Losartan normalizes endothelium-derived hyperpolarizing factor-mediated relaxation by activating Ca2+-activated K+ channels in mesenteric artery from type 2 diabetic GK rat.
Ca(2+)-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 K(Ca) channels [small (SK(Ca))-, intermediate (IK(Ca))-, and large (BK(Ca))-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 IK(Ca)-blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-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 BK(Ca)-blocker iberiotoxin had a significant inhibitory effect in only one of these groups, the losartan-treated GK. The relaxations induced by the SK(Ca)/IK(Ca) activator NS309 and the BK(Ca) 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 SK(Ca)/IK(Ca) activities and increasing BK(Ca) activity.
Matsumoto
Takayuki
T
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
Ishida
Keiko
K
Taguchi
Kumiko
K
Kobayashi
Tsuneo
T
Kamata
Katsuo
K
D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D001685:Biological Factors; D024681:Potassium Channels, Calcium-Activated; C067410:endothelium-dependent hyperpolarization factor; D019808:Losartan