title: Role of endothelium-derived hyperpolarising factor in acetylcholine-mediated vasodilatation in skin.
abstract: OBJECTIVE
  Acetylcholine (ACh) is an endothelium-dependent vasodilator used to investigate endothelial function in the microcirculation. The mediators of its vasodilatory effects are not clear, but endothelium-derived hyperpolarising factor (EDHF) is thought to contribute, and appears to have particular importance in smaller peripheral vessels. The aim of this study was to investigate the role of EDHF in ACh-mediated vasodilator responses in human forearm skin.
  
  
  METHODS
  Laser Doppler imaging was used to measure forearm skin blood flow responses to iontophoretic administration of ACh in 7 healthy men. ACh in a 10-mg/mL solution was administered in accumulating doses using increasing delivery currents of 10, 15, 20, 50 and 100 µA. The measurements were repeated on subsequent visits when the effects of EDHF were blocked using intra-arterial sulphaphenazole at 2 mg/min (a cytochrome P-450 inhibitor), nitric oxide (NO) was blocked using intra-arterial administration of the NO synthetase inhibitor l-NG-monomethyl arginine (l-NMMA) at 4 µmol/min, and prostanoids were blocked with oral aspirin 1 g.
  
  
  RESULTS
  The microvascular response to ACh was significantly attenuated by sulphaphenazole alone (P=0.018), l-NMMA alone (P<0.001) and the combination of sulphaphenazole plus l-NMMA (P<0.001), and aspirin had no additional effect.
  
  
  CONCLUSIONS
  EDHF is a significant contributor to the vasodilatory effects of ACh in the human dermal microcirculation. Information about abnormalities in specific pathways of endothelial function in patient groups may help in the targeting of appropriate drug therapies.
authors.affiliation: Vascular and Inflammatory Diseases Research Unit, The Institute of Cardiovascular Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. d.j.newton@dundee.ac.uk
authors.forename: D J
authors.initials: DJ
authors.lastname: Newton
authors.forename: J
authors.initials: J
authors.lastname: Davies
authors.forename: J J F
authors.initials: JJ
authors.lastname: Belch
authors.forename: F
authors.initials: F
authors.lastname: Khan
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage*; D000279:Administration, Cutaneous; D000328:Adult; D001685:Biological Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001783:Blood Flow Velocity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D064368:Healthy Volunteers; D006801:Humans; D007478:Iontophoresis; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D012039:Regional Blood Flow; D012867:Skin / Q000098:blood supply*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D001685:Biological Factors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine