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)

Recently, a new class of drugs has been developed with unique properties with regard to cardiovascular pharmacology: K(+)-channel openers. The increased K+ efflux from smooth muscle cells induced by these drugs is accompanied by a reduced intracellular availability of free Ca++, which in turn induces vascular relaxation. This property is currently being exploited to achieve peripheral and coronary artery dilatation in patients with ischemic heart disease. Cromakalim, pinacidil, and nicorandil, are the most extensively investigated agents in this class. Nicorandil, in addition to its K(+)-channel opener property, also shows a nitrate-like activity on guanylate cyclase of vascular smooth muscle cells. Clinical trials demonstrate that chronic administration of nicorandil can significantly increase exercise tolerance in patients with coronary artery disease. In experimental studies, this drug has also shown protective effects against myocardial injury induced by ischemia and reperfusion, by mechanisms partly independent of its vasodilating properties. These results suggest that K(+)-channel openers may have a relevant place in the pharmacological treatment of patients with ischemic heart disease.
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PMID:[Anti-angina activity of potassium-channel activators]. 802 48

We evaluated the preventive effect of postischemic reperfusion injury by Nicorandil-Mg cardioplegia given just prior to reperfusion as "terminal cardioplegia." Twenty seven dogs were placed on cardiopulmonary bypass and the aorta was cross-clamped for 90 min under hypothermic (17-19 degrees C) cardioplegic arrest. The canine hearts were divided into three groups: in group A (n = 10) the hearts reperfused without any treatment; in group B (n = 9) the hearts received coronary perfusion with Nicorandil-Mg solution (Nic, 8 mg/l; Mg, 20 mEq/l; glucose, 50 g/l) for 2 min just prior to reperfusion; and in group C (n = 8) the hearts received coronary perfusion with Nicorandil-Mg free solution (glucose, 50 g/l). During and after ischemia, the myocardial tissue PCO2 (t-PCO2) was continuously monitored by an ion-sensitive field effective transistor (ISFET) sensor. In addition, the myocardial tissue blood flow (TBF), oxygen consumption, and lactate flux were then calculated at 5, 10, 20, and 40 min of reperfusion. In the initial reperfusion period, Group B showed an improved TBF compared to group A and C (at 5 min, group B was 42.7 +/- 11.9; group A was 29.4 +/- 11.2, P < 0.025; and group C was 33.9 +/- 9.2% of the preischemic control level, P < 0.05). T-PCO2 in group B was significantly decreased at 5 min of reperfusion (group B, 127.5 +/- 22.5-->42.5 +/- 9.7; group A, 117.5 +/- 23.0-->85.2 +/- 17.4, P < 0.001; group C, 122.3 mmHg-->68.2 +/- 18.7 mmHg, P < 0.01), and group B had a better metabolic recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prevention of postischemic reperfusion injury: the improvement of myocardial tissue blood flow after ischemia by terminal nicorandil-Mg cardioplegia. 831 89

Nicorandil is a compound with hybrid properties of nitrates and adenosine triphosphate (ATP)-sensitive potassium channel (KATP) opening. The effects of nicorandil and isosorbide dinitrate (ISDN) were investigated in a model of 60-min coronary occlusion/180-min reperfusion in open chest pigs. Three groups of 10 pigs were randomly assessed to receive saline or equihypotensive doses of nicorandil or ISDN. Drug infusion was started at 30 min of ischemia and continued throughout reperfusion. Area at risk (AAR) and infarcted area (IA) were assessed by monastral blue dye-triphenyltetrazolium dual staining technique and calculated by planimetry. Myeloperoxidase concentration (MPO) in the non-ischemic area and in the IA was assessed as an index of presence of neutrophils. Measurements of reduced glutathione (GSH), oxidized glutathione (GSSG), lipofuscine, and malondialdehyde were performed on coronary vein blood as indexes of oxidative stress. IA, as a percentage of AAR, was 78 +/- 10% after saline, 61 +/- 12% after N (p < 0.05 vs. saline), and 69 +/- 14% after ISDN (not significant vs. saline). Cardiac output and left ventricular dP/dt were depressed during coronary occlusion in all groups and their recovery during reperfusion was earlier in the nicorandil group. In the saline group, MPO was increased in the IA compared to the nonischemic area (78 +/- 63 vs. 21 +/- 21 micrograms/mg prot, p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Limitation of myocardial infarct size by nicorandil after sustained ischemia in pigs. 858 91

