DIVALENT-CATION CHANNELS ACTIVATED BY PHENOTHIAZINES IN MEMBRANE OF RAT VENTRICULAR MYOCYTES

Phenothiazines (PTZ) such as chlorpromazine (CPZ) or trifluoperazine ( TPZ) induced a sustained divalent cation-permeable channel activity wh en applied on either side of inside-out patches or on external side of cell-attached patches of adult rat ventricular myocytes, The percenta ge of active patches was approximate to 20%. In the case of CPZ, the K -d of the dose-response curve was 160 mu M. CPZ-activated channels wer e potential-independent in the physiological range of membrane potenti al and were permeable to several divalent ions (Ba2+, Ca2+, Mg2+ Mn2+) , At least three levels of currents were usually detected with conduct ances of 23, 50 and 80 pS in symmetrical 96 mM Ba2+ solution and 17, 3 6 and 61 pS in symmetrical 96 mM Ca2+ solution. Saturation curves corr esponding to the three main conductances determined in Ba2+ symmetrica l solutions (tonicity compensated with choline-Cl) gave maximum conduc tances of 36, 81 and 116 pS (with corresponding half-saturating concen tration constants of 31.5, 38 and 34.5 mM). The corresponding conducta nce values were estimated to 1.7, 3.3 and 5.2 pS in symmetrical 1.8 mM Ba2+ and to 1.1, 2.4 and 3.7 pS in symmetrical 1.8 mM Ca2+ (the value in normal Tyrode solution). Channels were poorly permeable to monoval ent cations, such as Na, with a P-Ba/P-Na ratio of 10. A PTZ-induced c hannel activity similar to that described in cardiac cells was also ob served in cultured rat aortic smooth muscle cells but not in cultured neuroblastoma cells. PTZ-activated channels described in cardiac cells appear very similar to the sporadically active divalent ion permeable channels described in a previous paper (Coulombe et al., 1989), Surpr isingly, when 100 mu M CPZ were applied to myocytes studied in the who le-cell configuration, and maintained at a holding potential of -80 mV in the presence of 24 mM external Ca2+ or Ba2+, no detectable macrosc opic inward current could be observed, whereas the L-type Ca2+ current triggered by depolarizing pulses was markedly and reversibly reduced. The possible reasons are discussed.