KATP channels mediate the antihypertrophic effects afforded by κ-opioid receptor stimulation in neonatal rat ventricular myocytes

Recent evidence suggests that kappa-opioid receptor (OR) agonists and K-ATP channel activation exert antihypertrophic effects on cardiac myocytes. We studied the role of K-ATP channels in the antihypertrophic effects of ORs in primary cultures of neonatal rat ventricular myocytes exposed for 48 h to the alpha(1) adrenoceptor agonist phenylephrine and the relative contributions of mitochondrial K-ATP (mitoK(ATP)) and sarcolemmal K-ATP (sarcK(ATP)). Furthermore, we elucidated the pathway between ORs and K-ATP channels and their impact on intracellular Ca2+ ([Ca2+](i)) transients. Hypertrophy of cardiomyocytes was characterized by increases in i) total protein content; ii) cell size and iii) [H-3]leucine incorporation. Phenylephrine (10 mu M) increased the three parameters. Trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid methanesulfonate salt (U50,488H), a selective kappa-opioid receptor agonist, prevented phenylephrine-induced hypertrophy and [Ca2+](i) transients. The effect of U50,488H was abolished by nor-binaltorphimine, a selective kappa-OR antagonist, indicating that the effect was kappa-OR-mediated. The protein kinase C inhibitor chelerythrine and the K-ATP channel inhibitors glibenclamide (50 mu M), a nonselective K-ATP antagonist, and 5-hydroxydecanoic acid (100 mu M), a mitochondrial selective K-ATP antagonist, reversed the antihypertrophic effect of U50,488H, and there was no significant difference between the two K-ATP channel blockers. Moreover, we also determined the expression of the Kir6.2 subunits of the K-ATP channel, which increased in response to U50,488H in the presence of phenylephrine, but was suppressed by chelerythrine, glibenclamide and 5-hydroxydecanoic acid. U50,488H also attenuated the elevation of [Ca2+](i). This study suggests that K-ATP, and particularly the mitochondrial K-ATP,K- mediates the antihypertrophic effects of kappa-opioid receptor stimulation via the PKC signaling pathway.