Inhibition of voltage-gated K⁺ currents by endothelin-1 in human pulmonary arterial myocytes

Recent studies demonstrate that endothelin-1 (ET-1) constricts human pulmonary arteries (PA). In this study, we examined possible mechanisms by which ET-1 might constrict human PA. In smooth muscle cells freshly isolated from these arteries, whole cell patch-clamp techniques were used to examine voltage-gated K⁺ (K_V) currents. K_V currents were isolated by addition of 100 nM charybdotoxin and were identified by current characteristics and inhibition by 4-aminopyridine (10 mM). ET-1 (10^-8 M) caused significant inhibition of K_V current. Staurosporine (1 nM), a protein kinase C (PKC) inhibitor, abolished the effect of ET-1. Rings of human intrapulmonary arteries (0.8-2 mm OD) were suspended in tissue baths for isometric tension recording. ET-1-induced contraction was maximal at 10^-8 M, equal to that induced by K_V channel inhibition with 4-aminopyridine, and attenuated by PKC inhibitors. These data suggest that ET-1 constricts human PA, possibly because of myocyte depolarization via PKC-dependent inhibition of K_V. Our results are consistent with data we reported previously in the rat, suggesting similar mechanisms may be operative in both species.