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)

The effects of L-arginine on recovery of myocardial contractile function and oxidative metabolism were investigated in a model of reversible global normothermic, ischemic injury using an isolated, buffer-perfused rabbit heart preparation. One mM L-arginine was infused into hearts for 2 min at the onset (group 1) of a 35 min period of ischemia or at the onset of reperfusion (group 2). In non-ischemic hearts, L-arginine caused a slight increase in developed pressure but had no effects on diastolic pressure, oxygen consumption (MVO2), coronary flow, or lactate production. When administered either before or after ischemia-reperfusion. L-arginine caused a significant increase in the diastolic pressure-volume relationship (PVR) and decline in systolic function when compared to untreated control hearts receiving the same ischemic injury. Recovery of MVO2 and high energy phosphates (phosphocreatine and ATP), measured by 31P-NMR spectroscopy, were significantly impaired in L-arginine-treated hearts compared to reperfused control hearts. Lactate release on reperfusion was also higher in both arginine-treated groups. Nitric oxide release into the coronary circulation (measured in separate experiments by the conversion of [15N]L-arginine to [15N]nitrate/nitrite using gas chromatography/mass spectroscopy) was not increased by L-arginine administration. Thus, we conclude that L-arginine acts synergistically with ischemia reperfusion to augment myocardial injury, which includes inhibition of oxidative metabolism and mitochondrial function.
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PMID:Direct detrimental effects of L-arginine upon ischemia--reperfusion injury to myocardium. 747 86

Myocardial ischemia and reperfusion may result in endothelial dysfunction and reduced release of nitric oxide. With the use of an amperometric sensor, the first direct measurements of constitutive nitric oxide release from a beating heart were measured from the coronary effluent of isolated working rat hearts subjected to ischemia and reperfusion. Rats, six to eight per group, were randomly studied as follows: control (no pretreatment) and pretreatment with the nitric oxide donor L-arginine (3 mmol/L), its enantiomer D-arginine (3 mmol/L), nitric oxide inhibitor N omega-nitro-L-arginine methyl ester (100 mumol/L), and combined N omega-nitro-L-arginine methyl ester/L-arginine. Isolated hearts were pretreated for 10 minutes before 30 minutes of global ischemia and 30 minutes of reperfusion. A nonischemic control group (n = 4) was continuously perfused with oxygenated unsupplemented buffer. After ischemia/reperfusion, hearts supplemented with L-arginine recovered significantly (p < 0.05) increased developed pressure, first derivative of the aortic pressure (dP/dtmax), and aortic flow compared with all other hearts that underwent ischemia/reperfusion. In addition, nitric oxide release was significantly (p < 0.05) increased during reperfusion in the L-arginine group. During reperfusion, the recovery of aortic flow correlated with nitric oxide release (r = 0.81, p < 0.0001). We conclude that after ischemia/reperfusion, endothelial dysfunction results in decreased nitric oxide release, which can be ameliorated with L-arginine pretreatment. The direct cytoprotective properties of nitric oxide may contribute to improved functional recovery in hearts pretreated with L-arginine. Augmentation of the L-arginine/nitric oxide pathway may provide a new approach for improved recovery after cardiovascular operations.
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PMID:Constitutive nitric oxide release is impaired after ischemia and reperfusion. 747 33

The effects of aspirin and L-arginine (biological precursor of nitric oxide) on the production of hydroxyl radicals, cyclic guanosine monophosphate levels, vascular tone, and the recovery of the ischemic myocardium were investigated in isolated rat hearts subjected to ischemia and reperfusion. After 30 minutes of perfusion, hearts were arrested with St. Thomas' Hospital cardioplegic solution, global ischemia was induced at 37 degrees C for 45 minutes, and the hearts were then reperfused at 37 degrees C for 30 minutes. The percent change in recovery of pulse pressure and maximal change of this pressure with time were better in the group perfused with Krebs-Henseleit solution containing aspirin plus L-arginine (17% +/- 23%, p = 0.001, and 10% +/- 25%, p = 0.002, respectively) compared with these values in the control group perfused with Krebs-Henseleit solution alone (-7% +/- 14% and -11% +/- 16%, respectively). Coronary vascular resistance before and after ischemia were lower in the aspirin plus L-arginine group (0.19 +/- 0.03 dynes.sec/cm5, p = 0.001, and 0.23 +/- 0.04 dynes.sec/cm5, p = 0.01, respectively) compared with those of the control group (0.24 +/- 0.02 and 0.28 +/- 0.07 dynes.sec/cm5, respectively). Cyclic guanosine monophosphate levels increased from 22.5 +/- 6 pmol/100 mg of tissue in the control group to 37.1 +/- 8.9 pmol/100 mg (p = 0.002) in the aspirin plus L-arginine group. Adding N omega-nitro-L-arginine methyl ester to the perfusion medium caused a deterioration in pulse pressure and maximal change of this pressure with time, a decrease in cyclic guanosine monophosphate, and a rise in coronary vascular resistance. The addition of L-arginine to the solution in the Krebs-Henseleit solution plus aspirin group increased the production of hydroxyl radicals from 0.32 +/- 0.18 nmol/gm per 3 minutes to 0.75 +/- 0.33 nmol/gm per 3 minutes (p = 0.03). Despite the association of nitric oxide with increased hydroxyl radical production, it appears that nitric oxide has an overall beneficial effect on the recovery of the ischemic myocardium. The synergism between aspirin and arginine may be caused in part by the scavenging of hydroxyl radicals. Alternatively, by inhibiting the prostaglandin pathway, aspirin may reduce the generation of superoxide anion, a free radical that inactivates nitric oxide. The prolonged half-life of nitric oxide may explain the increased levels of cyclic guanosine monophosphate seen in the group perfused with Krebs-Henseleit solution plus aspirin plus L-arginine. Aspirin and L-arginine, both readily available, may be useful adjuncts to clinical cardioplegia strategy.
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PMID:Simultaneous manipulation of the nitric oxide and prostanoid pathways reduces myocardial reperfusion injury. 747 34

