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 the present study, using the technique of EPR spin trapping with DMPO a spin trap, we demonstrated formation of thiyl radicals from thiol-containing angiotensin converting enzyme (ACE) inhibitor captopril (CAP) and from its stereoisomer epicaptopril (EPICAP), a non-ACE inhibitor, in the process of .OH radical scavenging. Splitting constants of DMPO/thiyl radical adducts were identical for both thiols and were aN = 15.3 G, and aH = 16.2 G. Bimolecular rate constants for the reaction of CAP and EPICAP with .OH radicals were close to a diffusion-controlled rate (approximately 2 x 10(10) M-1s-1). Our data also show that both CAP and EPICAP reduce Fe(III) ions and that their respective thiyl radicals are formed in this reaction. In the presence of Fe(III), H2O2, and CAP, or EPICAP, .OH radicals were produced by a thiol-driven Fenton mechanism. Copper(II) ions were also reduced by these thiols, but no thiyl radicals could be detected in these reactions, and no .OH or other Fenton oxidants were observed in the presence of H2O2. Our data show direct evidence that thiol groups of CAP and EPICAP are involved in scavenging of .OH radicals. The direct .OH radical scavenging, together with the reductive "repair" of other sites of .OH radical attack, may contribute to the known protective effect of CAP against ischemia/reperfusion-induced arrhythmias. The formation of reactive thiyl radicals in the reactions of the studied compounds with .OH radicals and with Fe(III) ions may play a role in some of the known adverse effects of CAP.
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PMID:Reactions of captopril and epicaptopril with transition metal ions and hydroxyl radicals: an EPR spectroscopy study. 813 87

Enhanced formation of radicals during post-ischemic reperfusion, foremost of superoxide (O2-) and hydroxyl (OH) radicals, has been directly and indirectly demonstrated in a number of tissues. However, the close chemical interrelationship of O2- and OH with other non-radical oxidants, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), makes it prudent to speak of reactive oxygen metabolites in conjunction with cell and organ dysfunction incurred by reperfusion. In the case of the heart, evidence for the causal involvement of such reactive molecular species includes (1) the increased formation of lipid peroxides, (2) the ability to mimic all facets of reperfusion injury (arrhythmias, contractile and vascular dysfunction, infarct extension) by exogenously applying reactive oxygen species, and (3) the propensity of a great variety of antioxidative and radical scavenging measures to afford cardioprotection during reperfusion. Potential sources of reactive oxygen metabolites in the reperfused heart are the mitochondrial redox-chain, endothelial enzymes such as cyclooxygenase, monoaminooxidase, NO-synthase and xanthine oxidase, and formed blood constituents (platelets, monocytes, granulocytes). According to our own results, adenosine, endogenously formed in the heart during ischemia, rapidly enhances adhesion of granulocytes introduced into the coronary system at reperfusion. Furthermore, small numbers of these cells suffice to induce contractile dysfunction in an isolated guinea pig heart model of ischemia-reperfusion injury, the major mediator of damage being HOCl. The striking disparity between the enormous volume of experimental data supporting involvement of reactive oxygen metabolites in reperfusion damage and the virtual lack of clinical-therapeutic regimens employing anti-oxidative measures is largely due to a still rudimentary knowledge of the homeostatic control of formation and removal of radicals and oxidants. In particular, the inability to correctly assess the individual time-course and extent of oxidative stress seems to be a major problem. Also, confounding issues such as compartmentation of radical formation as opposed to radical scavenging and the unwitting down-regulation of endogenous protective systems (e.g., of uric acid in the course of inhibiting xanthine oxidase) need to be resolved. On the other hand, we have been able to demonstrate protection by ACE inhibitors elicited via endothelially produced nitric oxide (a scavenger of O2- and OH) in the isolated heart. Thus, enhancement of endogenous protection may offer a perspective for mitigating against reperfusion damage.
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PMID:[Possible significance of free oxygen radicals for reperfusion injury]. 815 62

