Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Control of hypertension and treatment of concomitant pathophysiologic conditions require use of multiple drugs in more than half of all patients. Unfortunately, most studies dealing with cardiovascular effects of antihypertensive drugs have focused on monotherapy. Thus, our knowledge of combination therapy in the treatment of hypertension is, to a great extent, extrapolation from monotherapy. Angiotensin-converting enzyme inhibitors in combination with calcium antagonists should be particularly efficacious in reducing left ventricular hypertrophy. Drug classes that either stimulate the renin-angiotensin system or the sympathetic nervous system are less likely to reduce left ventricular hypertrophy and should be avoided. In hypertensive patients with left ventricular dysfunction, beta-blockers should be combined with angiotensin-converting enzyme inhibitor, whereas in the postmyocardial ischemia patient, verapamil and angiotensin-converting enzyme inhibitors may exert some additional beneficial effects with regard to reinfarction rates. Some of the undesirable metabolic side-effects of diuretics can be mitigated by the addition of an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. Given that two drugs when used separately are beneficial in a disorder does not necessarily mean that their combination is equally or even more beneficial. Sometimes combination therapy is used to counteract different limbs of pathophysiologic cascade operative in hypertensive patients with complications or comorbidities.
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PMID:Cardiac effects of combination therapy in hypertension. 1085 47

Multiple indirect lines of evidence point at a cardioprotective role for enhanced bradykinin formation. In particular, the inhibition of angiotensin-converting enzyme, also known as kininase II, can protect against cardiac ischemia, putatively via accumulation of bradykinin. To address whether an increase in kinin formation is sufficient to protect against cardiac ischemia, we studied transgenic rats harboring the human tissue kallikrein gene TGR(hKLK1) under the control of the metallothionein promoter, which drives expression of the transgene in various organs including the heart. We subjected the isolated hearts from transgenic rats and their transgene negative littermates to ex vivo regional cardiac ischemia and reperfusion. During the experiment, the hearts were treated with either vehicle or the specific bradykinin type 2 receptor antagonist HOE 140 (10-9 M). In the transgenic rats, overflow of nucleotide breakdown products upon reperfusion was significantly less (455 +-54 nmol/min/g in transgene negative rats vs. 270+-57 nmol/min/g in the transgenic rats, P.
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PMID:Increased kallikrein expression protects against cardiac ischemia. 1102 68

Angiotensin-converting enzyme (ACE) activity in the myocardium and angiotensin-II (Ang-II) levels in plasma increase after myocardial ischemia, which lead to exacerbation of myocardial injury and cardiac dysfunction. We examined the protective role of novel antisense-oligodeoxynucleotide (AS-ODN) directed at ACE mRNA in myocardial ischemic injury. Sprague-Dawley rats were treated with ACE-AS-ODN (200 microg per rat, n = 8, i.v.) or inverted-ODN (IN-ODN, 200 microg per rat, n = 8, i.v.), given with 600 microg per rat of liposome DOTAP/DOPE. Hearts from AS-ODN- or IN-ODN-treated rats were excised, perfused in vitro, and subjected to 25 min of global ischemia followed by 30 min of reperfusion. Parallel groups of rats were given ACE inhibitor captopril (5 mg/kg, n = 8) or saline (n = 8) before excising the hearts. Ischemia/reperfusion resulted in myocardial dysfunction (increase in coronary perfusion pressure and LV end-diastolic pressure and a decrease in developed LV pressure) in the saline-treated rats. Myocardial dysfunction was associated with evidence of lipid peroxidation and enzyme leakage (MDA and LDH levels in the myocardium) and up-regulation of ACE protein expression. Administration of AS-ODN or captopril, but not IN-ODN, reduced Ang-II levels in the plasma, decreased ischemia/reperfusion-mediated cardiac functional deterioration and lipid peroxidation, and preserved LDH in the myocardium (all P < 0.05 versus the saline group). AS-ODN and captopril had equipotent effects on cardiac dynamics. ACE protein expression (western blot) was decreased in the hearts of the AS-ODN-treated group, but not in IN-ODN-treated rat hearts. In contrast, ACE protein expression was significantly increased in captopril-treated rat hearts. These observations suggest that AS-ODN directed at ACE mRNA can ameliorate myocardial dysfunction and injury after ischemia/reperfusion, and its use is associated with decreased expression of ACE protein in the ischemic myocardium.
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PMID:Protection against ischemia/reperfusion injury and myocardial dysfunction by antisense-oligodeoxynucleotide directed at angiotensin-converting enzyme mRNA. 1142 Jun 45

