RT Journal Article SR Electronic T1 Endothelium-dependent vasodilation in human mesenteric artery is primarily mediated by myoendothelial gap junctions, IKCa and NO JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.110.165795 DO 10.1124/jpet.110.165795 A1 Preet S Chadha A1 Lu Liu A1 Matt Rikard-Bell A1 Sevvandi Senadheera A1 Lauren Howitt A1 Rebecca L Bertrand A1 T Hilton Grayson A1 Timothy V Murphy A1 Shaun L Sandow YR 2010 UL http://jpet.aspetjournals.org/content/early/2010/12/20/jpet.110.165795.abstract AB Myoendothelial microdomain signalling via localised calcium-activated potassium channel (KCa) and gap junction connexins (Cxs) is critical for endothelium-dependent vasodilation in rat mesenteric artery. The present study determines the relative contribution of nitric oxide (NO) and gap junction-KCa mediated microdomain signalling to endothelium-dependent vasodilation in human mesenteric artery. The hypothesis tested was that such activity is due to NO and localized KCa and Cx activity. In mesenteric arteries from intestinal surgery patients, endothelium-dependent vasodilation was characterized using pressure myography with pharmacological intervention. Vessel morphology was examined using immunohistochemical and ultrastructural techniques. In vessel segments at 80 mmHg, the intermediate (I)KCa blocker TRAM-34 (1 µM) inhibited bradykinin (BK; 0.1 nM-3 µM)-induced vasodilation, while the small (S)KCa blocker apamin (50 and 100 nM), had no effect. Direct IKCa activation with 1-ethyl-2-benzimidazolinone (1-EBIO; 10-300 µM) induced vasodilation, whereas cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA; 1-30 µM), the SKCa activator, failed to dilate arteries; whilst dilation induced by 1-EBIO (10-100 µM) was blocked by TRAM-34. Bradykinin-mediated vasodilation was attenuated by putative gap junction block with carbenoxolone (100 µM), with remaining dilation being blocked by L-NAME (100 µM) and ODQ (10 µM); NO synthase and sGC blockers, respectively. In human mesenteric artery, myoendothelial gap junction and IKCa activity are consistent with Cx37 and IKCa microdomain expression and distribution. Data suggests that endothelium-dependent vasodilation is primarily mediated by NO, IKCa and gap junction Cx37 in this vessel. Myoendothelial microdomain signalling sites are present in human mesenteric artery and likely contribute to endothelium-dependent vasodilation via a mechanism that is conserved between species.