title: Roles of KATP channels in delayed cardioprotection and intracellular Ca(2+) in the rat heart as revealed by kappa-opioid receptor stimulation with U50488H.
abstract: The effect of preconditioning with U50488 H (UP), a selective kappa-opioid receptor (kappa-OR) agonist, on infarct size and intracellular Ca2+ ([Ca2+]i) in the heart subjected to ischaemic insults were studied and evaluated. U50488 H administered intravenously reduced the infarct size 18-48 h after administration in isolated hearts subjected to regional ischaemia/reperfusion (I/R). The effect was dose dependent. A peak effect was reached at 10 mg x kg-1 U50488 H and at 24 h after administration. The effect of 10 mg x kg-1 U50488 H at 24 h after administration was abolished by nor-binaltorphimine (nor-BNI), a selective kappa-OR antagonist, indicating the effect was kappa-OR mediated. The infarct reducing effect of U50488 H was attenuated when a selective blocker of mitochondrial (5-hydroxydecanoic acid, 5-HD) or sarcolemmal (HRM-1098) ATP-sensitive potassium channel (KATP) was coadministered with U50488 H 24 h before ischaemia or when 5-HD was administered just before ischaemia. U50488 H also attenuated the elevation in [Ca2+]i and reduction in electrically induced [Ca2+]i transient in cardiomyocytes subjected to ischaemic insults. The effects were reversed by blockade of KATP channel, which abolished the protective effect of preconditioning with U50488 H. The results indicated that mitochondrial KATP channel serves as both a trigger and a mediator, while sarcolemmal KATP channel as a trigger only, of delayed cardioprotection of kappa-OR stimulation. The effects of these channels may result from prevention/attenuation of [Ca2+]i overload induced by ischaemic insults.
authors.affiliation: Department of Physiology, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Mai
authors.initials: M
authors.lastname: Chen
authors.forename: Jing-Jun
authors.initials: JJ
authors.lastname: Zhou
authors.forename: Kenneth Wan-Lung
authors.initials: KW
authors.lastname: Kam
authors.forename: Jian-Song
authors.initials: JS
authors.lastname: Qi
authors.forename: Wing-Yi
authors.initials: WY
authors.lastname: Yan
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Tak-Ming
authors.initials: TM
authors.lastname: Wong
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000293:injuries; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015221:Potassium Channels / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D051381:Rats / Q000502:physiology; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D002118:Calcium