General anesthetics, typically octanol, were found to inhibit the influx of calcium in isolated sodium-loaded adult rat heart cells, using45Ca, quin 2, or indo 1. Inhibition by octanol, like inhibition by sodium, was competitive with calcium. Octanol and sodium together inhibited calcium influx synergistically. At physiological levels of extracellular calcium and sodium, the EC50was 177 ± 37 μM for octanol and 48 ± 5 μM for decanol. These values are threefold to fourfold larger than those reported to cause 50% loss of righting reflex in tadpoles, a measure of their anesthetic effectiveness. We conclude that general anesthetics inhibit Na-Ca exchange at the sarcokmma. We suggest that octanol inhibits like sodium, and the synergism stems from the cooperativity of sodium inhibition at the binding and regulatory sites of the exchanger. Insofar as Na-Ca exchange may regulate inotropy, the inhibition of Na-Ca exchange by general anesthetics could contribute to their negative inotropic effect.