title: In vivo location and mechanism of EDHF-mediated vasodilation in canine coronary microcirculation.
abstract: Responses of epicardial coronary arterioles to ACh were measured using stroboscopic fluorescence microangiography in dogs (n = 38). ACh (0.1 and 0.5 microg. kg(-1). min(-1) ic) dilated small (<100 micron, 11 +/- 2 and 19 +/- 2%, respectively) and large (>100 micron, , 6 +/- 3 and 13 +/- 3%, respectively) arterioles at baseline. Combined administration of N(omega)-monomethyl-L-arginine (L-NMMA; 1. 0 micromol/min ic) and indomethacin (10 mg/kg iv) eliminated ACh-induced dilation in large coronary arterioles but only partially attenuated that in small arterioles. Suffusion of a buffer containing 60 mM KCl (high KCl) completely abolished cromakalim-induced dilation in arterioles and in combination with L-NMMA plus indomethacin completely blocked ACh-induced dilation in small arterioles. This indicated that the vasodilation to ACh that persists in small arterioles after administration of L-NMMA and indomethacin is mediated via a hyperpolarizing factor. The ACh-induced vasodilation remaining after L-NMMA and indomethacin was completely blocked by the large-conductance potassium-channel antagonist iberiotoxin or by epicardial suffusion of miconazole or metyrapone, inhibitors of cytochrome P-450 enzymes. These observations are consistent with the view that endothelium-derived hyperpolarizing factor (EDHF) is a product of cytochrome P-450 enzymes and produces vasodilation by the opening of large-conductance potassium channels. We conclude that ACh-induced dilation in large coronary arterioles is mediated mainly by nitric oxide (NO), whereas, in small arterioles both NO and EDHF mediate dilation to ACh. These data provide the first direct evidence for an in vivo role of EDHF in small coronary arterioles.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. yasu@mcw.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: D W
authors.initials: DW
authors.lastname: Stepp
authors.forename: W M
authors.initials: WM
authors.lastname: Chilian
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D003331:Coronary Vessels / Q000502:physiology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000109:Acetylcholine