ENDOTHELIN DEPOLARIZES MYOCYTES FROM PORCINE CORONARY AND HUMAN MESENTERIC-ARTERIES THROUGH A CA-ACTIVATED CHLORIDE CURRENT

The effect of endothelin (ET) on membrane potential and current was studied in myocytes isolated from porcine coronary or from human mesenteric arteries at 3.6 mM extracellular Ca2+ concentration and 37-degrees-C. ET (1 - 100 nM) induced cell shortening and membrane depolarization from a resting potential of -50 mV to about -15 mV. Ca currents (I(ca), L-type) were transiently reduced by ET. At -50 mV, ET induced an inward current that peaked within 2 s and fell within 10 s to a sustained level. The current could be enlarged by reducing bath extracellular Cl- ion concentration, but removal of extracellular Na+ ions had no effect. The voltage dependence suggests that the ET-induced current is a Cl current (I(cl)) at potentials negative to - 30 mV; at more positive potentials K currents (I(k, ca)) are superimposed. The effects of ET on I(ca), I(l), I(K,Ca) and contraction were prevented by intracellular Ca chelators, suggesting a Ca-dependent activation mechanism. The ET effects were abolished by pretreatment with 20 mM caffeine or prior cell-dialysis with heparin [thought to block inositol triphosphate-induced sarcoplasmic reticular Ca release]. The results suggest that ET releases Ca from the SR through a phosphoinositol response and that the released Ca acts as second messenger in modulating the membrane currents.