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

摘要

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.