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)

Oxygen radicals and reactive oxygen species (ROS) are known to be generated in large amounts under inflammatory conditions and in the first few minutes of postischemic organ reperfusion. Due to the interaction of ROS with nitric oxide (NO), formed constitutively by endothelial cells, two alternatives are feasible. On the one hand, reaction with superoxide radicals may induce toxification (formation of peroxynitrite), and, on the other hand, by reacting with superoxide and hydroxyl radicals, NO can serve as a radical scavenger (formation of the innocuous anions, nitrate and nitrite, respectively). However, NO is considered to play a pivotal role in numerous physiological and pathophysiological processes, with effects arising from both lack and surfeit of this easily diffusible and chemically very reactive molecule. Physiologic contributions to vascular dilatation and inhibition of platelet and leukocyte activation, e.g., are infringed by enhanced inactivation of NO. Such inactivation occurs readily due to spontaneous reaction of NO with the superoxide radical, formed, e.g., by stressed endothelial cells and activated leukocytes. Conversely, overproduction of NO by induced NO synthase (iNOS) may lead to circulatory shock, cell apoptosis or even cell necrosis. Caution would, thus, seem to be warranted when attempting to interfere with homeostasis of NO. We have investigated the ability of NO to act as a radical scavenger during myocardial reperfusion in experimental and clinical settings. In the former, inhibition of angiotensin converting enzyme was employed to generate more endogenous NO (via bradykinin), in the latter, low-dose sodium nitroprusside was used as the donor of exogenous NO in patients undergoing coronary bypass grafting. Inhibition of leukocyte adhesion, attenuation of platelet activation and mitigation of redox-stress and inflammation were observed in both instances. Accordingly, modest enhancement of NO levels should afford cardioprotection during reperfusion.
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PMID:Reactive oxygen species and nitric oxide in myocardial ischemia and reperfusion. 1115 3

Omapatrilat represents a new class of drugs capable of inhibiting both ACE and neutral endopeptidase 24.11, the so-called vasopeptidase inhibitors. It therefore contributes to neurohumoral modulation, which might improve endothelial function in cardiovascular diseases. This study investigated the effect of omapatrilat in comparison to the ACE inhibitor captopril on systolic blood pressure and endothelial function in salt-induced hypertension. Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36+/-4 mg/kg per day), captopril (94+/-2 mg/kg per day), or placebo. Aortic rings were then isolated and suspended in organ chambers for isometric tension recording. Systolic blood pressure of salt-fed, placebo-treated animals increased to 196+/-6 mm Hg, which was prevented by omapatrilat (162+/-5 mm Hg, P<0.05) and captopril (164+/-7 mm Hg, P<0.05) to a comparable degree. In control rats, acetylcholine (10(-10) to 10(-5) mol/L) induced endothelium-dependent relaxation (97+/-4%), which was reduced by high-salt diet to 30+/-5% (P<0.005; n=6). Omapatrilat improved relaxation to a greater extent (86+/-5%) than did captopril (57+/-6%; P<0.05). eNOS protein expression and aortic nitrite/nitrate content were reduced in hypertensive rats and improved by both omapatrilat and captopril. Aortic endothelin-1 levels were increased in salt-fed animals and unaffected by omapatrilat or captopril. These data suggest that despite comparable blood pressure, omapatrilat is superior to captopril in improving endothelium-dependent relaxation in salt-sensitive hypertension.
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PMID:Vasopeptidase inhibition exhibits endothelial protection in salt-induced hypertension. 1130 11