Nicorandil is a clinically used nitrovasodilator that has a property as an opener of ATP-sensitive potassium (KATP) channels in vitro. We examined whether nicorandil at a clinically used dose augmented regional ischemia-induced monophasic action potential (MAP) shortening and increase in extracellular potassium concentration ([K+]o), and how it affected arrhythmia occurrence. Five-minute occlusion of a distal site of the left anterior descending coronary artery (LAD) was repeated at 30-min intervals in anesthetized open-chest dogs while recording MAP or measuring [K+]o with a potassium-sensitive valinomycin electrode from the epicardial center of the ischemic myocardium. Nicorandil (0.2-0.5 mg/kg) was administered intravenously (i.v.) 5 min before the third occlusion, and the data were compared with those during the second occlusion (control). During the second occlusion, MAP duration at 90% repolarization (APD90) shortened (mean rate for 5 min, 13 +/- 3%, n = 11) and [K+]o increased from 3.7 +/- 0.1 to 6.2 +/- 0.8 mM at 5 min (n = 12). These changes were reversed < or = 3 min after reperfusion. Before the third occlusion, baseline APD90 and [K+]o were not altered by nicorandil; however, the extent of occlusion-induced shortening of APD90 (25 +/- 4%) and [K+]o increase (7.8 +/- 1.6 mM) was augmented by the pretreatment. The drug effect was attenuated by a concomitant pretreatment with 5-hydroxydecanoate, a specific blocker of KATP channels (n = 2). The prevalence of ventricular fibrillation (VF) during occlusion/reperfusion sequence was reduced after nicorandil (1 of 25 vs. 5 of 25) without de novo VF. These results suggest that nicorandil at a clinical dose facilitates regional ischemia-induced activation of myocardial KATP channels without causing serious proarrhythmia. Such a property might help protect the myocardium against ischemia/reperfusion damage.
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PMID:Nicorandil augments regional ischemia-induced monophasic action potential shortening and potassium accumulation without serious proarrhythmia. 860 33

The effects of nicorandil on coronary collateral circulation during exercise-induced ischemia were compared between the different donor arteries in 13 patients with effort angina, 7 with complete obstruction of the left anterior descending artery (LAD) with well-developed collateral vessels from the right coronary artery (RCA) (LAD group), and 6 with complete occlusion of the RCA (segment 2-3) with well-developed collateral vessels from the LAD (RCA group). Initial percentage thallium (%TI) uptake (thallium-201 single photon emission computed tomography) and washout rate were measured in the anterior, septal and posterior regions during ergometer exercise. The submaximal treadmill exercise test was also performed using a cardiopulmonary monitoring system to measure Vo2 at anaerobic threshold (AT). After the controls were obtained, nicorandil (15 mg/day) was administered for 4 weeks, during which ergometer exercise and treadmill exercise tests were carried out repeatedly. A significant improvement of initial %TI uptake on exercise was observed in the LAD group with nicorandil therapy, but no improvement was shown in the RCA group. The AT significantly increased after nicorandil treatment in the LAD group (13.9 +/- 0.38-->16.8 +/- 1.18 ml/min/kg), reflecting the improvement of cardiac function through the increased collateral flow. However, in the RCA group, it remained unchanged, suggesting no improvement of cardiac function. Nicorandil was effective to increase collateral flow from the RCA, but ineffective on that from the LAD. Nicorandil is an effective coronary dilator and is reported to affect both large and small coronary arteries. The effect on the collateral circulation is dependent on the donor artery supplying different areas. The vasodilator effect of nicorandil is mainly on the LAD, which is large enough to supply blood to a wider area of the heart, rather than the RCA.
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PMID:[Effects of nicorandil on coronary collateral circulation depend on the donor arteries]. 895 99