Necrosis of the femoral head and osteopenia were examined histopathologically in stroke-prone spontaneously hypertensive rats (SHRSPs) aged 6 to 36 weeks and compared with that of spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs). Avascular necrosis of the femoral head was frequently observed, mainly in the young SHRSPs and SHRs (about 8 to 15 weeks of age). SHRSPs had the highest incidence of femoral head necrosis among the three strains. This necrotic change in the femoral head was considered to be secondary ischemia induced by angiospasm or arteriosclerosis, similar to the disorders observed in the brain, kidney, and heart in SHRSPs. However, the complication occurred in spite of treatment with antihypertensive agents (ACE inhibitor: enalapril, spirapril) even though other ischemic disorders such as brain hemorrhage and renal infarction were prevented, indicating that the femoral head necrosis in SHRSPs was not due to hypertensive complications induced by angiospasm or arteriosclerosis. Bone mineral density (BMD) of the femoral bone was significantly lower in SHRSPs, and the femoral heads in this strain were the most easily deformed by loads applied during compression tests. Histopathologically, the infarctions were encountered on the lateral side of the epiphysis, but no thrombi were observed. The lateral side of the epiphysis is the anatomic site where the weight load is greatest and the site where the nutritive artery enters. Our results strongly suggest that the coexistence of vulnerable bone matrix and physical weight load to the nutritive artery plays a crucial role in the occurrence of femoral head necrosis in SHRSPs, whether based on generalized or localized osteopenia.
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PMID:Femoral head necrosis and osteopenia in stroke-prone spontaneously hypertensive rats (SHRSPs). 826 49

Coronary artery occlusion results in the acute activation of the renin-angiotensin system and production of angiotensin II, a potent vasoconstrictor and positive inotropic agent. This has raised the possibility that angiotensin converting enzyme (ACE) inhibitors might be "cardioprotective" (that is, might attenuate myocardial injury, dysfunction and necrosis) in the setting of acute ischemia and infarction. Captopril, enalapril and ramipril have, in fact, been reported to acutely limit myocardial injury and necrosis in models of permanent coronary artery occlusion. The mechanisms responsible for this cardioprotection are complex, but include favorable alterations in myocardial oxygen supply/demand, and, in some instances, inhibition of bradykinin metabolism and/or increased prostaglandin synthesis. Other studies, however, have failed to document a reduction in infarct size with ACE inhibitor treatment. Results obtained in models of coronary occlusion/reperfusion have also been mixed. In models of brief transient ischemia not associated with necrosis, captopril and zofenopril have consistently been found to attenuate postischemic contractile dysfunction of the viable but "stunned" myocardium during the early hours following relief of ischemia. In contrast, there is no consensus on the effects of enalapril on the stunned myocardium: both positive and negative results have been obtained. Similar disparity has been reported in models of more prolonged ischemia/reperfusion resulting in subendocardial necrosis: some studies have reported myocardial salvage, while others have provided disturbing evidence of apparent exacerbation of myocardial necrosis with captopril and enalapril therapy. Thus, after a decade of investigative effort, the question of whether ACE inhibitors are "cardioprotective" in the setting of acute myocardial ischemia and infarction remains unresolved. Nonetheless, clinical protocols are in progress to assess the effects of early ACE inhibitor treatment in patients with acute myocardial infarction.
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PMID:"Cardioprotection" by ACE-inhibitors in acute myocardial ischemia and infarction? 835 29

