Ca2+-activated Cl- current can be triggered by Na+ current-induced SR Ca2+release in rabbit ventricle

The Ca2+-activated Cl- current [I-Cl(Ca)] contributes to the repolarization of the cardiac action potential under physiological conditions. I-Cl(Ca) i s known to be primarily activated by Ca2+ release from the sarcoplasmic ret iculum (SR). L-type Ca2+ current [I-Ca(L)] represents the major trigger for Ca2+ release in the heart. Recent evidence, however, suggests that Ca2+ en try via reverse-mode Na+/Ca2+ exchange promoted by voltage and/or Na+ curre nt (I-Na) may also play a role. The purpose of this study was to test the h ypothesis that I-Cl(Ca) can be induced by I-Na in the absence of I-Ca(L). M acroscopic currents and Ca2+ transients were measured using the whole cell patch-clamp technique in rabbit ventricular myocytes loaded with Indo-1. Ni cardipine (10 mu M) abolished I-Ca(L) at a holding potential of -75 mV as t ested in Na+-free external solution. In the presence of 131 mM external Na and in the absence of I-Ca(L), a 4-aminopyridine-resistant transient outwa rd current was recorded in 64 of 81 cells accompanying a phasic Ca2+ transi ent. The current reversed at -42.0 +/- 1.3 mV (n = 6) and at +0.3 +/- 1.4 m V (n = 6) with 21 and 141 mM of internal Cl-, respectively, similar to the predicted reversal potential with low intracellular Cl- concentration ([Cl- ](i)) (-47.8 mV) and high [Cl-](i) (-1.2 mV). Niflumic acid (100 mu M) inhi bited the current without affecting the Ca2+ signal (n = 8). Both the curre nt and Ca2+ transient were abolished by 10 mM caffeine (n. = 6), 10 mu M ry anodine (n = 3), 30 mu M tetrodotoxin (n = 9), or removal of extracellular Ca2+ (n = 6). These properties are consistent with those of I-Cl(Ca), previ ously described in mammalian cardiac myocytes. We conclude that 1) I-Cl(Ca) can be recorded in the absence of I-Ca(L), and 2) I-Na-induced SR Ca2+ rel ease mechanism is also present in the rabbit heart and may play a physiolog ical role in activating the Ca2+-sensitive membrane Cl- conductance.