The increase of radical forms of mitochondrial respiratory chain compounds (MRCC) is an indicator of an increased risk of the formation of oxygen radicals. Using electron paramagnetic resonance (EPR), we found an increase of signals corresponding to ubisemichinone radical (.QH) and ironsulfur proteins radical forms (-FeS) of these respiratory chain compounds during ischemia in the isolated perfused rat heart (.QH increased from 1.51 to 3.08, .FeS1 from 1.14 to 2.65 arbitrary units). During the 5-min reperfusion, the signals returned to normoxic levels. In isolated mitochondria exposed to anoxia and reoxygenation the radical forms of .QH and FeS2 changed in a similar manner as in the intact heart. A combination of in vivo captopril treatment and in vitro L-arginine administration significantly decreased the levels of MRCC radicals in the isolated myocardium (.QH from 2.61 to 1.72 and .FeS, from 1.82 to 0.46 under normoxia; .QH from 4.35 to 2.66 and .FeS1 from 1.93 to 1.35 during ischemia). This decrease in MRCC radical forms was associated with increased NO levels in the perfusate, determined as NO2- / NO3-, as well as tissue NO levels determined using EPR as the dinitrosyl iron complex (DNIC). These results provide new information about the cardioprotective effects of ACE inhibitors and L-arginine.
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PMID:The effect of captopril on nitric oxide formation and on generation of radical forms of mitochondrial respiratory chain compounds in ischemic rat heart. 1170 52

Aqueous solutions containing 100 to 1000 mg/L of 2,4-dichlorophenol (2,4-DCP) were oxidized in an upflowing fixed-bed reactor in this study of manganese-cerium composite catalysts, which were prepared by the coprecipitation of both manganese nitrate and ceric nitrate at various molar concentrations. Results showed that 2,4-DCP conversion by wet oxidation in the presence of the manganese-cerium composite catalysts was a function of the molar ratio of the manganese-cerium catalyst. The kinetic behavior of 2,4-DCP oxidation with catalysis could be explained by using a zero-order rate expression. Total organic carbon (TOC) removal by wet oxidation in the absence of any catalyst was nil, while approximately 68% TOC reduction was achieved during wet oxidation over a manganese-cerium (7:3 mol/mol) catalyst at 160 degrees C and an oxygen partial pressure of 1.0 MPa. Moreover, the 5-day biochemical oxygen demand/chemical oxygen demand ratios of all the effluent streams were determined to be greater than 0.45 as the wet catalytic processes were carried out at a liquid hourly space velocity less than 24 h (-1), indicating that they could be made more amenable to further biological treatment.
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PMID:Catalytic wet oxidation of 2,4-dichlorophenol solutions: activity of the manganese-cerium composite catalyst and biodegradability of the effluent stream. 1199 64

Clinical trials provide average effects of interventions but are not powered to identify differences in subgroup responses. African-Americans have been under-represented in most previous trials in patients with heart failure. Furthermore, physiologic differences have been demonstrated between African-Americans and whites in the mechanisms and response to therapy in hypertension. Review of previous heart failure trials reveals that African-Americans exhibit less benefit than whites from ACE inhibitors, angiotensin receptor blockers, and at least one b-blocker. In contrast, black patients experienced a greater benefit than white patients from the combination of nitrate and hydralazine. These data emphasize the need for trials in black patients to identify effective therapy. The first such trial, African-American Heart Failure Trial, is currently underway.
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PMID:Contemporary treatment of heart failure: is there adequate evidence to support a unique strategy for African-Americans? Pro position. 1211 58

