and perindoprilat significantly reduce myocardial ischaemia, not by a direct effect on the oxygen supply-demand ratio, but through modulation of neurohormonal activation, in particular of sympathetic activation during ischaemia, and, subsequently, by preventing systemic vasoconstriction. These effects are pronounced in left ventricular dysfunction, at least where perindoprilat is concerned. The possibility that ACE inhibitors improve endothelial function in concert with their modulating effects on ischaemia-induced neurohormonal activation and hence influence the occurrence of myocardial ischemia during long-term treatment needs further evaluation.
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PMID:Anti-ischaemic effects of converting enzyme inhibitors: underlying mechanisms and future prospects. 882 63

The D allele of an insertion/deletion (I/D) polymorphism in the angiotensin I-converting enzyme (ACE) gene is associated with a risk of myocardial infarction, and the relative risk associated with the ACE D allele is increased by the C allele of an angiotensin II type 1 receptor (AT1R) gene polymorphism (an A-->C transversion at nucleotide position 1166) [28]. The relation of the ACE and AT1R gene polymorphisms to coronary heart disease and the severity of coronary artery stenosis has now been investigated in 133 patients with myocardial infarction (MI) or angina pectoris who underwent coronary angiography and in 258 control subjects. The frequency of the ACE DD genotype as compared with non-DD was significantly higher in the patients who experienced an MI and in the low-risk patients than that in the controls (P < 0.05). The DD genotype showed a significantly increased risk of MI (odds ratio 1.85). The frequency of the AT1R A/C genotypes did not differ between the patients and the controls. The severity of coronary stenosis in the patients was estimated by the number of affected vessels (> 75% stenosis) and the coronary score of Gensini. Neither the number of affected vessels nor the coronary score differed among the ACE I/D genotypes. However, the number of affected vessels was significantly greater in patients with the AT1R AC genotype than in those with the 4A genotype (1.93 +/- 0.27 vs. 1.27 +/- 0.99; P < 0.05) (CC genotype was not found in the patients). After excluding patients with diabetes mellitus, the coronary score of those with the AC genotype was also significantly higher than in those with the AA genotype (51.7 +/- 34.4 vs. 18.2 +/- 23.3; P < 0.01). These results suggest that the ACE D allele is associated with the occurrence of myocardial infarction, while the AT1R C allele is involved in the development of the coronary artery stenosis.
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PMID:Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease. 884 48

Calcium antagonists are well accepted in the prevention of ischaemia in patients with chronic stable angina, unstable angina, variant angina, and silent ischaemia, and in the treatment of hypertension. Although all of these compounds increase myocardial oxygen supply by reducing coronary tone and decrease myocardial oxygen demand by reducing systolic pressure and myocardial contractility, the magnitude of these effects may differ from one agent to another. Some calcium antagonists, such as verapamil and diltiazem, reduce heart rate and attenuate heart rate increases in response to stress, while in contrast, dihydropyridine calcium antagonists such as nifedipine may cause reflex increases in heart rate. These differences may be of importance in light of epidemiologic evidence that lower heart rates are associated with a reduced long-term risk of cardiovascular mortality, and experimental data showing that a lower heart rate may protect against the development of atherosclerosis. Calcium antagonists also inhibit platelet aggregation and thrombus formation which may contribute to their anti-ischaemic effects. Clinical trial data suggest that calcium antagonists may stay the progression of atherosclerosis. Mechanisms underlying an anti-atherosclerotic effect may include attenuation of endothelial dysfunction, prevention of LDL, peroxidation, stimulation of LDL receptor activity, inhibition of superoxide radical generation, and inhibition of vascular smooth muscle cell growth. Heart-rate-controlling calcium antagonists, such as verapamil and diltiazem, may reduce reinfarction rates following acute myocardial infarction and thus may have a role in post-infarction patients who do not show evidence of heart failure. Their use in heart failure patients receiving an angiotension-converting enzyme inhibitor (ACE-I) is under investigation in several large trials. Because calcium antagonists have a mechanism of action different from ACE-I, the pairing of a heart-rate-controlling calcium antagonist with an ACE-I might be expected to offer additive cardioprotective and vascular protective effects.
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PMID:The role of calcium antagonists in ischaemic heart disease. 884 1

Hypertension is one of the most important cardiovascular risk factors. Without therapy hypertension leads to stroke, coronary heart disease with angina pectoris and myocardial infarction, kidney failure and/or peripheral vascular disease. The association between blood pressure and these cardiovascular complications can be demonstrated over the entire blood pressure range. The risk of stroke, myocardial infarction, renal failure or peripheral vascular disease increases with increasing blood pressure. Additional cardiovascular risk factors such as hyperlipidemia, smoking and diabetes involve a further increase in risk. Today hypertension can be effectively treated. To that end, diuretics, betablockers, ACE-inhibitors or calcium antagonists can be used. Alpha receptor antagonists and angiotensin AT1 receptor antagonists are also of value. The antihypertensive effectiveness of these drugs is comparable but may vary in individual patients. During antihypertensive therapy, a reduction in cerebrovascular and cardiac complications has been demonstrated for alpha methyldopa, diuretics and betablockers. In these studies, fatal and non-fatal strokes were reduced by 42%, while the reduction in cardiac events was less pronounced (14%). The reasons for this greater efficacy of antihypertensive therapy in the cerebral circulation are not clear. Other risk factors may be particularly important in the pathogenesis of coronary artery disease (e.g. genetic factors, hyperlipidemia and others) or hypertensive vascular changes in the coronary circulation may not be as reversible as they are in the cerebral circulation. The well documented correlation between stroke, myocardial infarction and hypertension, as well as the proven efficacy of antihypertensive therapy in preventing cardiovascular events, underscores the importance of effective and sustained blood pressure control in these patients.
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PMID:[Heart, brain and hypertension]. 884 9

