Diminution of contractile response by kappa-opioid receptor agonists in isolated rat ventricular cardiomyocytes is mediated via a pertussis toxin-sensitive G protein

Opioids directly decrease the contractile response of isolated ventricular cardiomyocytes to electrical stimulation. To investigate whether these effects are mediated via GTP-binding G(i/o) proteins we examined the influence of pertussis toxin on the effects of the kappa-opioid receptor agonist trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benz eneacetamide (U-50,488) methanesulphonate and on the as yet undescribed effects of the opioid peptide dynorphin A (1-8) on contraction. In isolated, electrically driven, rat ventricular cardiomyocytes both agents concentration dependently reduced cell shortening within 15 min, decreasing the contractile response by 79+/-4% (n=5) and 62+/-2% (n=6) of control values at maximal effective concentrations of 10 microM (U-50,488) and 1 microM [dynorphin A (1-8)], respectively. Pertussis toxin pre-treatment (200 ng/ml; 4.5-5 h) completely abolished the effects of U-50,488 and dynorphin A (1-8) on the contractile response, indicating that these effects are mediated via G(i/o) proteins. In addition, the non-selective opioid receptor antagonist (-)-naloxone and the kappa-opioid receptor antagonist nor-binaltorphimine antagonized the effects of U-50,488 and dynorphin A (1-8) on the contractile response. Furthermore, the mu- and delta-opioid receptor agonist (D-Ala2, D-Leu5)-enkephalin (DADLE) had no effects on contraction. These results indicate that the decrease in cell shortening is due to stimulation of kappa-opioid receptors. The direct effect of kappa-opioid receptor agonists on the contractile response thus represents an additional mechanism for decreasing cardiac contractility, besides the M-cholinoceptor- or adenosine receptor-mediated pathway. It is conceivable that increased release of endogenous dynorphins from the heart during hypoxia may protect the heart in a similar manner to adenosine.