The elderly patient may show normal physiological changes of the cardiovascular and respiratory systems that accompany aging, as well as features of intrinsic cardiac disease. The latter include: a past history of myocardial infarction or ischaemic heart disease; history of congestive cardiac failure; angina; arterial hypertension (BP >140/90mm Hg); and conduction disorders. A key aspect to the safe and effective anaesthetic management of the elderly patient with cardiac disease is a careful preoperative assessment and optimisation of pre-existing drug therapies. All cardiac medications should be continued up to and including the morning of surgery with the exception of anticoagulation involving warfarin, and perhaps large doses of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in patients with hypertension or heart failure. Anaesthetic techniques used in these patients should avoid episodes of excessive hypotension after induction of anaesthesia or large blood loss, or the combination of hypertension and tachycardia after noxious stimulation. The latter physiological disturbances are pivotal for the development of myocardial ischaemia. Both premedication (if used) and anaesthesia should avoid excessive sedation and respiratory depression. The choice of anaesthetic technique may vary between: a balanced technique involving an opiate and a volatile agent; an intravenous technique utilising infusions of propofol; or regional anaesthesia with or without additional sedation. There are no good data to suggest any one technique is better than the rest. The occurrence of ischaemia in the perioperative period may precede the postoperative development of significant cardiac morbidity and mortality (including myocardial infarction or unstable angina, congestive cardiac failure, cerebrovascular accidents, and severe arrhythmias). A number of strategies have been examined to reduce these adverse outcomes. The effect of acute beta-adrenoceptor blockade in treatment-naive patients is associated with reduction in the haemodynamic response to noxious stimuli and decreased ECG evidence of myocardial ischaemia, as well as a reduction in the number of cardiac adverse events. Other drugs (calcium channel antagonists, alpha(2)-agonists and adenosine modulators) have a less predictable influence on both myocardial ischaemia and hard cardiac outcomes. There is inadequate evidence at present to define the optimal time course for acute beta-blockade, or the groups of patients in whom preoperative beta-blockade should be initiated in the absence of contraindications. Nevertheless, addition of beta-blockers to the preoperative regimen should be considered in patients with evidence of or at risk for coronary disease undergoing major surgery. There is also evidence that long-term beta-adrenoceptor or calcium channel blockade or nitrate therapy for the high-risk cardiac patient offers little protection against silent myocardial ischaemia, nonfatal infarction, cardiac failure and cardiac death.
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PMID:Issues in the perioperative management of the elderly patient with cardiovascular disease. 1214 50

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted due to the development of nitrate tolerance. With initiation of nitroglycerin therapy one can detect neurohormonal activation and signs for intravascular volume expansion. These so called pseudotolerance mechanisms may compromise nitroglycerin's vasodilatory effects. Long-term treatment with nitroglycerin is also associated with a decreased responsiveness of the vasculature to nitroglycerin's vasorelaxant potency suggesting changes in intrinsic mechanisms of the tolerant vasculature itself may also contribute to tolerance. More recent experimental work defined new mechanisms of tolerance such as increased vascular superoxide production and increased sensitivity to vasoconstrictors secondary to an activation of the intracellular second messenger protein kinase C. As potential superoxide producing enzymes, the NADPH oxidase and the nitric oxide synthase have been identified. Nitroglycerin-induced stimulation of oxygen-derived free radicals together with NO derived from nitroglycerin may lead to the formation of peroxynitrite, which may be responsible for the development of tolerance as well as for the development of cross tolerance to endothelium-dependent vasodilators. The oxidative stress concept of tolerance and cross tolerance may explain why radical scavengers such as vitamin C or substances which reduce oxidative stress, such as ACE-inhibitors, AT1 receptor blockers or folic acid, are able to beneficially influence both tolerance and nitroglycerin-induced endothelial dysfunction. New aspects concerning the role of oxidative stress in nitrate tolerance and nitrate induced endothelial dysfunction and the consequences for the NO/cyclicGMP downstream target, the cGMP-dependent protein kinase will be discussed.
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PMID:Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies. 1237 19

The present study was aimed at investigating whether the regulation of vascular renin-angiotensin and endothelin (ET) systems is altered by a chronic blockade of nitric oxide (NO) synthesis. Male Sprague-Dawley rats were supplemented with N(G)-nitro-L-arginine methyl ester (L-NAME, 100mgl(-1)) in drinking water for 4 weeks to inhibit the endogenous synthesis of NO. The mRNA expressions of renin, angiotensin converting enzyme (ACE), type-1 angiotensin II receptor (AT1R), ET-1, type-A ET receptor (ET(A)), and neutral endopeptidase (NEP) were determined in the thoracic aorta by reverse transcription-polymerase chain reaction. The treatment with L-NAME significantly increased the blood pressure, while it decreased the tissue levels of nitrite/nitrate. The mRNA expression of renin, ACE, and AT1R was increased in the aorta. The protein expression of AT1R assessed by Western blot analysis was also increased. The expression of ET-1 and ET(A) mRNA was increased, whereas that of NEP mRNA decreased. The increased expression of renin-angiotensin and ET system genes and the decreased expression of NEP may in part be causally related with the development of hypertension induced by a chronic blockade of NO synthesis.
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PMID:Upregulation of vascular renin-angiotensin and endothelin systems in rats inhibited of nitric oxide synthesis. 1241 41

Several recent studies have shown that essential hypertension is associated with increased oxidative stress, which may cause hypertension via enhanced oxidation and inactivation of nitric oxide. In this study, we investigated the malondialdehyde, nitric oxide, and glutathione levels in newly diagnosed essential hypertensive patients and whether or not there was any effect of antihypertensive treatment with angiotensin II type 1 receptor antagonist, losartan or angiotensin converting enzyme inhibitor, enalapril on plasma malondialdehyde, nitric oxide, and glutathione values. We selected 17 patients (F/M: 10/7, mean age: 46.12 +/- 9.2 years) for enalapril therapy (10-20 mg/d) and 14 patients (F/M: 8/6, mean age: 47.7 +/- 7.5 years) for losartan therapy (50-100 mg/d), and compared them with 12 normotensive controls. At the beginning of the study, both treated groups showed significantly higher plasma malondialdehyde and lower glutathione and nitric oxide in exhaled air compared to the control group. After 9 weeks of enalapril and losartan treatment, both systolic and diastolic pressure were significantly reduced. Both enalapril and losartan produced a significant decrease in plasma malondialdehyde and a significant increase in plasma glutathione levels and nitric oxide in exhaled air after 9 weeks. Initial values of plasma nitrate levels in patient groups were similar to the control group and increased significantly after the treatment period. In conclusion, both losartan and enalapril may be regulators between oxidant stress and the antioxidant system.
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PMID:The effects of losartan and enalapril therapies on the levels of nitric oxide, malondialdehyde, and glutathione in patients with essential hypertension. 1253 48

The aortic pulse wave contour in isolated systolic hypertension often shows a prominent reflection peak, which combines with the incident wave arising from cardiac ejection so as to widen pulse pressure. We investigated the effects of an extended-release nitrate preparation and of 2 angiotensin II (AII) inhibitors (an AII receptor antagonist and an ACE inhibitor) on the aortic pulse wave contour and systemic blood pressure in hypertensive subjects with high augmentation index caused by exaggerated pulse wave reflection. Two double-blind, randomized, placebo-controlled crossover studies were carried out in a total of 16 elderly patients with systolic hypertension resistant to conventional antihypertensive therapy. In 1 study, pharmacodynamic responses to single doses of placebo, isosorbide mononitrate, eprosartan, and captopril were determined; in the other, single-dose isosorbide mononitrate and placebo were compared in subjects treated with AII inhibitors at baseline. Blood pressure was measured by sphygmomanometry and pulse wave components by applanation tonometry at the radial artery. All 3 agents were shown to decrease brachial systolic blood pressure, aortic systolic blood pressure, and aortic pulse pressure. Qualitative effects on the aortic pulse wave contour differed: augmentation index was not significantly altered by either captopril or eprosartan but was decreased (P<0.0001) by approximately 50% of the placebo value with isosorbide mononitrate in both study groups. We propose that isosorbide mononitrate corrected the magnified wave reflection in systolic hypertension of these elderly patients by an effect that was distinct from that exercised by either acute or chronic AII inhibition.
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PMID:Effects of isosorbide mononitrate and AII inhibition on pulse wave reflection in hypertension. 1257 98


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