The influence of DOCA-salt hypertension and chronic administration of the FAAH inhibitor URB597 on K2.3/K3.1-EDH-type relaxation in rat small mesenteric arteries.

The aim of this study was to examine the influence of deoxycorticosterone acetate-salt (DOCA-salt) hypertension and chronic treatment with the fatty acid amide hydrolase inhibitor, URB597, on small and intermediate conductance calcium-activated potassium channels and endothelium-dependent hyperpolarization (K2.3/K3.1-EDH) in rat small mesenteric arteries (sMAs). The EDH-type response was investigated, in endothelium-intact sMAs using a wire myograph, by examining acetylcholine-evoked vasorelaxation in the presence of N-nitro-L-arginine methyl ester and indomethacin (inhibitors of nitric oxide synthase and cyclooxygenase, respectively). In normo- and hypertension the efficacy of EDH-type relaxation was similar and inhibition of K2.3 and K3.1 by UCL1684 and TRAM-34, respectively, given alone or in combination, attenuated EDH-mediated vasorelaxation. K3.1 expression and NS309 (K2.3/K3.1 activator)-induced relaxation was reduced in sMAs of DOCA-salt rats. Endothelium denudation and incubation with UCL1684 and TRAM-34 attenuated the maximal NS309-evoked vasorelaxation in both groups. URB597 had no effect in functional studies, but increased the expression of K3.1 in the sMAs. K2.3/K3.1-EDH-mediated relaxation was maintained in the sMAs of DOCA-salt rats despite endothelial dysfunction and down-regulation of K3.1. Furthermore, K3.1 played a key role in the EDH-type dilator response of sMAs in normo- and hypertension. The hypotensive effect of URB597 is independent of K2.3/K3.1-EDH-type relaxation.