Evaluation of the antidysrhythmic effects of delta- and kappa-opioid receptor agonists and antagonists on calcium chloride-, adrenaline- and ischemia/reperfusion-induced arrhythmias in rats.
This study was undertaken to evaluate the involvement of delta- and kappa-opioid receptors in both ischemia- and reperfusion-induced arrhythmias, and to elucidate some of the plausible mechanisms conferring antidysrhythmic effects on opioid delta- and kappa-receptor agonists and antagonists. Different models of arrhythmia (calcium chloride [CaCl(2)]-, adrenaline-, and ischemia/reperfusion-induced arrhythmias) were employed. The following opioid agonists, antagonists and blockers were used in the study: [D-Ala(2), D-Leu(5)]enkephalin (DADLE), a selective delta-receptor agonist; trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U-50488H), a selective kappa-receptor agonist; Naltriben Methanesul-fonate (NTB), a selective delta(2)-antagonist with kappa-receptor agonist-like activity; natrindole, a non-selective delta(1)- and delta(2)-receptor antagonist; nor-binaltorphimine dehydrochloride (nor-BNI), a selective kappa-receptor antagonist; chelerythrine, a selective protein kinase C inhibitor, and glibenclamide, a selective blocker of ATP-sensitive K channel. Although results of the morphometric, enzymatic, hemodynamic, electrocardiographic and pharmacodynamic studies undertaken suggest that both opioid delta(1)- and kappa-receptors are involved in the phenomenon of ischemic heart preconditioning (IPC), the antidysrhythmic effects of the opioids seem to be mediated mainly via kappa-receptors. The antidysrhythmic effect of U50488H was found to be a consequence of its beta-blocking activity (which is comparable to that of propranolol, a Class II antiarrhythmic drug) and its ability to prolong myocardial action potential (QT-interval prolongation, which is comparable to that of amiodarone, a Class III antiarrhythmic drug). The antidysrrhythmic effects of the opioid compounds examined were almost completely abolished by glibenclamide or chelerythrine pretreatment. No calcium-channel blocking activity was observed in this investigation. The present observations suggested that opioid receptors displaying well known analgesic properties may have the potential to protect the myocardium during cardiac ischemia at the early stages of myocardial infarction (when early arrhythmias are the most common causes of death).
Department of Pharmacology, Faculty of Health Sciences, University of Durban-Westville, Durban, South Africa.
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Valtchanova-Matchouganska
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Missankov
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Ojewole
D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002122:Calcium Chloride / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004837:Epinephrine / Q000633:toxicity; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
D000701:Analgesics, Opioid; D000889:Anti-Arrhythmia Agents; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D002122:Calcium Chloride; D004837:Epinephrine