THE MODE OF ACTION OF SEVERAL OPIOIDS ON CARDIAC-MUSCLE

The objective of the experiments was to investigate the cellular basis of the inotropic effect on myocardium of several opioids which have b een implicated in producing cardiotoxic effects in human poisioning. O pioids exerted negative inotropic effects, with half-maximal concentra tions between 10 mu M (dextropropoxyphene) and 118 mu M (pethidine); a ll agents reduced the magnitude of the intracellular Ca2+ transient an d the L-type Ca2+ current, I-Ca, over a similar concentration range to that which reduced twitch tension. The depression of I-Ca correlated positively with the value of the opioid oil-water partition coefficien t. Effects were not antagonized by the opioid receptor antagonist nalo xone. Action potential upstroke rate was also reduced but at significa ntly higher concentrations. Resting potential and action potential dur ation were not consistently affected; none of the opioids tested alter ed intracellular pH. These data suggest that opioids exert a negative inotropic effect by their action on I-Ca; blockade of the Na+ current is not great enough to exert a significant action. The lack of effect of naloxone implies the actions are independent of the opioid receptor . The correlation of effects with the oil-water partition coefficient implies a non-specific effect dependent on the hydrophobicity of the a gent.