κ-Opioid receptor stimulation inhibits augmentation of Ca 2+ transient and hypertrophy induced by isoprenaline in neonatal rat ventricular myocytes — Role of CaMKIIδ B

Abstract

We aimed to further define the pathway mediating the inhibitory effects of κ-opioid receptor stimulation on Ca 2+ transients and hypertrophic responses to β 1-adrenoceptor stimulation. We determined the effects of Trans-(±)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid methanesulfonate salt (U50,488H), a selective κ-opioid receptor agonist, on the enhancement of spontaneous Ca 2+ transients and the induction of hypertrophy by isoprenaline, a β-adrenoceptor agonist, in cultured neonatal ventricular myocytes. The results were compared with those found with KN93, a selective Ca 2+/calmodulin-dependent kinase (CaMKII) inhibitor, propranolol, a β-adrenoceptor antagonist, and verapamil, a L-type Ca 2+ channel antagonist. Hypertrophy of cardiomyocytes was characterized by increases in (i) total protein content; (ii) cell size; and (iii) [ 3H]leucine incorporation. 10 μmol/l isoprenaline increased all three parameters. We also determined the expression of nuclear CaMKIIδ in response to U50,488H in the presence or absence of isoprenaline. To determine whether the effects of U50,488H were receptor-mediated, its effects were also measured following blockade of the κ-opioid receptor with nor-binaltorphimine. κ-Opioid receptor stimulation suppressed the stimulatory effect of isoprenaline on Ca 2+ transients and cardiac hypertrophy, as did KN93, propranalol and verapamil. U50,488H also suppressed the expression of nuclear CaMKIIδ B in the presence, but not in the absence of isoprenaline. These results suggest that the inhibitory effect of κ-opioid receptor stimulation on β 1-adrenoceptor stimulation may also involve CaMKIIδ.