Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of the ATP-sensitive potassium channel (KATP) during myocardial ischemia leads to potassium efflux, reductions in action potential duration and the formation of ventricular fibrillation (VF). Drugs that inactivate KATP should prevent these changes and thereby prevent VF. However, most KATP antagonists also alter pancreatic channels, which promote insulin release and hypoglycemia. Recently, a cardioselective KATP antagonist, HMR 1883, has been developed that may offer cardioprotection without the untoward side effects of existing compounds. Therefore, VF was induced in 13 mongrel dogs with healed myocardial infarctions by a 2-min coronary artery occlusion during the last minute of a submaximal exercise test. On subsequent days, the exercise-plus-ischemia test was repeated after pretreatment with HMR 1883 (3.0 mg/kg i.v., n = 13) or glibenclamide (1.0 mg/kg i.v., n = 7). HMR 1883 (P < .001) and glibenclamide (P < .01) prevented VF in 11 of 13 and 6 of 7 animals, respectively. Glibenclamide, but not HMR 1883, elicited increases in plasma insulin and reductions in blood glucose. Glibenclamide also reduced (P < .01) both mean coronary blood flow and left ventricular dP/dt maximum as well as the reactive hyperemia induced by 15-sec coronary occlusions (-30.3 +/- 11%), whereas HMR 1883 did not alter this increase in coronary flow (-3.0 +/- 4.7%). Finally, myocardial ischemia (n = 10) significantly (P < .01) reduced refractory period (control, 121 +/- 2 msec; occlusion, 115 +/- 2 msec), which was prevented by either glibenclamide or HMR 1883. Thus, the cardioselective KATP antagonist HMR 1883 can prevent ischemically induced reductions in refractory period and VF without major hemodynamic effects or alterations in blood glucose levels. These data further suggest that the activation of KATPs may play a particularly important role in both the reductions in refractory period and lethal arrhythmia formation associated with myocardial ischemia.
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PMID:HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part II: effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs. 973 12

ATP-sensitive potassium (K(ATP)) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial K(ATP) channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p<.05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (-0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, -0.14 mV; Q-J time, +15 ms), indicating the importance of K(ATP) channels in the genesis of these changes. In conclusion, the K(ATP) channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.
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PMID:ATP-sensitive potassium channel blocker HMR 1883 reduces mortality and ischemia-associated electrocardiographic changes in pigs with coronary occlusion. 1052 61

Ventricular fibrillation (VF) is a major cause of sudden cardiac death in which myocardial ischemia plays a leading role. During ischaemia activation of ATP-sensitive potassium channels (K(ATP)) occurs, leading to potassium efflux from cardiomyocytes and shortening of the action potential favoring the genesis of ventricular fibrillation. In confirmation of this concept the sulfonylurea glibenclamide, which stimulates insulin release by inhibition of pancreatic K(ATP) channels, has been shown to inhibit VF in different models of ischaemia by inhibition of myocardial K(ATP) channels. HMR 1883 (1-[15-12-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective K(ATP) channel blocker. The aim of this study was to show that with this compound it is possible to separate the antifibrillatory from the insulin-releasing effect for the treatment of patients at risk of ischaemia-induced arrhythmias and sudden death. In the present study HMR 1883 reduced VF in Sprague-Dawley rats during prolonged ischaemia and also diminished mortality and the duration of VF in a separate reperfusion experiment at 3 mg/kg and 10 mg/kg with no effect on blood glucose or insulin. Glibenclamide, which was antifibrillatory at 0.3 mg/kg and 1 mg/kg, increased plasma insulin and lowered blood glucose already at a dose as low as 0.01 mg/kg. In conclusion, based on its antifibrillatory action and the absence of significant pancreatic effects at therapeutic doses, HMR 1883 is of potential clinical utility for the prevention of severe arrhythmias in patients with ischaemic heart disease.
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PMID:HMR 1883, a cardioselective K(ATP) channel blocker, inhibits ischaemia- and reperfusion-induced ventricular fibrillation in rats. 1054 31

