Key result
Nitric oxide inhibition increases human pial artery tone ~7%, an effect reversed by ETA blockade.
Why the study?
The physiological function of endothelium-derived endothelin-1 in human pial arteries remains to be elucidated.
Endogenous endothelin-1 plays a role in the tonic response of human pial arteries following nitric oxide synthase inhibition and modulates serotonin-induced contraction and alpha2-adrenergic relaxation.
Suggests ET-1 role in cerebral vasoregulation after NOS inhibition; leaves open translation to human stroke models.
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 withNω-nitro-l-arginine (L-NA, 100 μmol/L) increased basal tone by 7±1%Emax(n=5). This increase in tone was fully abolished in the presence of BQ123 (1 μmol/L; ETAreceptor 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 μmol/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 α2-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 μmol/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 α2-adrenergic receptors generated an endothelium-dependent relaxation that was selectively inhibited by exogenous ET.
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Thorin et al. (1998) studied Epileptic lesions or tumors (n=10). Nω-nitro-l-arginine (L-NA) and BQ123 vs. Control response / basal conditions was evaluated on Change in basal tone (p=<.05). Inhibition of nitric oxide formation with L-NA increased basal tone by 7% in freshly isolated human pial arteries, which was fully abolished by the ETA receptor antagonist BQ123 (P<0.05).
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