M oderate alcohol intoxication in man, a ubiqitious social event, causes acute but reversible myocardial depression, the mechanism of which is unknown. We investigated whether this depression could be due to a direct effect of ethanol on the process of electromechanical coupling by simultaneously measuring the transmembrane action potential and contraction, or the cytosolic calcium transient (via aequorin photoluminescence) and contraction in isolated ferret right ventricular papillary muscle. Ethanol, in concentrations that are similar to plasma levels in man during intoxication (0.15 vol %), depressed the force of contraction approximately 10%. The step in the electromechanical process that was affected appeared to be the calcium-myofilament interaction, as there was no change in the transmembrane action potential or cytosolic calcium transient. This inhibition was quickly reversed by removal of the ethanol from the perfusate. On the other hand, higher concentrations of ethanol produced changes in contraction, the calcium transient, and the action potential, suggesting multiple levels of inhibition of electromechanical coupling. Increasing the perfusate calcium or use of the calcium channel agonist, BAY-K 8644, increased cytosolic calcium to near maximum but had little effect on contractility, confirming that the relationship between calcium and the myofilaments had been altered. These data suggest that the acute depression in ventricular function seen with alcohol consumption may be due to a direct effect on electromechanical coupling through inhibition of the calcium myofilament interaction.