Angiotensin I converting enzyme (kininase II; ACE) inhibitors are important therapeutic agents widely used for treatment in cardiovascular and renal diseases. They inhibit angiotensin II release and bradykinin inactivation; these actions do not explain completely the clinical benefits. We found that enalaprilat and other ACE inhibitors in nanomolar concentrations activate human bradykinin B(1) receptors directly in the absence of ACE and the B(1) agonist des-Arg(10)-Lys(1)-bradykinin. These inhibitors activate at the Zn(2+)-binding consensus sequence HEXXH (195-199) in B(1), which is present also in ACE but not in the B(2) receptor. Activation elevates [Ca(2+)](i) and releases NO from endothelial or transfected cells expressing the B(1) receptor but is blocked by Ca-EDTA, a B(1) receptor antagonist, the synthetic undecapeptide sequence (192-202) of B(1), and the mutagenesis of His(195) to Ala(195). Except for the B(1) antagonist, these agents and manipulations did not block activation by a peptide ligand. Thus, Zn(2+) is essential for B(1) receptor activation by ACE inhibitors at the zinc-binding consensus sequence. Ischemia or cytokines induce abundant B(1) receptor expression. B(1) receptor activation by ACE inhibitors, a novel mode of action reported here first, can contribute to their therapeutic effects by releasing NO in the heart and to some side effects.
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PMID:Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor. 1188 Mar 73

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 (AT (1)) receptor blockers improve ischemia-reperfusion induced arrhythmias and infarct size in several animal models. However, the effects of pretreatment with ACEIs or AT (1) receptor blockers on acute myocardial infarct size and arrhythmias are controversial. Thus, we sought to assess the comparative effects of pretreatment with ACEI captopril and AT (1)-receptor blocker losartan on myocardial infarct size and arrhythmias in a rat model of ischemia-reperfusion. We randomly assigned 92 male Wistar rats for arrhythmias ( n= 60) and necrosis ( n= 32) experiments. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion and to produce necrosis, the the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion. Captopril (3 mg kg (-1)) and losartan (0.2 and 2 mg kg (-1)) were given intravenously 10 min before occlusion. Captopril reduced the incidences of ventricular fibrillation (VF) and mortality associated with irreversible VF, whereas the studied doses of losartan did not. Captopril also decreased the number of ventricular beats on reperfusion. Losartan 2 mg kg (-1) reduced both the number of ventricular premature beats and the incidence of ventricular tachycardia (VT) on reperfusion, while losartan at dose of 0.2 mg kg (-1) had no effect on these arrhythmias. Compared to the control group, both captopril and losartan reduced myocardial infarct size in the rat model of ischemia-reperfusion, but this was statistically significant for captopril only. In this experimental model, although captopril did not reduce the incidence of reperfusion-induced VT, it was more effective than the AT (1)-receptor blocker losartan at preventing mortality associated with irreversible VF and to reduce myocardial infarct size in rat model of ischemia-reperfusion.
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PMID:Effects of captopril and losartan on myocardial ischemia-reperfusion induced arrhythmias and necrosis in rats. 1203 Jul 87

ACE or kininase II inhibitors are very important, widely used therapeutic agents for the treatment of a variety of diseases. Although they inhibit ACE, thus, angiotensin II release and bradykinin (BK) inactivation, this inhibition alone does not suffice to explain their successful application in medical practice. Enalaprilat and other ACE inhibitors at nanomolar concentrations activate the BK B1 receptor directly in the absence of ACE and the peptide ligands, des-Arg-kinins. The inhibitors activate at the Zn-binding pentameric consensus sequence HEXXH (195 -199) of B1, a motif also present in the active centers of ACE but absent from the BK B2 receptor. ACE inhibitors, when activating the B1 receptor, elevate intracellular calcium [Ca2+]i and release NO from cultured cells. Activation by ACE inhibitor was abolished by Ca-EDTA, a B1 receptor antagonist, by a synthetic undecapeptide representing the 192-202 sequence in the B1 receptor, and by site-directed mutagenesis of H195 to A. With the exception of the B1 receptor blocker, these agents and the mutation did not affect the actions of the peptide ligand des-Arg10-Lys1-BK. Ischemia and inflammatory cytokines induce B1 receptors and elevate its expression. Direct activation of the B1 receptor by ACE inhibitors can contribute to their therapeutic efficacy, for example, by releasing NO in vascular beds, or to some of their side effects.
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PMID:Activation of bradykinin B1 receptor by ACE inhibitors. 1248 93

Today, peripheral arterial disease (PAD) patients need effective medical care for an extended period of their lifetime. Therefore, different treatment modalities have to be tied sequentially into an effective therapeutic chain. First, preventive measures have to be reinforced and risk factors tightly controlled. Furthermore, antiplatelet agents have to be applied in every PAD patient to reduce the risk of cardiac and cerebral ischemic events, restenosis or reocclusion after revascularization, and possibly also progression of the PAD itself. Angiotensin-converting enzyme (ACE) inhibitors should be entertained in high-risk groups such as PAD patients with diabetes. In the claudicant, exercise therapy should be strongly encouraged and vasoactive drugs considered for those who are not good candidates for either exercise training or revascularization. In patients with disabling claudication or critical limb ischemia, revascularization procedures are highly effective. Especially for high-grade stenoses or short arterial occlusions, percutaneous transluminal angioplasty (PTA) should be the method of first choice followed by the best surgical procedure later on. To achieve good long-term efficacy, a close follow-up including objective tests of both the arterial lesion and hemodynamic status, surveillance of secondary preventive measures and risk factor control is mandatory.
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PMID:The challenges of treating peripheral arterial disease. 1451 13

