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Stankevicius E.,University of Aarhus | Stankevicius E.,Lithuanian University of Medicine | Dalsgaard T.,University of Aarhus | Kroigaard C.,University of Aarhus | And 7 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

This study was designed to investigate whether calcium-activated potassium channels of small (SK Ca or K Ca2) and intermediate (IK Ca or K Ca3.1) 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 Caand 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. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics. Source

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