Control of vascular tone by endogenous endothelin-1 in human pial arteries.
OBJECTIVE
Endothelin-1 (ET) has been shown to be involved in human pathological conditions, but its physiological function remains to be elucidated. The aim of this work was to assess whether endothelium-derived ET was involved in the overall responsiveness of freshly isolated human pial arteries.


METHODS
Samples of cerebral cortex, otherwise discarded, were obtained during tumor or epileptic lesion resections (n = 10 donors). Arterial segments were isolated and mounted on a microvessel myograph.


RESULTS
Inhibition of nitric oxide (NO) formation with N omega-nitro-L-arginine (L-NA, 100 micromol/L) increased basal tone by 7+/-1% Emax (n=5). This increase in tone was fully abolished in the presence of BQ123 (1 micromol/L; ET(A) receptor antagonist, P<.05) but potentiated by a subthreshold concentration of exogenous ET (1 nmol/L; 33+/-8% Emax; P<.05). In the presence of L-NA, serotonin (10 micromol/L)-induced tone was doubled compared with the control response (P<.05) but reduced by 90% in the presence of BQ123 (P<.05). In the absence of L-NA, BQ123 prevented serotonin-induced tone (n=3). Oxymetazoline, a selective alpha2-adrenergic receptor agonist, induced an endothelium-dependent relaxation of preconstricted human pial arteries. The relaxation was partially sensitive to NO synthase inhibition and fully prevented by the addition of ET, whereas substance P-induced relaxation was preserved. Glibenclamide (1 micromol/L), an inhibitor of ATP-sensitive K+ channels and tetraethylammonium (1 mmol/L), an inhibitor of Ca2+-activated K+ channels had no effect on oxymetazoline-induced relaxation.


CONCLUSIONS
The results of this study suggest first that ET is involved in the tonic response induced by NO synthase inhibition; second, part of the contractile response induced by serotonin is endothelium-dependent and sensitive to BQ123; and third, the data suggest that activation of alpha2-adrenergic receptors generated an endothelium-dependent relaxation that was selectively inhibited by exogenous ET.
Thorin
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Institut de Cardiologie de Montréal, Centre de Recherche, PQ, Canada. thorin@icm.umontreal.ca
Nguyen
T D
TD
Bouthillier
A
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D000293:Adolescent; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000328:Adult; D001158:Arteries / Q000187:drug effects; D001932:Brain Neoplasms / Q000601:surgery; D002540:Cerebral Cortex / Q000098:blood supply; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000601:surgery; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010109:Oxymetazoline / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply*; D026902:Potassium Channel Blockers; D012701:Serotonin / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010456:Peptides, Cyclic; D026902:Potassium Channel Blockers; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D012701:Serotonin; D013373:Substance P; D019789:Tetraethylammonium; D010109:Oxymetazoline; D019001:Nitric Oxide Synthase; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester