The role of extracellular Ca2+ (Ca(2+)o) in the modulation of cardiac Cl- currents (I(Cl)) such as those activated by cAMP or swelling is uncertain. The effects of Ca(2+)o and extracellular cadmium (Cd(2+)o) on Cl- currents in cultured chick cardiac myocytes were investigated in Na+- and K+-free internal and external solutions using the whole-cell patch-clamp technique. In the absence of Na+ and K+ internally and externally, the whole-cell current was predominantly I(Cl). In the absence of cAMP, removal of Ca(2+)o (+ 1 mM EGTA) resulted in an increase in the current that was suppressed by reduction of Cl(o)- with a rightward shift of the zero-current potential towards the CI- reversal potential. We designated this current as a Ca2+-inhibitable I(Cl). Addition of 0.5 mM Cd(2+)o with or without removal of Ca(2+)o also resulted in a 1.5- to 2.0-fold increase in I(Cl) that was attenuated by 1 mM DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid). Under similar conditions, I(Cl) activated by Cd(2+)o (in 1 mM Ca(2+)o solution) was not further increased by subsequent removal of Ca(2+)o, suggesting that addition of Cd(2+)o and removal of Ca(2+)o activated the same I(Cl). In contrast, exposure to 1 microM forskolin further enhanced I(Cl) in the presence of Cd(2+)o. With 10 microM cAMP in the pipette solution, Ca2+-inhibitable I(Cl) could be activated in myocytes that do not possess cAMP-activated Cl- channels, indicating that activation of Ca2+-inhibitable I(Cl) does not require cAMP. In the presence of cAMP, in cells that display the cAMP-activated I(Cl), removal of Ca(2+)o resulted in a further increase in I(Cl) comparable to the Ca2+-inhibitable I(Cl). The Ca2+-inhibitable I(Cl) was minimized when pipette solutions contained 1.5 microM Ca2+. These results suggest that removal of Ca(2+)o or application of Cd(2+)o activates a Ca2+-inhibitable I(Cl) that is distinct from the cAMP-activated I(Cl).

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