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

The effect of preconditioning with U50,488 H (UP), a selective kappa-opioid receptor (κ-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 κ-OR antagonist, indicating the effect was κ-OR mediated. 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 (KATP) was coadministered with U50,488 H 24 h before ischaemia or when 5-HD was administered just before ischaemia. 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 KATP channel, which abolished the protective effect of preconditioning with U50,488 H. The results indicated that mitochondrial KATP channel serves as both a trigger and a mediator, while sarcolemmal KATP channel as a trigger only, of delayed cardioprotection of κ-OR stimulation. The effects of these channels may result from prevention/attenuation of [Ca2+]i overload induced by ischaemic insults. British Journal of Pharmacology (2003) 140, 750–758. doi:10.1038/sj.bjp.0705475