Circadian rhythms in the functions of the body are well established, e.g. in cardiovascular (blood pressure, heart rate, blood flow, etc.), pulmonary, hepatic and renal functions. Also the symptoms and the onset of diseases are not randomly distributed within 24 hours of a day (e.g. coronary infarction, angina pectoris attacks, silent ischaemia, asthmatic attacks). Accordingly, the effects and/or pharmacokinetics of drugs can display significant daily variations. Recent data on the chronopharmacodynamics and chronopharmacokinetics of H2-blockers, antiasthmatics (theophylline, beta-agonists, glucocorticoids), cardiovascular active drugs (beta-blockers, organic nitrates, calcium channel blockers, ACE-inhibitors) are described as representative examples. The data demonstrate that biological rhythms can have an impact on drug therapy.
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PMID:The clinical relevance of chronopharmacology in therapeutics. 887 25

Besides the thrombolytic therapy several adjuvant therapeutic measures were identified which significantly improve the prognosis of patients with acute myocardial infarction (AMI). These measures include the treatment by means of acetylsalicylic acid (ASA), beta-blockers and ACE inhibitors. Early administration of ASA and beta-blockers are indicated in all patients with AMI who have no contraindications for this therapy. They are especially the patients with manifest heart failure or asymptomatic left ventricular dysfunction who benefit from ACE inhibitors. The effectivity of routine administration of other medicaments such as anticoagulants, nitrates, calcium channel blockers and magnesium, have not been convincingly proved. However, some selected patients with AMI can benefit from these medicaments. Intravenous administration of heparin is unambiguously justified only in thrombolysis with t-PA. Thrombolyses with streptokinase, urokinase, and anistreplase are justified only at high risk of thromboembolic complications. Their prevention and therapy include also the necessity to restrict the administration of pelentan. The use of nitrates is indicated in patients with AMI in case of sustaining stenocardia, arterial hypertension and manifest heart left ventricular failure. Until the definitive standpoint is gained regarding the effect of magnesium in patients with AIM, its administration remains especially indicated in cases of arterial hypertension, tachycardiac disturbances of the heart rhythm and states of assumed or proved hypomagnesiemia. In AMI cases when magnesium is used in order to protect the patient from reperfusion lesion, it must be administered prior to the reperfusion therapy. An intensive research in the field of therapeutical measures in patients with AMI still continues. It is certain that it will soon bring further knowledge which will in turn improve the prognosis and quality of life of patients with AMI. (Tab. 4, Ref. 133.)
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PMID:[Adjuvant therapy in patients with acute myocardial infarct]. 892 11

This review summarizes the results of several pharmacological interventions that have been evaluated in the management of acute myocardial infarction. Of these, thrombolytic therapy, aspirin, beta-blockers and angiotensin converting enzyme inhibitors have all been proven to reduce mortality risk and the latter three classes of drugs have also been shown to reduce morbidity. Routine use of heparin or nitrates is not recommended although they may be useful in specific circumstances such as post-infarction angina or large infarcts. Drugs that have as yet not been shown to have a role in the routine management of acute myocardial infarction include Class I antiarrhythmic agents, magnesium and calcium antagonists. Management of patients with acute myocardial infarction can now be appropriately based on the evidence generated from well conducted randomized clinical trials and appropriate therapeutic choices based on such information can be expected to reduce their morbidity and mortality risks.
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PMID:Treatment for acute myocardial infarction. Overview of randomized clinical trials. 896 Apr 44

Angina with left ventricular dysfunction exhibits a wide range of different presentations. Approximately 45% of patients referred for coronary artery bypass surgery have some degree of left ventricular dysfunction and, given that at least a third of those suffering from angina have a history of myocardial infarction, the prevalence of left ventricular dysfunction in such patients is likely to be substantial. The major prognostic factor in patients with coronary artery disease is the degree of left ventricular function and it is important to identify those with poor or reduced left ventricular function. High-risk patients, defined by exercise testing and echocardiography, should be considered for revascularization. For the majority of patients management should be medical, consisting of nitrates plus a beta-blocker or calcium antagonist. In severe ischaemia, the combination of these agents has been shown to provide additional efficacy. In patients with heart failure the newer calcium antagonist amlodipine has been shown to have a neutral effect upon survival, indicating that it may be used safely in patients with angina and left ventricular dysfunction. Progression of left ventricular dysfunction may be slowed through the use of angiotensin converting enzyme (ACE) inhibitors, which have also been shown to improve survival, although they should be used with caution, since there is evidence that ACE inhibitors may worsen angina in some patients.
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PMID:Angina and left ventricular dysfunction. 896 Apr 48


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