The in vitro effects of endothelin-1 on cerebral veins were studied using cylindrical segments, 5 mm long, from dog pial veins. Isometric responses to endothelin-1 (10 - 1 2 -10 - 7 M) and to the endothelin ET B receptor agonist, IRL 1620 (Suc-[Glu 9 ,Ala 1 1 , 1 5 ]endothelin-1-(8-21), 10 - 1 2 -10 - 7 M), were recorded in veins under control conditions and pretreated with the endothelin ET A receptor antagonist, BQ-123 (cyclo-(d-Asp-Pro-d-Val-Leu-d-Trp), 10 - 8 -10 - 5 M), and the endothelin ET B receptor antagonist, BQ-788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-l-leucyl]-1-(methox ycarbonyl)-d- tryptophyl]-d-norleucine monosudium, 10 - 6 and 10 - 5 M). The response to endothelin-1 was also recorded in veins pretreated with the nitric oxide synthesis inhibitor, N G -nitro-l-arginine methyl ester (L-NAME, 10 - 4 M), or the cyclooxygenase inhibitor, meclofenamate (10 - 5 M), and in veins without endothelium or placed in medium without Ca 2 + but with EDTA (0.1 mM). In control veins, endothelin-1 produced a concentration-dependent contraction (EC 5 0 = 2.0 10 - 1 0 M; maximal contraction = 113 ± 6 mg) and IRL 1620 induced no effects or a small contraction only with high concentrations (10 - 8 -10 - 6 M) (EC 5 0 = 1.5 10 - 8 M; maximal contraction = 9 ± 3 mg). BQ-123 shifted the response to endothelin-1 to the right in a parallel, concentration-dependent way, whereas BQ-788, L-NAME or meclofenamate did not modify the response to endothelin-1. Compared with the control, veins in a medium without Ca 2 + had similar EC 5 0 values, but a lower maximal contraction induced by endothelin-1 (57 ± 10 mg, P < 0.05), and veins without endothelium exhibited similar EC 5 0 values. Thus, endothelin-1 produces marked cerebral venoconstriction that could be mainly mediated by activation of endothelin ET A receptors, may be dependent on extracellular Ca 2 + , and may be independent of endothelium, nitric oxide and prostanoids.