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)

Digitalis and diuretics constitute conventional therapy of congestive heart failure, but systemic vasodilators offer an innovative approach in acute and chronic heart failure of decreasing increased left ventricular systolic wall tension (ventricular afterload) by reducing aortic impedance and/or by reducing cardiac venous return. Thus, vasodilators increase cardiac output (CO) by diminishing peripheral vascular resistance (PVR) and/or decrease increased left ventricular end-diastolic pressure (LVEDP) (ventricular preload) by diminishing venous tone. Concomitantly, there is reduction of myocardial oxygen demand, thereby reliably reducing angina pectoris in coronary disease, and potentially limiting infarct size and ischemia provided systemic arterial pressure remains normal. The vasodilators produce disparate modifications of cardiac function depending upon their differing alterations of preload versus impedance: nitrates principally cause venodilation (decrease LVEDP); nitroprusside, phentolamine and prazosin produce balanced arterial and venous dilation (decrease LVEDP and increase CO) provided left ventricular filling pressure is maintained at the upper limit of normal; whereas hydralazine predominantly effects arteriolar dilation (increases CO). With depressed CO plus highly increased LVEDP and increased PVR, nitrates also induce some increase of CO by reducing PVR. Combined nitroprusside and dopamine synergistically enhance CO and decrease LVEDP. Mechanical counterpulsation aids nitroprusside in acute myocardial infarction. The 30-minute venodilator action of sublingual nitroglycerin is extended for 4 to 6 hours by cutaneous nitroglycerin ointment, by sublingual and oral isosorbide dintrate, and by oral pentaerythritol tetranitrate and sustained-release nitroglycerin capsules. Ambulatory oral vasodilator therapy is provided by long-acting nitrates (relieve pulmonary congestion); hydralazine (improves fatigue); prazosin alone, combined nitrate-hydralazine combined prazosin-hydralazine (improve both dyspnea and fatigue).
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PMID:Afterload reduction and cardiac performance. Physiologic basis of systemic vasodilators as a new approach in treatment of congestive heart failure. 9 30

The effects of the beta-adernergic blocking drug acebutolol were studied in 23 patients with angina pectoris and angiographically documented coronary artery disease. Patients were evaluated clinically, by graded treadmill testing and by 24-hour Holter monitoring in the control state, after 2 weeks treatment with placebo, and after 2 weeks treatment with 600 mg. and then 1,200 mg. of acebutolol. Acebutolol (in a daily dose of 600 mg.) was an effective antianginal drug: the number of clinical attacks of angina pectoris (p less than 0.001) and the consumption of sublingual nitrate decreased (p less than 0.01), there was a significant increase in the treadmill effort tolerance as measured by the time to appearance of ischemic ECG changes (p less than 0.001) and the total work performed (p less than 0.001), and there was also a significant decrease in ischemic ST segment depression on 24-hour Holter monitoring. Treatment with 1,200 mg. acebutolol was associated with a further decrease in heart rate and a further improvement in effort tolerance on treadmill testing (p less than 0.05). On the large dose of the drug, however, there was no further clinical improvement, and no further improvement on 24-hour ECG monitoring; several patients complained of weakness and fatigue. Graded treadmill testing was an excellent objective method for assessing physical effort tolerance and its improvement after treatment with the beta-blocking drug. Twenty-four-hour Holter monitoring was a useful and complementary test, especially in patients who stopped exercising on the treadmill because of fatigue or weakness, and especially for assessing the efficacy of beta-blockade in controlling emotionally induced tachycardia and ischemia in the patient's own daily environment.
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PMID:Evaluation of the beta-blocking drug acebutolol in angina pectoris. 49 6

The relevance to man of experimental observations on coronary collateral blood flow (CCBF) in dogs has been questioned. The effect of 2 to 3 hour coronary occlusions in the anesthetized dog and a primate, the baboon, were therefore compared, with CCBF measured by injections of 85Kr distal to occlusion with precordial counting. Before killing, additional isotope was infused to compare inner/outer wall flow distribution and myocardial tissue samples were analyzed for electrolyte content. Effects of nitrates on hemodynamics and metabolism were also compared in dog and baboon. Similar values for CCBF and resistance following occlusions were found in dog and baboon (flow approximately 25 per cent control, calculated resistance increase four- to sevenfold). Greater subendocardial ischemia in both species was indicated by isotope distribution less to the inner wall, but electrolyte changes (k+ less and Na+ greater in the ischemic area compared to nonischemic) were similar transmurally in both species. Hemodynamic responses to nitrate infusion (isosorbide dinitrate) were similar, with increase in CCBF and decrease in resistance. In neither group were inner/outer wall isotope distribution or electrolyte changes influenced by nitrate. The coronary collateral response to occlusion is similar in dog and baboon in terms of both hemodynamics and metabolic changes. After 2 to 3 hours of coronary occlusion some hemodynamic benefit may be demonstrated with nitrates but no metabolic advantage, at least in the central area of ischemia.
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PMID:Comparison of the coronary collateral circulation in dogs and baboons after coronary occlusion. 82 26

