The objective of the experiments was to investigate the cellular basis of the inotropic effect on myocardium of several opioids which have been implicated in producing cardiotoxic effects in human poisoning. Opioids exerted negative inotropic effects, with half-maximal concentrations between 10 microM (dextropropoxyphene) and 118 microM (pethidine); all agents reduced the magnitude of the intracellular Ca2+ transient and the L-type Ca2+ current, ICa, over a similar concentration range to that which reduced twitch tension. The depression of ICa correlated positively with the value of the opioid oil-water partition coefficient. Effects were not antagonized by the opioid receptor antagonist naloxone. Action potential upstroke rate was also reduced but at significantly higher concentrations. Resting potential and action potential duration were not consistently affected; none of the opioids tested altered intracellular pH. These data suggest that opioids exert a negative inotropic effect by their action on ICa; 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 agent.