Negative allosteric modulation of endothelin ETA receptor function in resistance arteries
pretreatment with 5 μM NE in a concentration-dependent manner. NG-monomethyl-l-arginine acetate (L-NMMA)(100 μM), a NO synthesis inhibitor, reduced the quercetin (100 μM)-induced vasorelaxation from 97.0 ± 3.7% (n = 10, P b 0.05) to 78.0 ± 11.6% (n = 5, P b 0.05). Endothelium removal as well attenuated the vasodilatation. In the presence of both 100 μM L-NMMA and 10 μM indomethacin, the quercetin-induced vasorelaxation was further attenuated by high K (30 mM) or 10 μM tetraethylammonium (TEA,
... hylammonium (TEA, KCa channel inhibitor). Nicardipine caused less or no effect on the relaxation. The quercetininduced vasodilatation was attenuated by 0.3 μM apamin (SK channel inhibitor), but not by 30 nM charybdotoxin (BK and IK channel blockers). Under KCl-induced vasoconstriction, the quercetin-induced vasorelaxation was attenuated by PK-C inhibitors. Gö6983 (α-, β-, γ-, δand ζ-sensitive) produced a stronger relaxing effect than Ro-31-8425 (α-, β-, γand ε-sensitive). These results indicate that the vasorelaxation is dependent on the endothelium, and is also exerted by the modulation of SK channel and PK-Cδ. In rat mesenteric artery, the quercetin-induced vasodilatation was in part resistant to both 100 μM L-NG-nitro arginine methyl ester (L-NAME) and 100 μM indomethacin. The L-NAME-and indomethacin-resistant quercetininduced vasodilatation was attenuated by TEA (1 mM) and also by 100 μM 18α-and 50 μM 18β-glychrrhetinic acids (gap junction inhibitors). These results indicate that the vasorelaxation is also dependent on the endothelium and KCa channel, and is further produced by the modulation of the gap junction. Therefore, quercetin vasodilates the vascular smooth muscle mediated by endotheliumdependent and-independent mechanisms.