Colloidal lanthanum salts have an average particle size of 40 degrees A; consequently, this electron-opaque marker remains extracellular and does not cross the intact plasma membrane. The affinity of lanthanum for calcium-binding sites on mitochondrial membranes makes it possible to demonstrate loss of plasma membrane integrity at the cellular level in ischemic myocardium. Biopsies were obtained from infarcted, marginal and normal areas 3 1/2 hours after ischemia was produced in 9 anesthetized closed-chest dogs by electrically induced thrombosis of the left anterior descending coronary artery. The tissue was immediately fixed in 4% glutaraldehyde and 0.1 M cacodylate buffer containing 1.3% La(NO3)3, pH 7.4, for 2 hours. In normal control tissue prepared this way the lanthanum tracer, as expected, was confirmed to the extracellular spaces, including, basement membranes, gap junctions and portions of the intercalated discs. Specimens taken near the center of frank infarctions all contained intracellular as well as extracellular lanthanum. Intracellular lanthanum could be seen evenly distributed around lipid droplets and in focal deposits around mitochondria. Only when mitochondria were disrupted did lanthanum gain access to internal sites on mitochondrial membranes. Areas marginal to the infarct contained cells in varying stages of degeneration including many that appeared normal by morphologic criteria alone. Intracellular lanthanum was present in many but not all of the marginal cells in which degenerative changes could be seen. Similarly a few of the cells that appeared morphologically normal contained intracellular lanthanum. The entry of lanthanum into some of these marginal cells and its exclusion from adjacent cells demonstrated that ischemic injury affects the permeability properties of the plasma membrane and independently of other intracellular morphologic changes and that lanthanum can be a sensitive indicator of such alteration in membrane permeability.
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PMID:Colloidal lanthanum as a marker for impaired plasma membrane permeability in ischemic dog myocardium. 114 60

The effects of nicorandil, a nicotinamide nitrate with K(+)-channel-opening activity, was investigated in several models of ischemia-reperfusion injury in conscious and anesthetized dogs or isolated buffer-perfused rat hearts. In several models of reversible ischemic injury (stunned myocardium) in dogs, nicorandil resulted in an enhanced recovery of regional systolic shortening during reperfusion after a single episode of coronary artery occlusion (10-15 min). These beneficial actions of nicorandil were not shared by the nitrovasodilator sodium nitroprusside but were mimicked by the selective K(+)-channel opener EMD 52692. In a model of irreversible ischemia-reperfusion injury (i.e., 2 h of coronary occlusion followed by reperfusion) in anesthetized dogs, nicorandil produced a marked reduction of myocardial infarct size. An equihypotensive dose of the calcium antagonist nifedipine had no significant effect; however, EMD 52692 produced the same reduction in infarct size as had nicorandil. In isolated, perfused rat hearts subjected to 20 min of low-flow (1.0 ml/min) global ischemia followed by 30 min of reperfusion, nicorandil (7 microM) resulted in a significant improvement in the recovery of isovolumic left ventricular minute work during reperfusion compared with untreated hearts. Finally, the results of in vitro experiments indicated that nicorandil (10(-6) to 10(-3) M) produced a concentration-dependent inhibition of superoxide anion free radical production by human and canine neutrophils. The K(+)-channel opener EMD 52692 also inhibited superoxide production in canine neutrophils. These results indicate that nicorandil is a highly efficacious myocardial protective agent in several animal models of reversible or irreversible ischemia-reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardioprotective effects of nicorandil. 128 72