ATP-sensitive potassium channels (KATP) open during myocardial ischemia. The ensuing repolarising potassium efflux shortens the action potential. Accumulation of extracellular potassium is able to partially depolarise the membrane, reducing the upstroke velocity of the action potential and thereby impairing impulse conduction. Both mechanisms are believed to be involved in the development of reentrant arrhythmias during cardiac ischemia. The sulfonylthiourea HMR 1883 (1-[[5-[2-(5-chloro-O-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective KATP channel blocker for the prevention of arrhythmic sudden death in patients with ischemic heart disease. The aim of this study was to show that this compound, which has already shown antifibrillatory efficacy in dogs and rats, is able to inhibit ischemic changes of the action potential induced by coronary artery occlusion in anesthetised pigs. Action potentials were taken in situ with the technique of monophasic action potential (MAP) recording. In a control group (n=7), three consecutive occlusions of a small branch of the left circumflex coronary artery resulted in reproducible reductions in MAP duration and a decrease in upstroke velocity. In a separate group (n=7), HMR 1883 (3 mg/kg i.v.) significantly (P<0.05) reduced the ischemia-induced shortening of the MAP: during the first and second control occlusion of the coronary artery in the HMR 1883-group, MAP50 duration shortened from 218.5 +/- 3.0 ms to 166.7 +/- 3.3 ms and from 219.7 +/- 4.5 ms to 164.9 +/- 1.8 ms, respectively. After HMR 1883, during the third occlusion, MAP duration decreased from 226.9 +/- 3.6 ms to 205.3 +/- 4.3 ms only corresponding to 59% inhibition. HMR 1883 also improved the upstroke velocity of the MAP, which was depressed by ischemia: in the two preceding control occlusions ischemia prolonged the time to peak of the MAP, an index for upstroke velocity, from 10.83 +/- 0.43 ms to 39.42 +/- 1.60 ms and from 12.97 +/- 0.40 ms to 37.17 +/- 2.98 ms, respectively. With HMR 1883, time to peak during ischemia rose from 12.42 +/- 0.51 ms to 25.53+/-2.51 ms only, corresponding to an average inhibitory effect of 53.4%. The irregular repolarisation contour of the ischemic MAP was also improved. In conclusion, the present results indicate that HMR 1883 effectively blocks myocardial KATP channels during coronary ischemia in anesthetised pigs, preventing an excessive shortening of the action potential and improving excitation propagation.
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PMID:K(ATP) channel blocker HMR 1883 reduces monophasic action potential shortening during coronary ischemia in anesthetised pigs. 1068 70

We examined the role of the sarcolemmal and mitochondrial ATP-sensitive potassium (K(ATP)) channel in a rat model of myocardial infarction after stimulation with the selective delta(1)-opioid receptor agonist TAN-67. Hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk. TAN-67 significantly reduced infarct size/area at risk (29.6 +/- 3.3) versus control (63. 1 +/- 2.3). The sarcolemmal-selective K(ATP) channel antagonist HMR 1098, administered 10 min before TAN-67, did not significantly attenuate cardioprotection (26.0 +/- 7.3) at a dose (3 mg/kg) that had no effect in the absence of TAN-67 (56.3 +/- 4.3). Pretreatment with the mitochondrial selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before the 30-min occlusion completely abolished TAN-67-induced cardioprotection (54.3 +/- 2.7), but had no effect in the absence of TAN-67 (62.6 +/- 4.1), suggesting the involvement of the mitochondrial K(ATP) channel. Additionally, we examined the antiarrhythmic effects of TAN-67 in the presence or absence of 5-HD and HMR 1098 during 30 min of ischemia. Control animals had an average arrhythmia score of 10.40 +/- 2.41. TAN-67 significantly reduced the arrhythmia score during 30 min of ischemia (2.38 +/- 0. 85). 5-HD and HMR 1098 in the absence of TAN-67 produced an insignificant decrease in the arrhythmia score (8.80 +/- 2.56 and 4. 20 +/- 1.07, respectively). 5-HD administration before TAN-67 treatment abolished its antiarrhythmic effect (4.71 +/- 1.11). However, HMR 1098 did not abolish TAN-67-induced protection against arrhythmias (1.67 +/- 0.80). These data suggest that delta(1)-opioid receptor stimulation is cardioprotective against myocardial ischemia and sublethal arrhythmias and suggest a role for the mitochondrial K(ATP) channel in mediating these cardioprotective effects.
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PMID:Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive potassium channels. 1090 Feb 18

