PT  - JOURNAL ARTICLE
AU  - Edgaras Stankevičius
AU  - Thomas Dalsgaard
AU  - Christel Kroigaard
AU  - Lilliana Beck
AU  - Ebbe Boedtkjer
AU  - Mikkel W. Misfeldt
AU  - Gorm Nielsen
AU  - Olav Schjorring
AU  - Alun Hughes
AU  - Ulf Simonsen
TI  - 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
AID  - 10.1124/jpet.111.179242
DP  - 2011 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 842--850
VI  - 339
IP  - 3
4099  - http://jpet.aspetjournals.org/content/339/3/842.short
4100  - http://jpet.aspetjournals.org/content/339/3/842.full
SO  - J Pharmacol Exp Ther2011 Dec 01; 339
AB  - This study was designed to investigate whether calcium-activated potassium channels of small (SKCa or KCa2) and intermediate (IKCa or KCa3.1) 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. SKCa and IKCa 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 NG,NG-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 SKCa and IKCa channels, respectively. In small mesenteric arteries, NS309 relaxations were reduced slightly by ADMA, whereas apamin plus an IKCa channel blocker almost abolished relaxation. Iberiotoxin did not change NS309 relaxation. HUVECs expressed mRNA for SKCa and IKCa 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 SKCa and IKCa 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.