Effect of partial blockade of the Na+/Ca2+-exchanger on Ca2+ handling in isolated rat ventricular myocytes

SEA0400 is a selective inhibitor of the Na+/Ca2+ exchanger having equal potencies to suppress both the forward and reverse mode operation of the Na+/Ca2+ exchanger. Present experiments were designed to study the effect of partial blockade of Na+/Ca2+ exchanger on Ca2+ handling in isolated rat ventricular myocytes. Intracellular Ca2+ transient and cell shortening were measured in ventricular myocytes loaded with Fura-2-AM fluorescent dye. Partial blockade of Na+/Ca2+ exchanger was induced by superfusion of the cells with SEA0400 at a concentration of 0.3 μM. Amplitude of the intracellular Ca2+ transient and cell shortening was significantly increased by SEA0400 in both field stimulated and voltage clamped myocytes, without significant elevation of diastolic Ca2+ level and the decay time constant of the Ca2+ transient. In patch clamped myocytes the SEA0400 induced increase in the Ca2+ transient and cell shortening was accompanied by significant reduction of peak L-type Ca2+ current. These effects can be explained by the autoregulative nature of cardiac Ca2+ handling, as the reduced Ca2+ efflux from the cell results in an increased Ca2+ load to the sarcoplasmic reticulum leading to increased Ca2+ release, which in turn may decrease the L-type Ca2+ current by accelaration of Ca2+ dependent inactivation of L-type Ca2+ current. Our results suggest that complex changes in the Ca2+ cycling can occur after selective pharmacological inhibition of the Na+/Ca2+ exchanger.