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

Abstract

Recent evidence suggests that κ-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 α1 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 Ca 2+ ([Ca 2+] i) transients. Hypertrophy of cardiomyocytes was characterized by increases in i) total protein content; ii) cell size and iii) [ 3H]leucine incorporation. Phenylephrine (10 μM) increased the three parameters. Trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid methanesulfonate salt (U50,488H), a selective κ-opioid receptor agonist, prevented phenylephrine-induced hypertrophy and [Ca 2+] i transients. The effect of U50,488H was abolished by nor-binaltorphimine, a selective κ-OR antagonist, indicating that the effect was κ-OR-mediated. The protein kinase C inhibitor chelerythrine and the K ATP channel inhibitors glibenclamide (50 μM), a nonselective K ATP antagonist, and 5-hydroxydecanoic acid (100 μM), 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 [Ca 2+] i. This study suggests that K ATP, and particularly the mitochondrial K ATP, mediates the antihypertrophic effects of κ-opioid receptor stimulation via the PKC signaling pathway.