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)

Effects of therapy with the potassium-channel opener and vasodilator nicorandil were studied in reperfused infarction of hypertrophied hearts by using magnetic resonance imaging (MRI), hemodynamic measurements, and histochemical staining. Aortic banding was performed on 22 Sprague-Dawley rats to induce left ventricular (LV) hypertrophy; 11 were the controls. Eight weeks later, the left coronary artery was occluded for 25 minutes in all 33 animals, followed by 3 hours of reperfusion. During occlusion, 11 rats with LV hypertrophy received nicorandil (0.1 mg/kg bolus and 1.5 mg/kg/h for 3 hours). The new necrosis-specific contrast agent Gadophrin-3 was administered to all animals to delineate infarction on multislice T1-weighted spin-echo MRI. Nicorandil increased ischemic tolerance of LV hypertrophy as shown by the reduction of infarction size from 19.3% +/- 1.3% to 10.0% +/- 2.5% LV (P = .005). Infarction size in treated animals was identical to control (9.3% +/- 1.6%). Close correlation was found between MRI and postmortem findings. Functional MRI revealed an improvement in ejection fraction in nicorandil-treated hearts (48.5% +/- 3.4% vs 38.1% +/- 3.2%, P = .04). LV end-diastolic volume and pressure, aortic pressure, and peripheral vascular resistance were highest in untreated hypertrophied hearts. Brief ischemia caused severe injury in hypertrophied hearts. Infusing nicorandil increased the tolerance of hypertrophied hearts to ischemia. MRI is a suitable technique for the evaluation of new therapies in LV hypertrophy.
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PMID:Effect of potassium-channel opener therapy on reperfused infarction in hypertrophied hearts: demonstration of preconditioning by using functional and contrast-enhanced magnetic resonance imaging. 1537 40

Left ventricular (LV) hypertrophy and myocardial infarction play important roles in the progressive LV dysfunction. We hypothesized that the potassium-channel opener and nitrate-like vasodilator nicorandil prevents the development of LV hypertrophy and preserves myocardial viability. Twenty-four rats were subjected to aortic stenosis for 8 weeks to produce LV hypertrophy and assigned to non-treated and nicorandil-treated (3 mg/kg/d) groups. A third group (n = 12) without stenosis or treatment served as control. All 36 animals were subjected to reperfused infarction by 25-minute occlusion of the left coronary artery followed by 3 hours of reperfusion. Spin-echo magnetic resonance (MR) images were acquired to measure infarction size, LV mass, volumes, ejection fraction, and wall thickness. A necrosis-specific contrast agent, Gadophrin-3, was used to delineate necrotic myocardium. Aortic and LV pressures were measured invasively. At postmortem, LV mass and infarction size were determined and compared with MR findings. Nicorandil prevented the development of LV hypertrophy. Infarction size of nicorandil-treated animals was similar to control animals. Non-treated animals with aortic banding had higher LV mass (P < 0.001), lower ejection fraction (P = 0.006), and larger infarction size (P < 0.001) than treated and control animals. MR and postmortem data showed close agreement. Nicorandil therapy prevented the development of cardiac hypertrophy and protected myocardium against ischemia.
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PMID:Long-term oral treatment with nicorandil prevents the progression of left ventricular hypertrophy and preserves viability. 1577 22

Ischemia-reperfusion injury is responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. Recently, it has been reported that mitochondrial K(ATP) channel openers have an effect on myocardial protection via a pharmacological preconditioning action. However, it remains unclear as to whether K(ATP) channel openers can reduce ischemia-reperfusion injury in the liver. The aim of this study was to determine the effects of the mitochondrial K(ATP) channel opener, nicorandil, on ischemia-reperfusion injury in the rat liver. Male Wistar rats were subjected to 73% ischemia for 45 minutes followed by 120 minutes of reperfusion. Nicorandil (3 mg/kg) was orally administered 60 minutes before hepatic ischemia. Nicorandil significantly decreased plasma levels of alanine aminotransferase and lactate dehydrogenase by about 50% and inhibited the remarkably increased TUNEL-positive hepatocytes after reperfusion. Some mediators associated with apoptosis were analyzed by Western blotting. Cytochrome-c and caspase-3 levels in the cytosol increased after reperfusion; nicorandil inhibited the release of cytochrome-c and activation of caspase-3. The expression of Bax and Bcl-2 was significantly increased after reperfusion, being slightly inhibited by the administration of nicorandil. These results suggest that the protective effects of nicorandil against hepatic ischemia-reperfusion injury correlate with the inhibition of mitochondrial cytochrome-c release and caspase-3 activation. These findings demonstrate that nicorandil may become a therapeutic drug for ischemia reperfusion-related liver injury.
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PMID:Mitochondrial K(ATP) channel opener prevents ischemia-reperfusion injury in rat liver. 1580 66

