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Control of vascular tone by endogenous endothelin-1 in human pial arteries
E Thorin1, T D Nguyen, A Bouthillier
1Institut de Cardiologie de Montréal, Centre de Recherche, PQ, Canada. thorin@icm.umontreal.ca
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 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.