There are multiple mechanisms whereby ACE inhibitors could be beneficial during myocardial ischemia and reperfusion, including: i) reduced formation of angiotensin II, ii) decreased metabolism of bradykinin, iii) antioxidant activity, and iv) possibly other unknown mechanisms. Reduced formation of angiotensin II should be beneficial because this peptide exerts several actions that are potentially detrimental to the ischemic/reperfused myocardium, including vasoconstriction, increased release of norepinephrine, stimulation of phospholipase C and/or A2, and increased afterload with an attendant increase in oxygen demands. Reduced metabolism of bradykinin could be beneficial by increasing myocardial glucose uptake, by causing vasodilation, and by stimulating production of endothelium-derived relaxing factor and prostacyclin. Although earlier studies suggested that sulfhydryl-containing ACE inhibitors scavenge superoxide anions, recent data have shown that these drugs scavenge hydroxyl radical and hypochlorous acid with no effect on superoxide anion. Studies in isolated hearts have demonstrated that ACE inhibitors attenuate the metabolic, arrhythmic, and contractile dearrangements associated with ischemia and reperfusion, and have suggested that such beneficial effects are mediated by potentiation of bradykinin and/or increased synthesis of prostacyclin. Studies in models of myocardial stunning after brief (15-min) ischemia in vivo (anesthetized dogs) suggest that ACE inhibitors enhance the recovery of contractile function after a single brief ischemic episode. No data are available regarding the effect of these drugs on myocardial stunning after a prolonged, partly reversible episode, after multiple consecutive brief ischemic episodes, and after global ischemia. The mechanism for the salutary effects of ACE inhibitors on stunning remains a mystery. It may involve an antioxidant action (in the case of thiol-containing molecules) or potentiation of prostaglandins (in the case of non-thiol-containing molecules). What is clear is that the enhanced recovery of function effected by these drugs is not due to hemodynamic effects, inhibition of the converting enzyme per se, or an "antischemic" action (since the drugs were effective when given at the time of reperfusion). The effects of ACE inhibitors on myocardial infarct size remain controversial. Further studies will be necessary to conclusively establish whether ACE inhibitors can protect against the detrimental effects of myocardial ischemia and reperfusion. Nevertheless, the evidence provided thus far is encouraging and warrants an in-depth assessment of the role of these drugs in attenuating myocardial ischemia/reperfusion injury.
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PMID:Effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury: an overview. 835 31

Arterial hypertension is the most frequent cause of a disturbance of coronary microcirculation. Inspite of having normal epicardial coronary arteries, patients with arterial hypertension often have symptoms of angina pectoris and a positive exercise tolerance test. The angina pectoris-symptoms in patients with arterial hypertension are due to functional and structural alterations of the coronary microcirculation. Consequently, an antihypertensive therapy should not only aim at lowering blood pressure and reversing myocardial hypertrophy, but also improve coronary microcirculation in order to avoid the consequences of chronic ischemia on the myocardium. Until now, only experimental studies have indicated that antihypertensive therapy can improve coronary flow reserve. To determine to what extent under clinical conditions coronary flow reserve can be improved, in hypertensive patients maximal coronary blood flow, minimal coronary resistance, and coronary reserve (Dipyridamol) were studied before and after a long-term antihypertensive treatment (9-12 months) with the ACE-inhibitor enalapril (10-20 mg/d). To assess the chronic effects rather than the acute effects of the antihypertensive pharmacon, the coronary microcirculation was studied after intermission of medical therapy for a period of 1 week. Along with a decrease in LV muscle mass by about 8%, coronary reserve was improved after enalapril by 48%. It is likely that the observed increase in coronary reserve is related to the reversal of structural vascular abnormalities at the level of the coronary microcirculation. Consequently, it seems that reparation of hypertensive remodeling of the coronary microcirculation can be induced by ACE-inhibitor therapy.
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PMID:ACE-inhibitors and coronary microcirculation. 835 38

Among hypertensive patients, blacks are more likely than whites to have ischemia by electrocardiographic and 201Tl-myocardial stress imaging, possibly due to racial differences in the regulation of coronary blood flow or velocity. This investigation was undertaken to determine whether intensive antihypertensive therapy with two or more drugs can correct or reduce ischemia in black hypertensive patients. Thallium myocardial stress imaging and electrocardiographic and echocardiographic studies were performed on 13 black patients with essential hypertension and ischemic heart disease due to hypertensive heart disease (without significant obstructive epicardial coronary artery disease). The studies were made at baseline and after 4 to 48 months of intensive treatment, with a calcium antagonist and an angiotensin converting enzyme (ACE) inhibitor as the main components of the antihypertensive drug regimen. The majority of the patients with abolition or reversal of myocardial ischemia documented by 201Tl-myocardial imaging also had a significant reduction in left ventricular mass (LVM). However, some patients either did not have LV hypertrophy at baseline or had changes in LVM beyond the precision of the echocardiographic M-mode mass calculations. The finding indicated that factors other than reduction of LVM were involved in the reversal of the ischemia. The most likely factor was a change in the regulation of coronary blood flow. Reduction in LVM and reversal of myocardial ischemia determined either by electrocardiography or by thallium myocardial imaging studies may be considered indicators of the effectiveness of treatment.
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PMID:Correction of left ventricular ischemia in blacks with hypertensive heart disease. 839 11

