Activation of Ca2+-sensitive Cl- current by reverse mode Na+/Ca2+ exchange in rabbit ventricular myocytes

We investigated how Ca2+-sensitive transient outward current, I-to(Ca), is activated in rabbit ventricular myocytes in the presence of intracellular Na+ (Na-i(+)) using the whole-cell patch-clamp technique at 36 degrees C. In cells dialysed with Na+-free solutions, the application of nicardipine (5 mu M) to block L-type Ca2+ current (I-Ca) completely inhibited I-to(Ca). In cells dialysed with a [Na+](i)greater than or equal to 5 mM, however, I-to(Ca) could be observed after blockade of I-Ca, indicating the activity of an I-Ca-independently component. The amplitude of I-Ca-independent I-to(Ca) increased with voltage in a [Na+](i)-dependent manner. The block of Ca2+ release from the sarcoplasmic reticulum by caffeine, ryanodine or thapsigargin blocked I-Ca-independent I-to(Ca). In Ca2+-free bath solution I-to(Ca) was completely abolished. The application of 2 mM Ni2+ or the newly synthesized compound KBR7943, a selective blocker of the reverse mode of Na+/Ca2+ exchange. or perfusion with pipette solution containing XIP (10 mu M), a selective blocker of the exchanger, blocked I-Ca-independent I-to(Ca). From these results we conclude that, in the presence of Na-i(+). I-to(Cu) can be activated via Ca2+-induced Ca2+ release triggered by Na+/Ca2+ exchange operating in the reverse mode after blockade of I-Ca.