The cardioprotective efficacy of nicorandil in cardiac surgery was determined using a surgically relevant 4-hr cardioplegic arrest model. Each isolated rabbit heart was parabiotically blood-perfused using a modified Langendorff column. The magnitude of left ventricular developed pressure and rate of change of developed pressure over time were measured before (baseline) and after ischemia. Nicorandil was administered either pre-ischemia, post-ischemia, pre/post-ischemia, or continuously (before, during, and after ischemia). The endothelium of the coronary artery was observed by scanning electron microscopy. Serum myeloperoxidase activities were also measured. Although pretreatment with nicorandil did not affect recovery of developed pressure, administration of nicorandil after ischemia, or before and after ischemia, enhanced the recovery of developed pressure. Serum myeloperoxidase activity was decreased in the pre/post-ischemia and continuous groups. Endothelial reperfusion injury decreased in all nicorandil-treated groups. Administration of nicorandil attenuated ischemia-reperfusion injury of the myocardium and coronary endothelium while ameliorating leukocyte activation. In the event of unexpected prolonged cardioplegic arrest, administration of nicorandil, even just after declamping, may improve cardiac function. However, pre-ischemia administration alone was not helpful in the heart subjected to prolonged cardioplegic arrest.
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PMID:Nicorandil attenuates reperfusion injury after long cardioplegic arrest. 1754 Sep 88

Nicorandil, a selective mitochondrial K(ATP) channel opener, reinstates the waned protection after multiple cycles of preconditioning. In this study, we determined the signal transduction activated in heart after 3 or 8 cycles of preconditioning and prolonged ischemia in rabbits treated with placebo or nicorandil. In a first series (eight groups) we evaluated the (%) infarct to risk ratio after 30 min ischemia/3 h reperfusion and in a second series (six groups), we assessed the intracellular levels of cyclic GMP (c-GMP), protein kinase C (PKC) activity and p38-mitogen activated protein kinase (p38-MAPK) phosphorylation from heart samples taken during the long ischemia. Cardioprotection by 3 cycles of preconditioning (11.7+/-3.8% vs 45.9+/-5.2% in the control, P<0.001) was lost after 8 cycles (43.9+/-5.1%, P=NS vs control). Nicorandil restored it to the levels of classic preconditioning (13.7+/-2.4% vs 40.8+/-3.5% in respective controls, P<0.001). This was reversed by the p38-MAPK inhibitor SB203580 (48.8+/-5.1%) which had no protective effect in the control group (44.6+/-5.8%). In the placebo-treated rabbits, intracellular c-GMP and PKC were increased only in the group subjected to 3 cycles of preconditioning. Despite that nicorandil equalizes the intracellular levels of c-GMP, PKC and activated p38-MAPK at the long ischemia, specific alterations of p38-MAPK phosphorylation differentiate the protected groups. Our data delineate the signal transduction mechanism mediating the beneficial effect of nicorandil and imply that the recapture of the lost protection is due to a dynamic process of the intracellular mediators accompanied by an increase in p38-MAPK phosphorylation and not to an instantaneous event.
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PMID:p38-MAPK is involved in restoration of the lost protection of preconditioning by nicorandil in vivo. 1803 32

Ischemia followed by reperfusion is known to negatively affect mitochondrial function by inducing a deleterious condition termed mitochondrial permeability transition. Mitochondrial permeability transition is triggered by oxidative stress, which occurs in mitochondria during ischemia-reperfusion as a result of lower antioxidant defenses and increased oxidant production. Permeability transition causes mitochondrial dysfunction and can ultimately lead to cell death. A drug able to minimize mitochondrial damage induced by ischemia-reperfusion may prove to be clinically effective. We aimed to analyze the effects of nicorandil, an ATP-sensitive potassium channel agonist and vasodilator, on mitochondrial function of rat hearts and cardiac HL-1 cells submitted to ischemia-reperfusion. Nicorandil decreased mitochondrial swelling and calcium uptake. It also decreased reactive oxygen species formation and thiobarbituric acid reactive substances levels, a lipid peroxidation biomarker. We thus confirm previous reports that nicorandil inhibits mitochondrial permeability transition and demonstrate that nicorandil inhibits this process by preventing oxidative damage and mitochondrial calcium overload induced by ischemia-reperfusion, resulting in improved cardiomyocyte viability. These results may explain the good clinical results obtained when using nicorandil in the treatment of ischemic heart disease.
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PMID:Nicorandil protects cardiac mitochondria against permeability transition induced by ischemia-reperfusion. 1841 69

