κ-opioid receptor stimulation inhibits cardiac hypertrophy induced by β1-adrenoceptor stimulation in the rat

To test the hypothesis that κ-opioid receptor stimulation inhibits cardiac hypertrophy induced by β1-adrenoceptor stimulation, we determined the effects of trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate salt (U50,488H), a selective κ-opioid receptor agonist, on cardiac hypertrophy induced by isoprenaline, a selective β-adrenoceptor agonist, in neonatal ventricular myocytes upon blockade of β2-adrenoceptor. Hypertrophy of cardiomyocytes was determined by increases in (i) total protein content; (ii) [3H]leucine incorporation; and iii) cell size. 10 μmol/l isoprenaline increased all three parameters. The effects were abolished by 2 μmol/l propranolol, a β-adrenergic receptor antagonist, or 300 nmol/l CGP20712A, a β1-adrenoceptor antagonist, but not by 100 nmol/l ICI118,551, a β2-adrenoceptor antagonist. The effects were also abolished by Rp-cAMPs 100 μmol/l, a protein kinase A inhibitor and not by pertussis toxin 5 mg/l. The effects of isoprenaline in the presence or absence of ICI118,551 were also abolished by 1 μmol/l U50,488H. The inhibitory effects of U50,488H were abolished by 1 μmol/l nor-binaltorphimine, a selective κ-opioid receptor antagonist. U50,488H also abolished the increases in the amplitude and frequency of the spontaneous intracellular Ca2+ transient induced by 10 μmol/l isoprenaline in the presence or absence of ICI118,551, an effect also abolished by nor-binaltorphimine. In conclusion the results show that κ-opioid receptor stimulation abolished both the cardiac hypertrophy and enhanced amplitude and frequency of the spontaneous intracellular Ca2+ transient induced by β1-adrenoceptor stimulation.