Effects of drugs interacting with opioid receptors during normal perfusion or ischemia and reperfusion in the isolated rat heart— an attempt to identify cardiac opioid receptor subtype(s) involved in arrhythmogenesis

Abstract

Cardiac opioid receptors have been shown to be involved in the genesis of arrhythmias during ischemia and reperfusion. The present study was aimed at elucidating the receptor subtype(s) involved in arrhythmogenesis. Two series of experiments were conducted. In the first, effects of prototype opioid agonists, namely, (D-Ala 2, NMe 4, Gly-ol)-Enkephalin (DAGO), U50,488H and (D-Pen 2, Pen 5)-Enkephalin (DPDPE) and (D-Ala 2, D-Leu 2)-Enkephalin (DADLE), representing μ-, k- and δ-agonists, respectively, in disturbing the normal cardiac rhythm in the isolated perfused rat heart were investigated. Both DAGO and U50,488H were arrhythmogenic, whereas the effects of the δ-agonists, DPDPE and DADLE at a same dose range (44–396 nmol/heart) as that of DAGO were almost negligible. U50,488H was by far the most potent as it induced ventricular arrhythmias including frequent PVC and VT even at a dose (44 nmol/heart) at which other agonists either produced no or negligible effect. In the second series of experiments, the antiarrhythmogenic effects of μ-antagonist (naloxone) and k-antagonist (MR 2266) against arrhythmias arising during ischemia and reperfusion were compared. The effects of MR 2266 were significantly greater than that of naloxone. Results of the present study suggest that the cardiac k-receptors are the most likely receptor-subtype involved in arrhythmogenesis during ischemia and reperfusion.