INHIBITION OF VOLTAGE-GATED K-1( CURRENT IN RAT INTRAPULMONARY ARTERIAL MYOCYTES BY ENDOTHELIN)

Although endothelin (ET)-1 is an important regulator of pulmonary vasc ular tone, little is known about the mechanisms by which ET-1 causes c ontraction 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 il-aminopyridin e, but not the Ca2+-activated K+-channel antagonist charybdotoxin (ChT X), caused membrane depolarization. In the presence of 100 nM ChTX, ET -1 (10(-10) to 10(-7) M) caused a concentration-dependent inhibition o f K+ current (56.2 +/- 3.8% at 10(-7) M) and increased the rate of cur rent inactivation. These effects of ET-1 on K+ current were markedly r educed 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-a ctetate and 1,2-dioctanoyl-sn-glycerol). These data suggest that ET-1 modulated pulmonary vascular reactivity by depolarizing pulmonary arte rial smooth muscle, due in part to the inhibition of Ky current that o ccurred via activation of the phospholipase C-protein kinase C signal transduction pathway.