The role of cation and cellular energy homeostasis in ATP-sensitive K(+)(K(ATP)) channel-induced cardioprotection is poorly understood. To evaluate this, rapidly interleaved(23)Na and(31)P NMR spectra were acquired from isolated rat hearts exposed to direct K(ATP)channel activation from nicorandil or pinacidil. Nicorandil attenuated ATP depletion and intracellular Na(+)(Na(+)(i)) accumulation, delayed the progression of acidosis during zero-flow ischemia and prevented ischemic contracture. The K(ATP)channel inhibitor 5-hydroxydecanoate abolished these effects. Pinacidil did not alter Na(+)(i)accumulation, ATP depletion or pH during ischemia under the conditions employed. Both agonists greatly improved the post-ischemic functional recovery. Both agonists also dramatically improved the rate and extent of the reperfusion recoveries of Na(+)(i), PCr and ATP. The Na(+)(i)and PCr reperfusion recovery rates were tightly correlated, suggesting a causal relationship. Separate atomic absorption tissue Ca(2+)measurements revealed a marked reperfusion Ca(2+)uptake, which was reduced two-fold by pinacidil. In conclusion, these results clearly indicate that while K(ATP)channel-induced metabolic alterations can vary, the functional cardioprotection resulting from this form of pharmacological preconditioning does not require attenuation of acidosis, cellular energy depletion, or Na(+)(i)accumulation during ischemia. Rather than preservation of cationic/energetic status during ischemia, the cardioprotective processes may involve a preserved capability for its rapid restoration during reperfusion. The enhanced reperfusion Na(+)(i)recovery may be enabled by the improved reperfusion cellular energy state. This accelerated Na(+)(i)recovery could play an important cardioprotective role via a potential causal relationship with the reduction of reperfusion tissue Ca(2+)uptake and resultant reperfusion injury.
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PMID:The effect of K(atp)channel activation on myocardial cationic and energetic status during ischemia and reperfusion: role in cardioprotection. 1118 Oct 22

The human heart progressively becomes more tolerant to ischemia after repeated balloon inflations during percutaneous transluminal coronary angioplasty (PTCA). The present study investigated whether nicorandil, a hybrid between nitrate and an ATP-sensitive potassium channel opener, affects this ischemic preconditioning. Sixteen patients with stable angina pectoris caused by left anterior descending artery lesions were subjected to 2 balloon inflations of 2-min duration with a 3-min reperfusion period. Seven of these patients served as the control group and in the remaining 9 patients, nicorandil was administered intravenously (6 mg/h) throughout the PTCA procedure (nicorandil group). The lactate extraction ratio (LER) was obtained at 30 s after each ischemic event (LERpost-1 and LERpost-2) in both groups. In the control group, LERpost-1 was more negative than LERpost-2 (-185.7+/-74.2 vs -98.0+/-37.3%, p<0.01). The ratio of the sum of the ST elevation in the precordial leads during the second inflation (sumST-2, 0.94+/-0.66 mV) to that during the first inflation (sumST-1, 1.43+/-1.17 mV) was 0.72+/-0.16 in the control group, which was less than the ratio in the nicorandil group (1.06+/-0.13, p<0.01). Nicorandil abolished the difference between the 2 ischemic events (LERpost-1, -45.1+/-41.6 vs LERpost-2, -43.5+/-51.1%; sumST-1, 1.38+/-0.80 vs sumST-2, 1.46+/-0.90 mV). LER was less negative in the nicorandil group than that in the control group (LERpost-1, -45.1+/-41.6 vs -185.7+/-74.2%, p<0.01; LERpost-2, -43.5+/-51.1 vs -98.0+/-37.3%, p<0.05). Thus, nicorandil improved lactate metabolism during PTCA without significantly influencing ST-elevation. In conclusion, intravenous pre-administration of nicorandil appears to precondition the human heart during PTCA.
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PMID:Nicorandil, a hybrid between nitrate and ATP-sensitive potassium channel opener, preconditions human heart to ischemia during percutaneous transluminal coronary angioplasty. 1140 35

