CA2-ACTIVATED CL- AND K+ CHANNELS AND THEIR MODULATION BY ENDOTHELIN-1 IN RAT PULMONARY ARTERIAL SMOOTH-MUSCLE CELLS()

Using the patch-clamp recording technique, we observed that endothelin -1 (ET-1; 0 . 8-16 nM) enhanced a voltage-activated outward current (I -out) and induced periodic oscillations of inward current in smooth mu scle cells isolated from small pulmonary arteries (200-400 mu m in dia meter). Anion substitution experiments revealed that the ET-1-induced inward current was carried by Cl- ions. Application of bosentan (10 mu M; an ET(A) and ET(B) receptor antagonist) and FR 139317 (1-10 mu M; a selective ET(A) receptor antagonist) prevented initiation of inward currents or enhancement of I-out by ET-1. The ET(B) receptor agonist t etra-Ala-endothelin-1 (1-20 nM) failed to evoke these responses. Caffe ine (10 mM) induced a single transient inward current and prevented an y further activation of inward current, or enhancement of I-out, by su bsequent application of 16 nM ET-1, suggesting that these currents wer e mediated by Ca2+ release from internal stores. Rapid intracellular r elease of Ca2+ by photolysis of nitr-5 activated an inward Cl- current and increased the magnitude of I-out. These results demonstrate the e xistence of Ca2+-activated Cl- and K+ channels in pulmonary arterial s mooth muscle. The physiological role of these channels is at present u ncertain, although their activation may be involved in the contractile responses of pulmonary arterial smooth muscle to ET-1.