Roles of K ATP channels in delayed cardioprotection and intracellular Ca 2+ 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 Ca 2+ ([Ca 2+ ] 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 (K ATP ) 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 [Ca 2+ ] i and reduction in electrically induced [Ca 2+ ] 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. 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 κ ‐OR stimulation. The effects of these channels may result from prevention/attenuation of [Ca 2+ ] i overload induced by ischaemic insults.British Journal of Pharmacology (2003) 140 , 750–758. doi: 10.1038/sj.bjp.0705475