Peroxynitrite (ONOO-), the reaction product of superoxide (O2-) and nitric oxide (NO), may be a major cytotoxic agent produced during inflammation, sepsis, and ischemia/reperfusion. Bovine Cu,Zn superoxide dismutase reacted with peroxynitrite to form a stable yellow protein-bound adduct identified as nitrotyrosine. The uv-visible spectrum of the peroxynitrite-modified superoxide dismutase was highly pH dependent, exhibiting a peak at 438 nm at alkaline pH that shifts to 356 nm at acidic pH. An equivalent uv-visible spectrum was obtained by Cu,Zn superoxide dismutase treated with tetranitromethane. The Raman spectrum of authentic nitrotyrosine was contained in the spectrum of peroxynitrite-modified Cu,Zn superoxide dismutase. The reaction was specific for peroxynitrite because no significant amounts of nitrotyrosine were formed with nitric oxide (NO), nitrogen dioxide (NO2), nitrite (NO2-), or nitrate (NO3-). Removal of the copper from the Cu,Zn superoxide dismutase prevented formation of nitrotyrosine by peroxynitrite. The mechanism appears to involve peroxynitrite initially reacting with the active site copper to form an intermediate with the reactivity of nitronium ion (NO2+), which then nitrates tyrosine on a second molecule of superoxide dismutase. In the absence of exogenous phenolics, the rate of nitration of tyrosine followed second-order kinetics with respect to Cu,Zn superoxide dismutase concentration, proceeding at a rate of 1.0 +/- 0.1 M-1.s-1. Peroxynitrite-mediated nitration of tyrosine was also observed with the Mn and Fe superoxide dismutases as well as other copper-containing proteins.
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PMID:Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. 141 74

Nitrate monotherapy was assessed by treadmill exercise stress testing in 18 patients with significant but relatively asymptomatic myocardial ischemia who were receiving no other antianginal therapy. In addition, prolonged ambulatory electrocardiographic monitoring was performed in 7 patients with demonstrable ischemia during baseline monitoring. After baseline assessment, 5 treatment periods were used in a random order (each of 1 week duration), incorporating 2 dose levels of transdermal nitrate (10 and 20 mg/24 hours) and isosorbide dinitrate (ISDN) (30 and 60 mg/day in divided doses) with a 10-hour nitrate-free interval every 24 hours, as well as a placebo period using a double-blind technique. All treatment periods (including placebo) showed a significant (p < 0.01) 45 to 69% prolongation in the time to 1 mm ST depression during exercise. Paired baseline times of 231 +/- 28 and 233 +/- 30 seconds increased to 367 +/- 37 seconds with 30 mg/day of ISDN, 393 +/- 37 seconds with 60 mg/day of ISDN, 381 +/- 31 seconds with 10 mg/day of transdermal nitrate, and 372 +/- 33 seconds with 20 mg/day of transdermal nitrate. The value for placebo was 342 +/- 29 seconds, which was not significantly different from active treatment (p > 0.1). Some patients appeared to individually respond to > or = 1 nitrate preparation significantly more than to placebo, but this appeared to be unpredictable and largely independent of dosage level and route of administration. There was a qualitatively similar but statistically insignificant reduction in total ischemic time during ambulatory monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Placebo effect of nitrate monotherapy for myocardial ischemia. 144 72

The organic nitrates have remarkably diverse actions that are or should be beneficial in patients with ischemic heart disease. These drugs are effective in all the important ischemic syndromes. Preliminary data in patients with acute infarction suggest that the drugs may be truly cardioprotective, resulting in improved mortality. This review has not discussed the role of nitrates in congestive heart failure or LV dysfunction, a subject of great importance. The nitrates are useful adjunctive agents in these syndromes, and the two VeHfT trials support the concept that long-term nitrate administration, in conjunction with hydralazine, may favorably alter the natural history of heart failure. This cardioprotective effect is similar to that suggested for the post-MI patient. The data are not strong enough for definitive conclusions at this time. The clinical benefits of nitrates in decreasing subjective (angina) and objective indices of ischemia in stable and unstable angina, as well as limited data in asymptomatic myocardial ischemia, are unequivocal and are as favorable as those for beta blockers or calcium antagonists. Tolerance is an important problem that unfavorably influences the potential benefits of nitrate therapy. I believe that this problem can be avoided with well-designed dosing regimens. Current research into endothelial biology in health and disease has further supported a physiologic role for the organic nitrates in patients with ischemic heart disease. The nitrate-platelet story, while controversial, is promising and offers another positive rationale for nitrate administration. The concept of nitrates replenishing disordered EDRF release or action is an exciting one. Physicians should feel fortunate to have such a remarkable group of drugs available for their patients.
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PMID:Use of nitrates in ischemic heart disease. 151 14

