The role of L-type Ca2+ current and Na+ current-stimulated Na/Ca exchange in triggering SR calcium release in guinea-pig cardiac ventricular myocytes

Objective: This study examines the relative ability of sodium current (I-Na)-stimulated reverse mode Na/Ca exchange and the L-type calcium current (I-Ca) to trigger calcium-induced calcium release (CICR) in guinea-pig ventricular myocytes. Methods: Cytosolic Ca2+ transients were recorded from enzymatically dissociated guinea-pig ventricular mycocytes using Indo-1. Macroscopic membrane currents were simultaneously recorded using the whole-cell patch-clamp technique. Results: At room temperature (22-25 degrees C) Ca2+ transients were associated with the activation of I-Na, I-Ca or I-Na plus I-Ca in combination. However, after I-Ca was blocked by verapamil (10 mu M), no Ca2+ transient could be evoked by the activation of I-Na alone at either -40 or +5 mV. Similar results were obtained with 5 and 8 mM intracellular sodium, and when the temperature of the bathing solution was raised to 35 degrees C and cAMP (10 mu M) added to the pipette solution. Conclusions: From consideration of the relative magnitudes of the Ca2+ influx via Ic, and Na/Ca exchange and thermodynamic considerations, we suggest that I-Ca is the major source of 'trigger' calcium for CICR (and cardiac contraction) under normal conditions. Although the Na/Ca exchanger was incapable of triggering CICR under the conditions of these experiments, we suggest that it may become more important when cytosolic Ca2+ is elevated, a condition which will also lead to decrease the amplitude of I-Ca. (C) 1997 Elsevier Science B.V.