Losartan normalizes endothelium-derived hyperpolarizing factor-mediated relaxation by activating Ca2+ -activated K+ channels in mesenteric artery from type 2 diabetic GK rat

Ca2+ -activated k+ (k ca) channels are important for endothelium-derived hyperpolarizing factor (edhf) signaling. since treatment with angiotensin ii receptor blockers (arbs) improves vasculopathies in type 2 diabetic patients,we asked whether the edhf-type relaxation and its associated kca channels [small (skca)-,intermediate (ikca)-,and large (bkca)-conductance channels] are abnormal in mesenteric arteries isolated from goto-kakizaki (gk) rats at the chronic stage of type 2 diabetes (34 - 38 weeks) and whether an arbs (losartan,25 mg · kg-1 · day-1 for 2 weeks) might correct these abnormalities. although the acetylcholine chloride-induced edhf-type relaxation in mesenteric arteries from gk rats was reduced versus the wistar controls,it was significantly restored by losartan treatment. the sk ca -blocker apamin or the ikca -blocker 1-[(2-chlorophenyl)diphenylmethyl]-1 h -pyrazole (tram-34) inhibited such relaxations in the losartan-treated or -untreated wistar groups and in the losartan-treated gk group,but not in the losartan-untreated gk group. the bkca -blocker iberiotoxin had a significant inhibitory effect in only one of these groups,the losartan-treated gk. the relaxations induced by the skca /ikca acti-vator ns309 and the bkca activator ns1619,which were impaired in gk rats,were normalized by losartan treatment. we conclude that losartan improves edhf-type relaxation in gk rats at least partly by normalizing skca/ikcaactivities and increasing bkca activity. © 2010 the japanese pharmacological society.