Daily life ischemia has generated considerable interest because most of it is silent and associated with increased risk of adverse outcome. Coronary vasomotion, as well as increases in myocardial oxygen demand, seem important in the pathogenesis of this form of ischemia, so treatment with nitrates seems rational. Administration of sublingual nitroglycerin hourly, over 12 hours, was shown to decrease both silent and painful ischemic episodes in patients with effort angina. Subsequently, isosorbide dinitrate or mononitrate, given either as an intravenous infusion or orally, was shown to decrease both silent and painful ischemic episodes in patients with unstable rest angina and in those with severe angina. More recently, 6 studies have reported using transdermal nitroglycerin for daily life ischemia. Three of these reported open-label uncontrolled observations and suggested that ischemia frequency may be reduced approximately 60-80% during treatment with doses of 10-30 mg/day, with a duration of treatment ranging from 1 hour to 14 days. In 2 of these reports the duration of ischemia also decreased. The other 3 studies were randomized, double-blind, placebo-controlled studies with a total enrollment of 86 patients. These studies provided mixed results. One suggested that evidence for partial tolerance develops within 1 day of treatment, using large continuous or intermittent doses (mean, 52 mg/day). Another suggested that no tolerance develops to intermittent dosing (18 mg/16 hr out of 24 hr) during exercise testing but no effect is seen on daily life ischemia. The remaining study suggested that tolerance does not develop using small doses (15 mg/day) continuously over 14 days for ischemia during daily life, and that this response is different from that observed using the calcium antagonist nifedipine. These limited observations and conflicting results underscore a need for additional larger controlled trials, employing topical nitrate therapy in low intermittent doses for daily life ischemia.
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PMID:Daily life ischemia and nitrate therapy. 152 27

The role of anions in the initiation of ischemia- and reperfusion-induced arrhythmias is unknown. We examined the antiarrhythmic effects of isotonic substitution of extracellular Cl- with NO3- by using the rat Langendorff preparation (n = 12 per group). During 30 minutes of regional ischemia, the incidence of ventricular fibrillation (VF) was reduced from 50% in hearts perfused with control solution (containing a Cl-:NO3- ratio of 100:0) to 25%, 0% (p less than 0.05), 0% (p less than 0.05), and 0% (p less than 0.05) by perfusion with solution containing Cl-:NO3- ratios of 75:25, 50:50, 25:75, and 0:100, respectively. The incidence of reperfusion-induced VF was also reduced from 58% to 25%, 8% (p less than 0.05), 8% (p less than 0.05), and 0% (p less than 0.05), respectively. Similar effects were produced in hearts reperfused after briefer durations of ischemia (10 or 15 minutes). Substitution of NO3- for Cl- also facilitated spontaneous termination of VF. Heart rate and occluded zone size were not affected by anion manipulation. Coronary flow was affected by NO3-, but changes did not correlate with arrhythmias. During ischemia, electrocardiographic changes indicative of class III activity (widening of the ventricular complex) were produced by anion substitution. These changes occurred selectively in the ischemic tissue with no significant influence before ischemia onset. However, the relation between this effect and arrhythmia reduction was not linear and a cause-effect relation is therefore unlikely. In separate groups of hearts (n = 12 per group), switching from 100:0 to 0:100 Cl-:NO3- solution or vice versa 10 seconds after coronary occlusion or just before reperfusion demonstrated that 1) protection against ischemia-induced VF resulted partly from an action in the ischemic zone and partly from an action in the nonischemic zone, and 2) protection against reperfusion-induced VF resulted principally from an action occurring during reperfusion and within the reperfused tissue. To assess whether benefit was offset by deleterious effects on contractile function in nonischemic tissue, we constructed Starling curves in isolated rate hearts. The 0:100 Cl-:NO3- solution had no effect on compliance or contractility at physiological end-diastolic pressures but reduced the slope of the peak systolic pressure-volume relation by approximately 20% as end-diastolic pressure was increased above 10 mm Hg. In conclusion, anions appear to play a hitherto unrecognized role in arrhythmogenesis in ischemia and reperfusion. Manipulation of anion homeostasis may represent a novel target for antiarrhythmic drug development.
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PMID:Anion manipulation: a new antiarrhythmic approach. Action of substitution of chloride with nitrate on ischemia- and reperfusion-induced ventricular fibrillation and contractile function. 155 Nov 89


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