Whether nicorandil is effective at preventing ventricular tachyarrhythmia (VT) during acute myocardial ischaemia is still controversial. We examined effects of nicorandil on the induction of VT during acute myocardial ischaemia. Optical action potentials were recorded from the entire transmural wall of arterially perfused canine left ventricular wedges. Ischaemia was produced by arterial occlusion for 20 min. During endocardial pacing, nicorandil shortened mean action potential duration (APD) in the transmural wall before ischaemia and further shortened it during ischaemia without increasing dispersion of APD. HMR1098, a selective blocker of sarcolemmal ATP-sensitive K(+) channels, inhibited the shortening of APD by nicorandil before and during ischaemia. Ischaemia decreased transmural conduction velocity (CV). Nicorandil partially restored CV to a similar extent in the absence and presence of HMR1098. In contrast, HMR1098 did not suppress the ischaemic conduction slowing in the absence of nicorandil. Nicorandil suppressed the increased dispersion of local CV during ischaemia. Isochrone maps on the initiation of VT showed that reentry in the transmural surface resulted from the excitation of the epicardial region of transmural surface. Nicorandil significantly increased the size of non-excited area in the epicardial region of the transmural wall, thereby significantly reducing the incidence of VT induced during ischaemia. HMR1098 inhibited this effect of nicorandil. These results suggest that nicorandil prevents VT during acute global ischaemia primarily by augmenting the inactivation of epicardial muscle through the activation of sarcolemmal K(ATP) channels.
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PMID:Mechanisms of preventive effect of nicorandil on ischaemia-induced ventricular tachyarrhythmia in isolated arterially perfused canine left ventricular wedges. 1848 46

Aim of the work was to study effect of nicorandil [N-(2-nitrooxiethyl) nicotinamide, SG75] on blood pressure (BP), heart rate (HR) and rhythm disturbances during regional ischemia and reperfusion of the heart in rats in vivo and its ability to limit acute myocardial infarction (MI). Nicorandil was obtained by nitrating nicotinamide ethanol using produced by industry ethylnicotinate. MI in Wistar rats was modeled by 40-min occlusion of anterior descending coronary artery (ADCA) and subsequent 60-min reperfusion. Nicorandil (3,2 mmol/kg) was administered intravenously before occlusion. Nitroglycerine was used as preparation of comparison; it was administered in the same dose. MI area and zone at risk (ZR) were measured by computer planimetry after staining of left ventricular sections with 2, 3, 5-triphenyltetrazolium chloride. Lowering of mean BP under influence of nicorandil during ADCA occlusion and subsequent reperfusion were deeper and longer than under influence of nitroglycerine. Contrary to nitroglycerine administration of nicorandil did not cause decrease of HR. Administration of both drugs postponed origination of rhythm disturbances during ischemia but did not affect their duration. MI dimension assessed by MI/ZR ratio after administration of nicorandil and nitroglycerine was significantly lowered down to 22 +/- 4 and 32 +/- 3%, respectively, compared with 47 +/- 3% in control. The results obtained evidence that in this model of ischemic and reperfusion damage of the heart vasodilating properties of nicorandil combined with decrease of postischemic loss of cardiomyocytes in ZR are comparable with effects of nitroglycerine.
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PMID:[The study of vasodilative and antiischemic function of nicorandil in regional ischemia and reperfusion of rat heart in vivo]. 1853 1

ATP-sensitive potassium channels (K(ATP) channels) regulate vascular tone and cardiac contraction through their action on the membrane potential of smooth muscle cells and cardiomyocytes. Because aging and diseases alter K(ATP) channel activity, many pharmacological treatments aimed at improving their function, therefore cardiovascular function, have been evaluated. Nicorandil, a K(ATP) channel opener, nitric oxide donor and antioxidant, is used as a treatment of angina pectoris and induces vasodilation, blood pressure decrease and cardioprotection in aging as well as after ischemia-reperfusion. Here, using the patch-clamp technique, we have studied the effect a chronic low dose of nicorandil (0.1 mg/kg per day for 2 months), on the activity of cardiomyocyte K(ATP) channels as a function of age, in newborn, 4-, 12- and 24-month old rats. Nicorandil exerted an anti-oxidant and protective action on cardiomyocyte K(ATP) channels, especially in aged animals, leading to restoration of a normal channel activity. These findings could justify further therapeutical applications.
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PMID:Nicorandil protects ATP-sensitive potassium channels against oxidation-induced dysfunction in cardiomyocytes of aging rats. 1901 89

The purpose of this study was to assess the effects of the addition of Nitroglycerin or Nicorandil to University of Wisconsin solution in long-term myocardial preservation. In a model of heterotopic heart transplantation in pigs, the donor heart was preserved for 24 hours by means of continuous perfusion in this solution, in the presence or absence of these drugs. During this period, the oxygenation and pH of the solution were measured, as were lactate concentrations and enzyme release. At regular intervals following reperfusion we measured the concentrations of enzymes, antioxidants, glutathione peroxidase, glutathione reductase, malondialdehyde, endothelin and nitrite, and, two hours later, samples of both ventricles were taken for a morphological study. In the treated groups there was a higher lactate production during preservation and, during reperfusion, the signs of contracture and the elevation of enzyme levels were more marked than in the untreated groups. In contrast, the glutathione reductase concentrations did not decrease during the first phase of reperfusion and were directly correlated with those of antioxidants, endothelin levels increased less than in the untreated groups and, in the case of nitroglycerin, the nitrite concentration was significantly greater than in the remaining groups. We conclude that nitroglycerin and nicorandil improved the oxidative state and endothelial function and did not produce substantial morphological changes, but increased cell necrosis and contracture, possibly due to the duration of ischemia.
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PMID:Supplementation of University of Wisconsin solution with Nitroglycerin and Nicorandil in long-term myocardial preservation: effects on the oxidative state, endothelial function and morphology. 1979 47


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