Isoflurane mimics the cardioprotective effect of acute ischemic preconditioning with an acute memory phase. We determined whether isoflurane can induce delayed cardioprotection, the involvement of ATP-sensitive potassium (K(ATP)) channels, and cellular location of the channels. Neonatal New Zealand White rabbits at 7-10 days of age (n = 5-16/group) were exposed to 1% isoflurane-100% oxygen for 2 h. Hearts exposed 2 h to 100% oxygen served as untreated controls. Twenty-four hours later resistance to myocardial ischemia was determined using an isolated perfused heart model. Isoflurane significantly reduced infarct size/area at risk (means +/- SD) by 50% (10 +/- 5%) versus untreated controls (20 +/- 6%). Isoflurane increased recovery of preischemic left ventricular developed pressure by 28% (69 +/- 4%) versus untreated controls (54 +/- 6%). The mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) completely (55 +/- 3%) and the sarcolemmal K(ATP) channel blocker HMR 1098 partially (62 +/- 3%) attenuated the cardioprotective effects of isoflurane. The combination of 5-HD and HMR-1098 completely abolished the cardioprotective effect of isoflurane (56 +/- 5%). We conclude that both mitochondrial and sarcolemmal K(ATP) channels contribute to isoflurane-induced delayed cardioprotection.
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PMID:Delayed cardioprotection by isoflurane: role of K(ATP) channels. 1206 75

The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure. However, it has been suggested that the mitochondrial KATP channels are involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of the administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and 3-pyridyl pinacidil), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) and a specific sarcolemmal KATP channel blocker (HMR 1883; 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3- methylthiourea) prior to and during coronary occlusion, as well as prior to and during post-ischemic reperfusion, on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n = 80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n = 186), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. In both Group I and Group II, early intravenous infusion of nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), 3-pyridyl pinacidil (3.0 micrograms/kg bolus + 1.0 microgram/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/3-pyridyl pinacidil, just prior to and during ischemia, increased survival rate (75%, 67%, 86% and 75% vs. 60% in the control subgroup in Group I; 67%, 75%, 75% and 67% vs. 43% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or 3-pyridyl pinacidil at the onset of and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and 3-pyridyl pinacidil were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker, but not by pretreatment with HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in the necrotic zone of myocardium in all sixteen subgroups in Group II suggest little anti-free radical property of nicorandil and 3-pyridyl pinacidil. Therefore, we may conclude that intervention by intravenous administration of nicorandil and 3-pyridyl pinacidil (through the selective activation of mitochondrial KATP channels), increases survival rate and exhibits antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits, when administered prior to and during coronary occlusion. The mitochondrial KATP channel may be considered to be a potentially important site of cardioprotection and antiarrhythmic activity.
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PMID:Selective mitochondrial KATP channel activation by nicorandil and 3-pyridyl pinacidil results in antiarrhythmic effect in an anesthetized rabbit model of myocardial ischemia/reperfusion. 1273 55

The roles of cardiomyocyte sarcolemmal ATP-sensitive K(+) (K(ATP)) and mitochondrial K(ATP) channels in the cardioprotection and antiarrhythmic activity induced by K(ATP) channel openers remain obscure, though the mitochondrial K(ATP) channels have been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of administration of non-hypotensive doses of ATP-sensitive K(+) channel (K(ATP)) openers (nicorandil and cromakalim), a specific mitochondrial K(ATP) channel blocker (5-hydroxydecanoate (5-HD)) and a specific sarcolemmal K(ATP) channel blocker (HMR 1883; (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n=80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30min. In Group II (n=184), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. Both in Groups I and II, early intravenous infusion of nicorandil (100 micro g/kg bolus+10 micro g/kg/min), cromakalim (0.2 micro g/kg/min), HMR 1883 (3mg/kg)/nicorandil and HMR 1883 (3mg/kg)/cromakalim just prior to and during ischemia increased survival rate (75%, 67%, 86% and 75% versus 60% in the control subgroup in Group I; 75%, 75%, 75% and 67% versus 50% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or cromakalim at the onset and during reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and cromakalim were abolished by pretreating the rabbits with 5-HD (5mg/kg, i.v. bolus), a selective mitochondrial K(ATP) channel blocker but not by HMR 1883 (3mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-free radical property of nicorandil and cromakalim.We, therefore, conclude that intervention by intravenous administration of nicorandil and cromakalim (through the selective activation of mitochondrial K(ATP) channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion. The mitochondrial K(ATP) channel may be a potential site of cardioprotection and antiarrhythmic activity.
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PMID:Mitochondrial K ATP channel activation is important in the antiarrhythmic and cardioprotective effects of non-hypotensive doses of nicorandil and cromakalim during ischemia/reperfusion: a study in an intact anesthetized rabbit model. 1274 97