Previous studies show that (1) hypoxemia depletes immature myocardium of amino acid substrates and their replenishment improves ischemic tolerance, (2) reoxygenation on cardiopulmonary bypass causes oxygen-mediated damage without added ischemia, and (3) this damage may be related to the nitric oxide-L-arginine pathway that is affected by amino acid metabolism. This study tests the hypothesis that priming the cardiopulmonary bypass circuit with glutamate and aspartate limits reoxygenation damage. Of 22 immature Duroc-Yorkshire piglets (< 3 weeks old), five were observed over a 5-hour period (control), and five others underwent 30 minutes of CPB without hypoxemia (cardiopulmonary bypass control). Twelve others became hypoxemic by reducing ventilator inspired oxygen fraction to 6% to 7% (oxygen tension about 25 mm Hg) before reoxygenation on cardiopulmonary bypass for 30 minutes. Of these five were untreated (no treatment), and the cardiopulmonary bypass circuit was primed with 5 mmol/L glutamate and aspartate in seven others (treatment). Left ventricular function before and after bypass was measured by inscribing pressure-volume loops (end-systolic elastance). Myocardial conjugated diene levels were measured to detect lipid peroxidation, and antioxidant reserve capacity was tested by incubating cardiac muscle with the oxidant t-butylhydroperoxide to determine the susceptibility to subsequent oxidant injury. CPB (no hypoxemia) allowed complete functional recovery without changing conjugated dienes and antioxidant reserve capacity, whereas reoxygenation injury developed in untreated hearts. This was characterized by reduced contractility (elastance end-systolic recovered only 37% +/- 8%*), increased conjugated diene levels (1.3 +/- 0.1 vs 0.7 +/- 0.1*), and decreased antioxidant reserve capacity (910 +/- 59 vs 471 +/- 30 malondialdehyde nmol/g protein at 2 mmol/L t-butylhydroperoxide*). In contrast, priming the cardiopulmonary bypass circuit with glutamate and aspartate resulted in significantly better left ventricular functional recovery (75% +/- 8% vs 37% +/- 8%*), minimal conjugated diene production (0.8 +/- 0.1 vs 1.3 +/- 0.1*), and improved antioxidant reserve capacity (726 +/- 27 vs 910 +/- 59 malondialdehyde nmol/g protein*) (*p < 0.05 vs cardiopulmonary bypass control). We conclude that reoxygenation of immature hypoxemic piglets by the initiation of cardiopulmonary bypass causes myocardial dysfunction, lipid peroxidation, and reduced tolerance to oxidant stress, which may increase vulnerability to subsequent ischemia (i.e., aortic crossclamping). These data suggest that supplementing the prime of cardiopulmonary bypass circuit with glutamate and aspartate may reduce these deleterious consequences of reoxygenation.
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PMID:Studies of hypoxemic/reoxygenation injury: without aortic clamping. VIII. Counteraction of oxidant damage by exogenous glutamate and aspartate. 747 74