Patients with cardiac syndrome X (typical chest pain and normal coronary arteriograms) represent a heterogeneous syndrome, which encompasses different pathogenic mechanisms. Although symptoms in most patients with cardiac syndrome X are non-cardiac, a sizable proportion of them have angina pectoris due to transient myocardial ischemia. Thus radionuclide myocardial perfusion defects, coronary sinus oxygen saturation abnormalities and pH changes, myocardial lactate production and stress-induced alterations of cardiac high energy phosphate suggest an ischemic origin of symptoms in at least a proportion of patients with cardiac syndrome X. Microvascular abnormalities, caused by endothelial dysfunction, appear to be responsible for myocardial ischemia in patients with cardiac syndrome X. Endothelial dysfunction is likely to be multifactorial in these patients and it is conceivable that risk factors such as hypertension, hypercholesterolemia, diabetes mellitus and smoking can contribute to its development. Most patients with cardiac syndrome X are postmenopausal women and estrogen deficiency has been therefore proposed as a pathogenic factor in female patients. Additional factors such as abnormal pain perception may contribute to the pathogenesis of chest pain in patients with angina pectoris and normal coronary angiograms. Although prognosis is good regarding survival, patients with cardiac syndrome X have an impaired quality of life. Management of this syndrome represents a major challenge to the treating physician. Understanding the mechanism underlying the condition is of vital importance for patient management. Thus diagnostic tests should aim at identifying the cause of the symptoms in the individual patient, i.e. myocardial ischemia, increased pain perception, abnormalities of adrenergic tone, non-cardiac mechanisms, etc. Moreover, it is important to bear in mind that treatment of cardiac syndrome X should be mainly directed towards improving quality of life, as prognosis is usually good in these patients. Conventional antianginal agents such nitrates, calcium channel antagonists, beta-adrenoceptor antagonists and nicorandil are effective particularly in patients in whom chest pain and ECG changes are clearly suggestive of myocardial ischemia and in those with objective documentation of ischemia. Angiotensin-converting enzyme inhibitors have been shown to be useful in syndrome X patients with increased adrenergic tone, borderline systemic hypertension, and those with documented endothelial dysfunction. Analgesic interventions of different sorts have been proposed based on the hypothesis that somatic and visceral perception of pain is altered in cardiac syndrome X patients. Pharmacological agents such as imipramine and aminophylline, and neural electrical stimulation techniques have been assessed in recent years with encouraging results. Psychological treatment, particularly cognitive therapy, appears to be useful in defined patient subsets. Relaxation techniques such as transcendental meditation have been successfully used in small studies and shown to improve not only chest pain but also exercise-induced ST segment changes. Reports indicate that these techniques improve quality of life.
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PMID:Cardiac syndrome X. Diagnosis, pathogenesis and management. 1555 28

Angiotensin-converting enzyme inhibitors have been shown to prolong survival, decrease infarct size, and improve ventricular function in patients who have congestive heart failure, and in those who have sustained a myocardial infarction. This review will summarize the evidence to show that angiotensin-converting enzyme inhibitors can also benefit patients undergoing coronary artery bypass graft surgery by minimizing perioperative ischemia, and reducing long-term cardiovascular events.
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PMID:The use of angiotensin-converting enzyme inhibitors in patients undergoing coronary artery bypass graft surgery. 1579 29

Most patients with acute heart failure present with increased left ventricular filling pressure and high or normal blood pressure; only a minority present with cardiogenic shock. In this context, therapy with vasodilators in the acute setting can improve both hemodynamics and symptoms. Vasodilators are usually given in conjunction with diuretics, although much of the acute effect of loop diuretics may be due to venodilation. Currently available agents include nitroglycerin, nitroprusside, and nesiritide. Nitroglycerin relieves pulmonary congestion primarily through direct venodilation, but may dilate coronary arteries and increase collateral blood flow at higher doses, an effect desirable in patients with ischemia. Tachyphylaxis may develop, necessitating incremental dosing. The major adverse effects of nitrates are hypotension and headache. Nitroprusside is a balanced arterial and venous vasodilator with a very short half-life, facilitating rapid titration. Afterload reduction lowers blood pressure and can increase stroke volume. The major complications of nitroprusside therapy are hypotension, and toxicity from accumulation of cyanide or thiocyanate, usually in patients with renal insufficiency treated for more than 24 h. Nesiritide, a recombinant form of human B-type natriuretic peptide (BNP), is a venous and arterial vasodilator that may also potentiate the effect of concomitant diuretics. Hypotension is the most common side effect. In addition, meta-analyses have suggested that nesiritide may worsen renal function and decrease survival at 30 days compared to conventional therapies. Resolution of these concerns awaits completion of appropriately powered prospective clinical trials. Angiotensin-converting enzyme (ACE) inhibitors have vasodilatory effects, but intravenous infusion of enalapril within 24 h of ischemic chest pain is not recommended. Oral ACE inhibition may be used to reduce afterload in other settings if blood pressure permits. Use of calcium antagonists in acute heart failure is not recommended.
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PMID:Vasodilators in acute heart failure. 1744 37


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