Endothelin-1-induced in vitro cerebral venoconstriction is mediated by endothelin ETA receptors.
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(-12)-10(-7) M) and to the endothelin ET(B) receptor agonist, IRL 1620 (Suc-[Glu9,Ala11,15]endothelin-1-(8-21), 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 endothelin ETB receptor antagonist, BQ-788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(me thoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium, 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 Ca2+ but with EDTA (0.1 mM). In control veins, endothelin-1 produced a concentration-dependent contraction (EC50 = 2.0 x 10(-10) 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) (EC50 = 1.5 x 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 Ca2+ had similar EC50 values, but a lower maximal contraction induced by endothelin-1 (57 +/- 10 mg, P < 0.05), and veins without endothelium exhibited similar EC50 values. Thus, endothelin-1 produces marked cerebral venoconstriction that could be mainly mediated by activation of endothelin ETA receptors, may be dependent on extracellular Ca2+, and may be independent of endothelium, nitric oxide and prostanoids.
Fernandez
N
N
Departamento de Fisiologia, Facultad de Medicina, Universidad Autonoma, Madrid, Spain.
Monge
L
L
Garcia-Villalon
A L
AL
Garcia
J L
JL
Gomez
B
B
Dieguez
G
G
D000818:Animals; D002118:Calcium / Q000502:physiology; D002550:Cerebral Veins / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*
D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C074308:sovateltide; D009569:Nitric Oxide; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium; D009638:Norepinephrine