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 when applied on either side of inside-out patches or on external side of cell-attached patches of adult rat ventricular myocytes. The percentage of active patches was approximately 20%. In the case of CPZ, the Kd of the dose-response curve was 160 microM. CPZ-activated channels were potential-independent in the physiological range of membrane potential and were permeable to several divalent ions (Ba2+, Ca2+, Mg2+, Mn2+). At least three levels of currents were usually detected with conductances of 23, 50 and 80 pS in symmetrical 96 mM Ba2+ solution and 17, 36 and 61 pS in symmetrical 96 mM Ca2+ solution. Saturation curves corresponding to the three main conductances determined in Ba2+ symmetrical solutions (tonicity compensated with choline-Cl) gave maximum conductances of 36, 81 and 116 pS (with corresponding half-saturating concentration constants of 31.5, 38 and 34.5 mM). The corresponding conductance 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 monovalent cations, such as Na, with a PBa/PNa ratio of 10. A PTZ-induced channel activity similar to that described in cardiac cells was also observed 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). Surprisingly, when 100 microM CPZ were applied to myocytes studied in the whole-cell configuration, and maintained at a holding potential of -80 mV in the presence of 24 mM external Ca2+ or Ba2+, no detectable macroscopic 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.
Lefevre
T
T
Laboratoire de Cardiologie Moléculaire et Cellulaire (CNRS URA 1159), Hôpital Marie Lannelongue, Le Plessis Robinson, France.
Coraboeuf
E
E
Ghazi
A
A
Coulombe
A
A
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001464:Barium / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002413:Cations, Divalent / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D006352:Heart Ventricles / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology*
D014150:Antipsychotic Agents; D002147:Calmodulin; D002413:Cations, Divalent; D007473:Ion Channels; D013449:Sulfonamides; D014268:Trifluoperazine; D001464:Barium; C017967:W 7; D002746:Chlorpromazine