title: Ca(2+)-activated Cl(-) current can be triggered by Na(+) current-induced SR Ca(2+) release in rabbit ventricle.
abstract: The Ca(2+)-activated Cl(-) current [I(Cl(Ca))] contributes to the repolarization of the cardiac action potential under physiological conditions. I(Cl(Ca)) is known to be primarily activated by Ca(2+) release from the sarcoplasmic reticulum (SR). L-type Ca(2+) current [I(Ca(L))] represents the major trigger for Ca(2+) release in the heart. Recent evidence, however, suggests that Ca(2+) entry via reverse-mode Na(+)/Ca(2+) exchange promoted by voltage and/or Na(+) current (I(Na)) may also play a role. The purpose of this study was to test the hypothesis that I(Cl(Ca)) can be induced by I(Na) in the absence of I(Ca(L)). Macroscopic currents and Ca(2+) transients were measured using the whole cell patch-clamp technique in rabbit ventricular myocytes loaded with Indo-1. Nicardipine (10 microM) abolished I(Ca(L)) at a holding potential of -75 mV as tested 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 outward current was recorded in 64 of 81 cells accompanying a phasic Ca(2+) transient. The current reversed at -42. 0 +/- 1.3 mV (n = 6) and at +0.3 +/- 1.4 mV (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 microM) inhibited the current without affecting the Ca(2+) signal (n = 8). Both the current and Ca(2+) transient were abolished by 10 mM caffeine (n = 6), 10 microM ryanodine (n = 3), 30 microM tetrodotoxin (n = 9), or removal of extracellular Ca(2+) (n = 6). These properties are consistent with those of I(Cl(Ca)) previously 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 Ca(2+) release mechanism is also present in the rabbit heart and may play a physiological role in activating the Ca(2+)-sensitive membrane Cl(-) conductance.
authors.affiliation: Research Centre, Montréal Heart Institute, Montreal H1T 1C8.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: D
authors.initials: D
authors.lastname: Chartier
authors.forename: S
authors.initials: S
authors.lastname: Nattel
authors.forename: N
authors.initials: N
authors.lastname: Leblanc
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018118:Chloride Channels / Q000502:physiology*; D004351:Drug Resistance; D004553:Electric Conductivity; D004594:Electrophysiology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006352:Heart Ventricles; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009529:Nicardipine / Q000494:pharmacology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012964:Sodium / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D018118:Chloride Channels; D012964:Sodium; D015761:4-Aminopyridine; D009529:Nicardipine; D002118:Calcium