Nicorandil is a hybrid potassium channel opener, and recent experimental studies have demonstrated its efficacy in myocardial protection against ischemia-reperfusion. This clinical study was designed to examine the myocardial protective effect of nicorandil administered during cardiopulmonary bypass. Seventy adult patients, 53 men and 17 women, undergoing elective coronary artery bypass grafting were randomly assigned to two groups, one receiving nicorandil during cardiopulmonary bypass (group N, n = 35) and the other receiving no nicorandil for control (group C, n = 35). Nicorandil was administered at each dose of 0.1 mg/kg into the cardiopulmonary bypass circuit according to the following schedule: (1) bolus injection at the initiation of cardiopulmonary bypass, (2) continuous infusion for 5 min before aortic cross-clamping, (3) bolus administration at 5 min before reperfusion, and (4) continuous infusion for 5 min before reperfusion. The time required for achieving cardiac arrest after the initial cardioplegia was significantly reduced in group N in comparison with that in group C. After aortic unclamping, the number of patients showing a significant ST segment change on the electrocardiogram was significantly fewer in group N, whereas the number of patients showing spontaneous recovery of heart beat was significantly greater. As for the myocardial protective effect, group N showed lower plasma levels of malondialdehyde, human-heart fatty acid-binding protein, and peak creatine kinase-MB, and required lower doses of catecholamine. Our results suggest that nicorandil administration during cardiopulmonary bypass provides enhanced myocardial protective effects against ischemia-reperfusion in patients undergoing coronary artery bypass grafting.
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PMID:Controlled nicorandil administration for myocardial protection during coronary artery bypass grafting under cardiopulmonary bypass. 1144 99

The present study investigated the effects of ischemic preconditioning (IPC) and nicorandil pretreatment on myocardial storage in a donor heart preservation model. Isolated rat hearts were separated into groups: group 1, non-preconditioned control group; group 2, 2.5 min of normothermic ischemia followed by 15 min of normothermic Langendorff perfusion (one IPC cycle); and group 3, 2 cycles of IPC. All hearts were subsequently stored in University of Wisconsin solution at 4 degrees C for 2, 4 and 6h, and the concentrations of high-energy phosphate metabolites were measured for each time point. Heart function parameters (aortic flow, coronary flow and cardiac output) were measured when the heart was reperfused following the 2, 4 or 6 h of preservation. The effects of nicorandil, an ATP-sensitive potassium channel opener, on heart function following preservation were also evaluated. Nicorandil was injected intravenously before heart harvesting. The results showed that the energy status was well preserved in the IPC groups. The 2-cycle IPC group showed better recovery of heart function following preservation. Pretreatment with nicorandil also improved functional recovery of the heart following preservation. The present study showed that IPC of the rat heart resulted in improved myocardial energy metabolism and functional recovery after hypothermic preservation, and that nicorandil has potential for pharmacological preconditioning in heart preservation for transplantation.
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PMID:Ischemic preconditioning and nicorandil pretreatment improve donor heart preservation. 1144 5

Nicorandil (SG75) is a potent K+-channel activator with an additional nitro moiety. In the present study we investigated the potential mechanisms (K+-channel activation and nitric oxide [NO] release) for the effects of nicorandil on isolated perfused rat hearts during total global ischemia using 31P-nuclear magnetic resonance. After a 10-min control perfusion, hearts were subjected to treatment with nicorandil-containing (100, 300, or 1000 microM) buffer for 10 min, 15 min of total global ischemia, and 30 min of reperfusion. At high dose (10(-3) M), nicorandil reduced ATP depletion during ischemia by 26% compared with untreated hearts. Blockade of K+ channels by glibenclamide prevented this protective effect. At all doses (10(-4) to 10(-3) M), nicorandil reduced the accumulation of protons during ischemia compared with untreated hearts (pH 6.22 +/- 0.03 vs. 6.02 +/- 0.05 in untreated hearts at the end of ischemia). This effect was preserved after blockade of K+ channels by glibenclamide. Hearts treated with nitroglycerine before ischemia also showed reduced proton accumulation. Therefore, NO release accompanied by increased coronary flow before ischemia, which is caused by the nitro moiety of nicorandil and nitroglycerine treatment, results in reduced proton accumulation. During reperfusion, a pro-arrhythmic effect was observed in hearts treated with the nonpharmacologically high dose of nicorandil (1000 microM). Thus, we conclude that the effects of nicorandil are caused by the simultaneous action of both mechanisms K+-channel activation and NO release. The activation of K+ channels prevents deterioration of ATP during ischemia, whereas NO release and increased coronary flow reduce the accumulation of protons--and thus the decrease in pH--during ischemia.
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PMID:Mechanisms of the effects of nicorandil in the isolated rat heart during ischemia and reperfusion: a 31P-nuclear magnetic resonance study. 1177 27


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