Mechanisms of opioid delta (delta) and kappa ( kappa) receptors' cardioprotection in ischaemic preconditioning in a rat model of myocardial infarction.
It has been demonstrated that brief periods of coronary artery occlusion before a prolonged period of sustained occlusion paradoxically protect the myocardium against infarction. The mechanisms involved in this phenomenon, termed "ischaemic preconditioning" (IPC) are still not clear, although it has been established that opioid receptors are involved. The aim of this study was to probe some of the plausible mechanisms involved in the phenomenon by using an in vivo model of myocardial infarction in intact rat, a model that allows electro-cardiographic and enzymatic in addition to morphometric evaluation of the development of 24-hour myocardial infarction. Selective opioid delta-receptor agonist (DADLE) and antagonist (natrindole), and opioid kappa-receptor agonist (U-50488H) and antagonist (nor-BNI) were used. To clarify some of the mechanisms of IPC, we used selective inhibitors of the anticipated cellular systems involved. Pertussis toxin (inhibitor of adenylate cyclase G(I/o) protein), glibenclamide (inhibitor of K(ATP ) channel) and chelerythrine (inhibitor of PKC) were used. Results obtained showed that: Both opioid delta- and kappa-receptors were involved in the beneficial effect of IPC, although we were unable to differentiate between opioid receptor subtypes (delta1, delta2 and kappa1, kappa2). Opioid delta- and kappa-receptors displayed different effects in IPC. After 30 minutes of left coronary occlusion and 2-hour reperfusion, opioid delta-receptor agonist DADLE significantly decreased (p < 0.05) the infarct size (by 66%--from % IS/AAR 59.80 in the control, untreated infracted rats to % 20.40), without a significant effect (p > 0.05) on the occurrence of early arrhythmias. Opioid kappa-receptor agonist U-50488H produced mainly antiarrhythmic effects. It decreased % IS/AAR by 44%, reduced the occurrence of early arrhythmias by 77%, and decreased ventricular ectopic beats by 80%. Both opioid delta- and kappa-receptor agonists significantly reduced (p < 0.05 ) early (2-hour) mortality by 22% and 19% respectively. The above opioid delta- and kappa-receptor cardiac effects were abolished by the use of respective specific opioid delta- and kappa-receptor antagonists. The beneficial effects of opioid delta- and kappa-receptor agonists persisted for at least 24 hours post-infarction. It is most likely that both opioid delta- and kappa-receptors act via common cellular mechanisms involving: activation of ATP-sensitive (sarcolemmal) K+ channel via G(I/o) proteins (based on the results of our experiments with K(ATP) channel antagonist, glibenclamide); phosphatidylinositol pathway via activation of protein kinase C (judging from the results of our experiments with the inhibitor of PKC, chelerythrine); and the recently proposed "cross talk" between beta (1)-adrenergic and opioid receptors in cardiac myocytes (involving inhibition of adenylate cyclase by G(I/o) proteins). Exploring the possibility of this signaling pathway will be the next step in our experimental studies.
Tara Hospital, The H. Morose Centre, Johannesburg, South Africa.
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Valtchanova-Matchouganska
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Ojewole
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology*; D006334:Heart Function Tests; D006439:Hemodynamics / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D012016:Reference Values; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D002316:Cardiotonic Agents; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D016308:Enkephalin, Leucine-2-Alanine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer