Inhibition of voltage-gated K⁺ current in rat intrapulmonary arterial myocytes by endothelin-1

Although endothelin (ET)-1 is an important regulator of pulmonary vascular tone, little is known about the mechanisms by which ET-1 causes contraction in this tissue. Using the whole cell patch-clamp technique in rat intrapulmonary arterial smooth muscle cells, we found that ET-1 and the voltage-dependent K⁺ (K(V))-channel antagonist 4-aminopyridine, but not the Ca²⁺-activated K⁺-channel antagonist charybdotoxin (ChTX), caused membrane depolarization. In the presence of 100 nM ChTX, ET-1 (10^-10 to 10^-7 M) caused a concentration-dependent inhibition of K⁺ current (56.2 ± 3.8% at 10^-7 M) and increased the rate of current inactivation. These effects of ET-1 on K⁺ current were markedly reduced by inhibitors of protein kinase C (staurosporine and GF 109203X) and phospholipase C (U-73122) or under Ca²⁺- free conditions and were mimicked by activators of protein kinase C (phorbol 12-myristate 13-actetate and 1,2-dioctanoyl-sn-glycerol). These data suggest that ET-1 modulated pulmonary vascular reactivity by depolarizing pulmonary arterial smooth muscle, due in part to the inhibition of K(V) current that occurred via activation of the phospholipase C-protein kinase C signal transduction pathway.