The opioid antagonist naloxone abolishes infarct limitation by myocardial ischemic preconditioning, suggesting that one or more endogenous opioid peptides can mediate cardiac protection against ischemic damage. We tested the hypothesis that the naturally occurring opioid peptide Met5-enkephalin (ME) modulates myocardial infarct size in vivo. Experiments were conducted in barbiturate-anesthetized open-chest rabbits subjected to regional myocardial ischemia-reperfusion. ME was administered via osmotic minipump for 24 h. Infarct size was assessed with tetrazolium and is expressed as a percentage of the area at risk. Exogenous ME reduced the amount of the risk zone infarcted by approximately 60% compared with saline-treated controls. ME-induced protection was sensitive to opioid receptor blockade with naloxone [NAL 50 +/- 2% vs. ME + NAL 39 +/- 3%, P = not significant (NS)] and also to blockade of sarcolemmal and mitochondrial ATP-sensitive K+ (KATP) channels [5-hydroxydecanoate (5-HD) 33 +/- 3% vs. ME + 5-HD 43 +/- 8%, P = NS; and HMR-1098 60 +/- 3% vs. ME + HMR-1098 54 +/- 7%, P = NS]. We conclude that ME limits ischemic injury in vivo by an opioid receptor-mediated mechanism that involves both sarcolemmal and mitochondrial KATP channels.
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PMID:Sustained exogenous administration of Met5-enkephalin protects against infarction in vivo. 1286 77

Recent evidence suggests that the mitochondrial K(ATP) channels may be involved as a subcellular mediator in cardioprotection afforded by ischemic and pharmacological preconditioning by K(ATP) activators. The present study investigated the effects of administration of non-hypotensive doses of ATP-sensitive K(+) channel (K(ATP)) openers, nicorandil (NIC) and pinacidil (PIN), and specific blockers of mitochondrial (5-hydroxydecanoate) and sarcolemmal (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methyl-thiourea, HMR 1883) K(ATP) channels prior to and during coronary occlusion and post-ischemic reperfusion on survival rate, ischemia- and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized rabbits. In Group I, myocardial ischemia-induced arrhythmias were provoked by tightening a ligature over the left main coronary artery for 30 min. In Group II, arrhythmias were induced by reperfusion following a 20 min ligation of the same artery. Both in Group I and Group II, early iv administration of NIC (0.47 mg/kg), PIN (0.1 mg/kg), HMR 1883 (3 mg/kg)/NIC and HMR 1883/PIN just prior to and during ischemia increased survival rate (75%, 86%, 75% and 75%, respectively, vs. 55% in the control in Group I; 75%, 75%, 75% and 67%, respectively, vs. 50% in the control in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late iv administration of NIC or PIN just prior to reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects were abolished by pretreating rabbits with 5-hydroxy-decanoate (5 mg/kg, iv bolus). In the present study, higher levels of malondialdehyde and lower levels of reduced glutathione and superoxide dismutase in necrotic zone of myocardium in all subgroups in Group II suggest little anti-free radical property of NIC and PIN. Therefore, it may be assumed that mitochondrial K(ATP) channel opening leads to mitochondrial generation and release of ROS providing for IPC and antiarrhythmic activity. The mitochondrial rather than sarcolemmal K(ATP) channel may represent a potential site of cardioprotection and antiarrhythmic activity.
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PMID:Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model. 1470 74


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