Potent Constrictor Actions of Endothelin-1, Endothelin-2, and Endothelin-3 in Rat Isolated Portal Vein

In rings of rat portal vein, endothelin-1, endothelin-2, and endothelin-3 caused graded slow contractions and potentiated spontaneous contractions. The apparent EC50 values and maximal responses to 30 nM endothelin were 1.4 nM and 0.96 g for endothelin-1, 5.2 nM and 0.65 g for endothelin-2, and 1.7 nM and 0.62 g for endothelin-3 (n = 4-12). At concentrations producing half the contraction triggered by 80 mM KCl, the order of potencies was endothelin-1 greater than U46619 = angiotensin II greater than bradykinin greater than substance P greater than phenylephrine. Longitudinal portal-mesenteric vein preparations developed very modest contractions to endothelin-1 (0.13 g at 30 nM; n = 5), but their responses to 80 mM KCl and phenylephrine were greater than those of rings. Responses of rings to endothelin-1 were profoundly reduced in Ca(2+)-free medium, but less inhibition was obtained after incubation with nicardipine (up to 1 microM) and/or nickel (up to 0.5 mM), phorbol (up to 0.3 microM), staurosporine (up to 10 nM), or cromakalim (3 microM). Indomethacin (5.6 microM) did not affect responses to endothelin-1. Cromakalim (0.1-3 microM) also relaxed rings constricted with 0.3 nM endothelin-1, and this effect was partially reversed by glibenclamide (3 microM). Thus, endothelins, especially endothelin-1, are potent constrictors of portal vein rings but not of portal-mesenteric vein strips. Their action appears to rely largely on Ca2+ influx from the external medium (only in part via L- and T-type Ca2+ channels) and activation of protein kinase C but not on eicosanoid generation.(ABSTRACT TRUNCATED AT 250 WORDS)