ENDOTHELIN-1-INDUCED IN-VITRO CEREBRAL VENOCONSTRICTION IS MEDIATED BY ENDOTHELIN ET(A) RECEPTORS

The in vitro effects of endothelin-l on cerebral veins were studied us ing cylindrical segments, 5 mm long, from dog pial veins. Isometric re sponses to endothelin-l (10(-12)-10(-7) M) and to the endothelin ET(B) receptor agonist, IRL 1620 (Suc-[Glu(9),Ala(11,15) ]endothelin-1-(8-2 1), 10(-12)-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 endothel in ET(B) receptor antagonist, BQ-788 carbonyl]-4-methyl-L-leucyl]-1(me thoxycarbonyl)-D- tryptophyl]-D-norleucine monosudium, 10(-6) and 10(- 5) M). The response to endothelin-l was also recorded in veins pretrea ted with the nitric oxide synthesis inhibitor, N-G-nitro-L-arginine me thyl ester (L-NAME, 10(-4) M), or the cyclooxygenase inhibitor, meclof enamate (10(-5) M), and in veins without endothelium or placed in medi um without Ca2+ but with EDTA (0.1 mM). In control veins, endothelin-l produced a concentration-dependent contraction (EC(50) = 2.0 x 10(-10 ) M; maximal contraction = 113 +/- 6 mg) and IRL 1620 induced no effec ts or a small contraction only with high concentrations (10(-8)-10(-6) M) (EC(50) = 1.5 x 10(-8) M; maximal contraction = 9 +/- 3 mg). BQ-12 3 shifted the response to endothelin-l to the right in a parallel, con centration-dependent way, whereas BQ-788, L-NAME or meclofenamate did not modify the response to endothelin-1. Compared with the control, ve ins in a medium without Ca2+ had similar EC(50) values, but a lower ma ximal contraction induced by endothelin-1 (57 +/- 10 mg, P < 0.05), an d veins without endothelium exhibited similar EC(50) values. Thus, end othelin-1 produces marked cerebral venoconstriction that could be main ly mediated by activation of endothelin ET(A) receptors, may be depend ent on extracellular Ca2+, and may be independent of endothelium, nitr ic oxide and prostanoids.