Kappa-opioid receptor stimulation inhibits growth of neonatal rat ventricular myocytes

The effects of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate salt (U50,488H), a selective kappa-opioid receptor agonist, on growth in neonatal ventricular myocytes were determined. In 15% serum culture medium, U50,488H at 0.1-1 microM significantly reduced the protein content, [3H]leucine uptake and cell size of the myocytes. The effect of U50,488H on protein content was abolished in the presence of 1 microM nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist. In a 0.4% serum medium, U50,488H at 0.1-1 microM had no effect on myocyte growth. Interestingly, 1 microM U50,488H abolished the stimulatory effects of 1 microM norepinephrine on protein content, [3H]leucine uptake and cell size of the myocytes in the low serum medium. The effect of U50,488H was abolished by 1 microM nor-BNI. With the exception of cell size, the effects of norepinephrine were completely abolished by blockade of both alpha- and beta-adrenoceptors, but only partially blocked by blockade of either adrenoceptors. These results provide first evidence that kappa-opioid receptor stimulation inhibits growth of the neonatal ventricular myocyte as a result of direct action as well as by inhibiting sympathetic stimulation of the heart. The stimulatory effects of sympathetic activity on growth occurs via both alpha- and beta-adrenoceptors.