Involvement of opioid delta (delta)- and kappa (kappa)-receptors in ischemic preconditioning in a rat model of myocardial infarction

Abstract

There is controversy in the literature regarding the involvement of opioid delta (DOP, OP1)- and kappa (KOP,OP2)-receptors in ischemic preconditioning (IPC). Previous studies on this subject in our laboratories and elsewhere have been performed on either isolated heart muscles of experimental animals, or in open-heart surgery rats. To highlight this problem, we introduced an in vivo model of myocardial infarction in rats, which not only allowed electrocardiographic and enzymatic evaluation, but also morphometric assessment of myocardial infarction. In addition to these parameters, a direct receptor ligand study was undertaken, using [3H]-DPDPE, a specific opioid delta-receptor ligand. In our pharmacodynamic studies, we used the selective opioid delta-receptor agonist D-Ala2,D-Leu5 enkephalin (DADLE) and antagonist natrindole. For the evaluation of opioid kappa-receptors, the selective opioid agonist U-50488H and antagonist nor-BNI were employed. Ischemic preconditioning showed the best beneficial effect, compared with pharmacological stimulation of either opioid delta- or kappa-receptors. In normal rat myocytes, two types of opioid delta-receptors exist, namely, low-affinity and high-affinity opioid receptors. In acute myocardial infarction (30-min ischemia), the low-affinity type opioid receptors disappeared, most likely as a result of receptor downregulation due to an excessive release of enkephalins. There was no change in the density of the high-affinity opioid receptor type, but their affinity significantly increased (p < 0.05) by 58%. The radioligand receptor studies showed that opioid delta 1-receptor type was involved not only in triggering, but also in maintaining, the preconditioned state. On the basis of our pharmacodynamic studies, we suggest that both opioid delta 1- and kappa-receptors are involved in the phenomenon of IPC, but with different effects. After 30 min of left coronary artery occlusion, opioid delta-receptor agonist DADLE decreased the infarct size/area at risk from 59.80% in control, untreated, infarcted rats, to 20.40% in treated rats, without a significant effect (p > 0.05) on the occurrence of early cardiac arrhythmias. Opioid kappa-receptor agonist U-50488H produced an opposite effect on the myocardium. It decreased the infarct size/area at risk by 44%, decreased occurrence of early arrhythmias by 77% and also decreased ventricular ectopic beats by 80%. The opioid delta- and kappa-receptor agonists used in this study significantly reduced (p < 0.05) early (2 h) postinfarction mortality by 22% and 19%, respectively. Further studies are in progress to differentiate between the role of opioid kappa 1- and kappa 2-receptors and the molecular mechanisms of the effects of both opioid delta- and kappa-receptors.