κ-Opioid receptor stimulation inhibits augmentation of Ca2+ transient and hypertrophy induced by isoprenaline in neonatal rat ventricular myocytes — Role of CaMKIIδB

We aimed to further define the pathway mediating the inhibitory effects of κ-opioid receptor stimulation on Ca2+ transients and hypertrophic responses to β1-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 Ca2+ 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 Ca2+/calmodulin-dependent kinase (CaMKII) inhibitor, propranolol, a β-adrenoceptor antagonist, and verapamil, a L-type Ca2+ 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 Ca2+ transients and cardiac hypertrophy, as did KN93, propranalol and verapamil. U50,488H also suppressed the expression of nuclear CaMKIIδB in the presence, but not in the absence of isoprenaline. These results suggest that the inhibitory effect of κ-opioid receptor stimulation on β1-adrenoceptor stimulation may also involve CaMKIIδ.