Ischemia and reperfusion have been shown to cause damage to the endothelium as well as to the cardiac myocyte. Although the vasodilator response has been shown to be impaired following ischemia and reperfusion, the effect of a short period of global ischemia on the contractile response of the coronary vasculature is not clear. In the present study, coronary vasoconstriction in response to U46619, PGF2 alpha, 5-HT, and KCl was found to be depressed for at least 15 min following 15 min of in vitro global ischemia in rats hearts. Vasodilator blockers or inactivators were used in an effort to restore this depressed coronary response. Indomethacin (5 microM) was used to block production of vasodilator prostaglandins, L-NAME (30 microM) to block production of nitric oxide (NO), and adenosine deaminase (2.4 units/ml of coronary flow) to inactivate adenosine. None of these agents restored the normal coronary constrictor response following ischemia. When superoxide dismutase and catalase (both 20 micrograms/ml of coronary flow) were infused for 5 min before and after ischemia, the coronary response recovered more than 100% of its preischemic value by 15 min of reperfusion, but still remained depressed at 5 min reperfusion. These data suggest that free radicals produced during ischemia and/or reperfusion may be at least partly responsible for this temporary "stunning" of the coronary vasculature. Since the impaired contractile response was still present at 5 min reperfusion when the buffer was supplemented with oxygen radical scavengers, another mechanism must also be involved in this "stunning" process.
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PMID:Effects of short term ischemia and reperfusion on coronary vascular reactivity and myocardial function. 747 69

Experiments were designed to evaluate function of the endothelium and smooth muscle of coronary arteries following storage of hearts in cardioplegia containing an inhibitor of lipid peroxidation (H 290/51, cis-7-methyl-9-methoxy-5,5a, 6,10b tetrahydroindeno [2,1-b] indole). Canine hearts were perfused with crystalloid cardioplegia (Plegisol, 15 ml/kg, 4 degrees C) and left circumflex arteries were isolated and studied either immediately (group I, n = 6), or after storage of the hearts at 4 degrees C for 10 (group II, n = 6) or 24 hr with (group III, n = 6) or without (group IV, n = 6) addition of H 290/51. The final concentration of H 290/51 was 1 mumol/L. Arteries were removed, cut into rings, and suspended in organ chambers for measurements of isometric force. In selected rings, the endothelium was removed in order to study the function of the smooth muscle. In order to discriminate effects of ischemia/reperfusion and protective properties on coronary endothelium or smooth muscle, drugs with different mechanisms were used. The function of the endothelium were studied with the alpha 2-adrenergic agonist UK 14,304, bradykinin and A 23187. The smooth muscle function were studied with isoproterenol and nitric oxide. Endothelium-dependent relaxations to the alpha 2-adrenergic agonist UK 14,304 and bradykinin, but not to A 23187, were reduced significantly in arteries from hearts stored for 24 hr in cardioplegic solution alone. Relaxations of arteries from hearts stored for 24 hr with H 290/51 were comparable to those arteries from hearts that were not stored. Endothelium-independent relaxations to isoproterenol and nitric oxide among the different groups were comparable. These results suggest that storage of canine hearts with crystalloid cardioplegia selectively inhibits endothelium-dependent relaxations mediated by receptor activation. Inhibition of lipid peroxidation with H 290/51 preserves these relaxations and may therefore represent a therapeutic alternative to preserve hearts used for transplantation.
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PMID:Protective effects of an indenoindole antioxidant on coronary endothelial function after long-term storage. 748 33

The mechanism underlying reactive hyperemia was investigated in the feline hindquarters vascular bed under natural- and constant-flow conditions. A 30-s occlusion of the distal aorta produced a marked hyperemic increase in distal aortic blood flow that was attenuated by the ATP-sensitive K+ (K+ATP) channel blocking agent, glibenclamide. When blood flow to the hindquarters vascular bed was held constant with a pump, interruption of blood flow for 5- to 90-s periods produced reactive vasodilator responses that increased in magnitude and duration as the period of ischemia increased. The magnitude and duration of the reactive vasodilator responses were reduced by K+ATP channel antagonists and an inhibitor of nitric oxide synthase, whereas indomethacin had no significant effect. In the pulmonary vascular bed, under constant-flow, elevated tone conditions, a 30-s period of ischemia produced a small reactive vasodilator response and a larger secondary vasoconstrictor response. The present data suggest that reactive hyperemia in the hindquarters vascular bed is mediated by the opening of K+ATP channels and nitric oxide release and that the reactive hyperemic response is not pronounced in the pulmonary circulation.
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PMID:Role of K+ATP channels and EDRF in reactive hyperemia in the hindquarters vascular bed of cats. 750 68

