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)
Guimarães
C L
CL
Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Calixto
J B
JB
Rae
G A
GA
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D019806:Cromakalim; D016232:Endothelins / Q000187:drug effects / Q000494:pharmacology* / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008642:Mesenteric Veins / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D010704:Phorbols / Q000494:pharmacology; D011169:Portal Vein / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D019311:Staurosporine; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000470:Alkaloids; D001578:Benzopyrans; D016232:Endothelins; D010704:Phorbols; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009529:Nicardipine; D011493:Protein Kinase C; D019311:Staurosporine; D005905:Glyburide; D002118:Calcium; C033085:phorbol; D007213:Indomethacin