Roles of KATP channels in delayed cardioprotection and intracellular Ca2+ in the rat heart as revealed by κ-opioid receptor stimulation with U50,488H

1 The effect of preconditioning with U50,488 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. U50,488 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 kg(-1) U50,488 H and at 24 h after administration. The effect of 10 mg kg(-1) U50,488 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. 2 The infarct reducing effect of U50,488 H was attenuated when a selective blocker of mitochondrial (5-hydroxydecanoic acid, 5-HD) or sarcolemmal (HRM-1098) ATP-sensitive potassium channel (K-ATP) was coadministered with U50,488 H 24 h before ischaemia or when 5-HD was administered just before ischaemia. 3 U50,488 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 K-ATP channel, which abolished the protective effect of preconditioning with U50,488 H. 4 The results indicated that mitochondrial K-ATP channel serves as both a trigger and a mediator, while sarcolemmal K-ATP 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.