Ischemia of a vascular bed followed by reestablishment of blood flow results in an accelerated and severe form of tissue injury known as "reperfusion injury." We have investigated reperfusion injury in cats subjected to either myocardial ischemia-reperfusion or splanchnic ischemia-reperfusion. In both cases, a critical early event after reperfusion is endothelial dysfunction characterized by reduced release of endothelium-derived relaxing factor now known to be nitric oxide (NO). Endothelial dysfunction leads to adherence of polymorphonuclear (PMN) leukocytes to the dysfunctional endothelium. Infusion of a sydnonimine NO donor (C87-3754), but not a similar compound lacking the NO moiety (C88-3934), just before reperfusion protected in both forms of ischemia-reperfusion. In the first case, C87-3754, but not C88-3934, attenuated myocardial necrosis, and in the second case, the NO donor improved survival and moderated the indices of shock. In both cases, C87-3754 preserved the endothelium of the ischemic-reperfused vasculature and exerted anti-PMN effects (i.e., reduced PMN adherence to the endothelium or attenuated PMN release of superoxide radicals). Thus, an NO donor infused at a rate calculated to replace the lost NO from the vascular endothelium of the ischemic region exerts significant protective effects on reperfusion of that ischemic vascular bed.
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PMID:Protection of ischemia-reperfusion injury by sydnonimine NO donors via inhibition of neutrophil-endothelium interaction. 750 65

The cardioprotective actions of SPM-5185, a novel cysteine-containing nitric oxide (NO) donor, were investigated in two models of myocardial ischemia-reperfusion (MI-R) injury. In the first study, dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion followed by 270 min of reperfusion. During reperfusion, animals were randomly assigned to receive intracoronary SPM-5185 (500 nM) or the NO-deficient analogue of SPM-5185, SPM-5267 (500 nM). Transmural myocardial blood flow to the ischemic zone was not different between the SPM-5185 group of dogs and the SPM-5267 group (0.04 +/- 0.01 and 0.03 +/- 0.01 ml/min/g, respectively). Similarly, the area of left ventricular myocardium placed at risk by LAD coronary artery occlusion was equivalent in dogs receiving SPM-5185 (33.6 +/- 3%) and SPM-5267 (30.4 +/- 2%). However, the necrotic area, expressed as a percentage of the area at risk, was reduced by 70% in the SPM-5185-treated dogs (14.5 +/- 4 vs. 47.5 +/- 9%; p < 0.001). Furthermore, cardiac myeloperoxidase activity indicated that fewer neutrophils accumulated in the necrotic zone of the SPM-5185-treated dogs. In the second study, dogs were subjected to 30 min of global myocardial ischemia followed by 1 h of cardioplegic arrest and 1 h of reperfusion. SPM-5185 (10 microM) added to the blood cardioplegia solution resulted in a 95 +/- 14% post-ischemic recovery of contractile function compared with 36 +/- 8% (p < 0.05) in vehicle-treated dogs. Additionally, SPM-5185 treatment completely preserved coronary arterial vasorelaxation to acetylcholine after ischemia and reperfusion and resulted in a 62% reduction in cardiac tissue myeloperoxidase activity (p < 0.05). We conclude that (a) SPM-5185 exerts significant cardioprotection from MI-R injury after regional or global ischemia, and (b) this cardioprotection appears to be related to the inhibition of neutrophil-mediated injury.
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PMID:Endothelial and myocardial cell protection by a cysteine-containing nitric oxide donor after myocardial ischemia and reperfusion. 750 67

The hemodynamic profile and antiarrhythmic properties of pirsidomine, a nitric oxide donor, were examined in pigs. Intravenous administration of pirsidomine (1 mg/kg) to chloralose-anesthetized open-chest pigs resulted in a decreased afterload, and a reduced myocardial contractility and myocardial oxygen consumption (assessed by rate-pressure product), with no alterations in heart rate. After induction of regional myocardial ischemia by occlusion of the left anterior descending coronary artery, pigs given pirsidomine experienced fewer ventricular ectopic beats (119 +/- 29) than control animals did (217 +/- 53; p < 0.05), seen primarily as a reduction in the number of couplets and triplets. Although the incidence of ventricular fibrillation was unaffected by pirsidomine, the time to onset of this arrhythmia was significantly prolonged by this intervention (21.3 +/- 0.9 min versus 16.1 +/- 2.5 min in controls; p < 0.05). Furthermore, the ST-segment depression seen throughout the 30-min occlusion period in controls was not sustained beyond 5 min postocclusion in pirsidomine-treated pigs. Taken together, and in the absence of an ex vivo antiplatelet effect with this dose of pirsidomine, these results suggest that the antiarrhythmic effect of pirsidomine lies in its hemodynamic effects, resulting in a reduction of ischemia. The ex vivo effect of pirsidomine on free radical generation from isolated leukocytes was also investigated. Luminol-enhanced chemiluminescence produced by leukocytes in response to phorbol myristate acetate was markedly depressed in cells isolated from blood withdrawn after administration of pirsidomine, compared with cells tested before drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pirsidomine, a novel nitric oxide donor, suppresses ischemic arrhythmias in anesthetized pigs. 750 68


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