Venoconstriction to endothelin-1 in humans: role of calcium and potassium channels

Abstract

Recent studies in vitro have suggested that there may be an interaction between endothelin-1 and ATP-sensitive K+ channels in vascular smooth muscle. Here we have investigated whether agents acting on membrane Ca2+ and K+ channels modulate endothelin-1-induced venoconstriction in vivo in human subjects. In a series of studies, six healthy subjects received, on separate occasions, local infusions into dorsal hand veins of endothelin-1 coinfused with 1) the ATP-sensitive K+ channel opener, cromakalim; 2) the dihydropyridine Ca2+ antagonist, nicardipine; 3) a control vasodilator, hydralazine; and 4) saline placebo. Endothelin-1 caused local venoconstriction with a maximum reduction in vein size of 66 +/- 4% at 60 min (P = 0.0001 vs. basal). Cromakalim prevented endothelin-1-induced venoconstriction (9 +/- 10% maximum constriction; P = 0.68 vs. basal). By contrast, nicardipine, in a dose sufficient to block depolarization-induced constriction caused by K+ infusion, had only a partial effect on endothelin-1-induced venoconstriction (35 +/- 8% maximum constriction; P = 0.001 vs. basal; P = 0.02 vs. endothelin-1), whereas a 10-fold higher dose of nicardipine had no additional effect and hydralazine had no effect. In further studies, cromakalim, but not nicardipine, reversed endothelin-1-induced venoconstriction. Cromakalim did not prevent constriction induced by norepinephrine. Although calcium entry through dihydropyridine-sensitive Ca2+ channels may account in part for the vasoconstrictor action of endothelin-1 in humans, the abolition of endothelin-1 responses by a K+ channel opener suggests additional mechanisms of action for endothelin-1.