Control of vascular tone by endogenous endothelin-1 in human pial arteries

Background and Purpose-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 mu mol/L) increased basal tone by 7+/-1%E-max (n = 5). This increase in tone was fully abolished in the presence of BQ123 (1 mu mol/L; ETA receptor antagonist, P<.05) but potentiated by a subthreshold concentration of exogenous ET (1 nmol/L; 33+/-8%E-max; P<.05). In the presence of L-NA, serotonin (10 mu mol/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 alpha(2)-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 mu mol/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 alpha(2)-adrenergic receptors generated an endothelium-dependent relaxation that was selectively inhibited by exogenous ET.