To establish that bradykinin is formed in the heart we measured bradykinin in the venous effluent from rat isolated hearts perfused with Krebs-Henseleit buffer. In addition, we examined the effect on bradykinin outflow of the angiotensin converting enzyme (ACE) inhibitor, ramiprilat. From rat isolated normoxic hearts a bradykinin outflow of 0.85 +/- 0.1 ng ml-1 perfusate g-1 wet weight was measured. Perfusion with ramiprilat increased the bradykinin concentration to 2.8 +/- 0.3 ng ml-1 perfusate g-1 wet weight. During ischaemia bradykinin outflow maximally increased 8.2 fold to 7.0 +/- 0.5 ng ml-1 perfusate g-1, and in ramiprilat-perfused hearts 5.8 fold to 16.0 +/- 1.8 ng ml-1 perfusate g-1. In the reperfusion period bradykinin outflow normalized to values measured in the respective pre-ischaemic period. The presents data show that bradykinin is continuously formed in the rat isolated heart. Ischaemia increases bradykinin outflow from the heart. Presumably by inhibiting degradation of kinins, ACE inhibition significantly increased the bradykinin concentration during normoxia, ischaemia and reperfusion.
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PMID:Ramiprilat increases bradykinin outflow from isolated hearts of rat. 844 80

The susceptibility to ventricular arrhythmias under the conditions of cardiac ischemia and reperfusion was investigated in the Langendorff heart preparation of rats fed for eight weeks a standard chow enriched with 2% of pulverized wild garlic leaves. The isolated hearts were perfused with a modified Krebs-Henseleit solution. The incidence of ventricular fibrillation (VF) during 20 min occlusion of the descending branch of the left coronary artery (LAD) was significantly reduced in the wild garlic group as compared to untreated controls (20% vs 88%). The same holds for the size of the ischemic zone (33.6% vs 40.9% of heart weight). In the reperfusion experiments (5 min after 10 min ischemia), ventricular tachycardia (VT) occurred in 70% of the wild garlic group vs 100% in untreated controls and VF in 50% vs 90%. The time until occurrence of extrasystoles, VT or VR was prolonged. No significant alterations in cardiac fatty acid composition could be observed. Although the prostacyclin production was slightly increased in hearts of the wild garlic group, inhibition of cyclooxygenase by acetylsalicylic acid (ASA; aspirin) could not completely prevent the cardioprotective effects suggesting that the prostaglandin system does not play a decisive role in the cardioprotective action of wild garlic. Furthermore, a moderate angiotensin converting enzyme (ACE) inhibiting action of wild garlic was found in vitro as well as in vivo that could contribute to the cardioprotective and blood pressure lowering action of wild garlic. Whether a free radical scavenging activity of wild garlic is involved in its cardioprotective effects remains to be established.
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PMID:Cardioprotective actions of wild garlic (allium ursinum) in ischemia and reperfusion. 845 76

Hypertensive crisis is a life-threatening situation caused by acute elevation of blood pressure. The rise in blood pressure is very rapid and thus overwhelms protective adaptive mechanisms in the arterioles which occur under physiological conditions. Endothelial damage results. Focal vessel wall ischemia, inappropriate constriction and dilatation of arterioles, and increase in vascular permeability develop and cause functional disturbances of the heart, central nervous system or kidneys. Without immediate treatment, irreversible organ damage results due to ischemia and hemorrhage. The goal of therapy is to lower blood pressure by 25% within one hour. Blood pressure should be maintained at this level for 24 hours. Thereafter, blood pressure may be reduced by an additional 25% or to 180/100 mm Hg. Initial reduction in blood pressure by 55% may provoke irreversible end organ ischemia and infarction although blood pressure still may be well above the normal range. Most frequently, hypertensive crisis is treated with sodium nitroprusside as it allows controlled reduction in blood pressure due to its very rapid onset but short duration of action. Cyanide toxicity may develop in patients treated with high doses of sodium nitroprusside or with renal or kidney failure. Other agents used may have disadvantages such as unpredictable antihypertensive effects (calcium channel blockers, angiotensin converting enzyme inhibitor [ACEI]), tachycardia (calcium channel blockers, phentolamine, dihydralazine) or reduced renal blood flow (betablocker, ACEI).
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PMID:[Hypertensive crisis]. 849 71


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