title: Opening of small and intermediate calcium-activated potassium channels induces relaxation mainly mediated by nitric-oxide release in large arteries and endothelium-derived hyperpolarizing factor in small arteries from rat.
abstract: This study was designed to investigate whether calcium-activated potassium channels of small (SK(Ca) or K(Ca)2) and intermediate (IK(Ca) or K(Ca)3.1) conductance activated by 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309) are involved in both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation in large and small rat mesenteric arteries. Segments of rat superior and small mesenteric arteries were mounted in myographs for functional studies. NO was recorded using NO microsensors. SK(Ca) and IK(Ca) channel currents and mRNA expression were investigated in human umbilical vein endothelial cells (HUVECs), and calcium concentrations were investigated in both HUVECs and mesenteric arterial endothelial cells. In both superior (∼1093 μm) and small mesenteric (∼300 μm) arteries, NS309 evoked endothelium- and concentration-dependent relaxations. In superior mesenteric arteries, NS309 relaxations and NO release were inhibited by both N(G),N(G)-asymmetric dimethyl-l-arginine (ADMA) (300 μM), an inhibitor of NO synthase, and apamin (0.5 μM) plus 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) (1 μM), blockers of SK(Ca) and IK(Ca) channels, respectively. In small mesenteric arteries, NS309 relaxations were reduced slightly by ADMA, whereas apamin plus an IK(Ca) channel blocker almost abolished relaxation. Iberiotoxin did not change NS309 relaxation. HUVECs expressed mRNA for SK(Ca) and IK(Ca) channels, and NS309 induced increases in calcium, outward current, and NO release that were blocked by apamin and TRAM-34 or charybdotoxin. These findings suggest that opening of SK(Ca) and IK(Ca) channels leads to endothelium-dependent relaxation that is mediated mainly by NO in large mesenteric arteries and by EDHF-type relaxation in small mesenteric arteries. NS309-induced calcium influx appears to contribute to the formation of NO.
authors: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Faculty of Health Sciences, Aarhus University, 8000 Aarhus C, Denmark.
authors: Edgaras
authors: E
authors: Stankevicius
authors: Thomas
authors: T
authors: Dalsgaard
authors: Christel
authors: C
authors: Kroigaard
authors: Lilliana
authors: L
authors: Beck
authors: Ebbe
authors: E
authors: Boedtkjer
authors: Mikkel W
authors: MW
authors: Misfeldt
authors: Gorm
authors: G
authors: Nielsen
authors: Olav
authors: O
authors: Schjorring
authors: Alun
authors: A
authors: Hughes
authors: Ulf
authors: U
authors: Simonsen
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001030:Apamin / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D061307:Human Umbilical Vein Endothelial Cells; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010091:Oximes / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000502:physiology*; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D000873:Anthracenes; D001685:Biological Factors; D007211:Indoles; D010091:Oximes; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; C411671:TRAM 34; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D001030:Apamin; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D011407:Propane