We have demonstrated that ISO produces part of its negative inotropic action through activation of the plasmalemmal Na+/K+ pump, and reduction of [Na+]i. This action is mediated by the beta-adrenergic receptor through activation of adenylate cyclase. The reduction of [Na+]i is most probably translated to a change in the contractile state of the cell through activation of the Na+/Ca2+ exchanger. While the exchanger is at equilibrium when the cell is at rest, after ISO it would extrude Ca2+ at the expense of the increased Na+ gradient, resulting in a decrease Ca2+ availability and a reduction in the magnitude of subsequent contractions. We have also seen that the previous calcium history of the myoplasm can influence the time course of future calcium transients. Prolonged large increases in [Ca2+]i can accelerate the rate of its removal and depress basal [Ca2+]i levels. This action is most probably mediated through a Ca2+/calmodulin dependent protein kinase. We have observed that MLCK is both necessary and sufficient to produce contraction of Bufo marinus stomach smooth muscle. There is also evidence that an as yet unidentified Ca(2+)-calmodulin dependent protein kinase is acting to limit the magnitude and the duration of the Ca2+ transient by feeding back on processes involved in Ca2+ signal generation.