title: Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation.
abstract: The identity of endothelium-dependent hyperpolarizing factor (EDHF) in the human circulation remains controversial. We investigated whether EDHF contributes to endothelium-dependent vasomotion in the forearm microvasculature by studying the effect of K+ and miconazole, an inhibitor of cytochrome P-450, on the response to bradykinin in healthy human subjects. Study drugs were infused intra-arterially, and forearm blood flow was measured using strain-gauge plethysmography. Infusion of KCl (0.33 mmol/min) into the brachial artery caused baseline vasodilation and inhibited the vasodilator response to bradykinin, but not to sodium nitroprusside. Thus the incremental vasodilation induced by bradykinin was reduced from 14.3 +/- 2 to 7.1 +/- 2 ml x min(-1) x 100 g(-1) (P < 0.001) after KCl infusion. A similar inhibition of the bradykinin (P = 0.014), but not the sodium nitroprusside (not significant), response was observed with KCl after the study was repeated during preconstriction with phenylephrine to restore resting blood flow to basal values after KCl. Miconazole (0.125 mg/min) did not inhibit endothelium-dependent or -independent responses to ACh and sodium nitroprusside, respectively. However, after inhibition of cyclooxygenase and nitric oxide synthase with aspirin and NG-monomethyl-L-arginine, the forearm blood flow response to bradykinin (P = 0.003), but not to sodium nitroprusside (not significant), was significantly suppressed by miconazole. Thus nitric oxide- and prostaglandin-independent, bradykinin-mediated forearm vasodilation is suppressed by high intravascular K+ concentrations, indicating a contribution of EDHF. In the human forearm microvasculature, EDHF appears to be a cytochrome P-450 derivative, possibly an epoxyeicosatrienoic acid.
authors.affiliation: Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Halcox
authors.forename: S
authors.initials: S
authors.lastname: Narayanan
authors.forename: L
authors.initials: L
authors.lastname: Cramer-Joyce
authors.forename: R
authors.initials: R
authors.lastname: Mincemoyer
authors.forename: A A
authors.initials: AA
authors.lastname: Quyyumi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001241:Aspirin / Q000008:administration & dosage; D001685:Biological Factors / Q000378:metabolism*; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001916:Brachial Artery / Q000502:physiology; D001920:Bradykinin / Q000008:administration & dosage; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; 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; D005542:Forearm / Q000098:blood supply* / Q000502:physiology; D006801:Humans; D007261:Infusions, Intra-Arterial; D008825:Miconazole / Q000008:administration & dosage; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D009599:Nitroprusside / Q000008:administration & dosage; D010656:Phenylephrine / Q000008:administration & dosage; D010991:Plethysmography; D011189:Potassium Chloride / Q000008:administration & dosage; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D014665:Vasodilator Agents / Q000008:administration & dosage; D014666:Vasomotor System / Q000187:drug effects / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009599:Nitroprusside; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D011189:Potassium Chloride; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D001241:Aspirin; D001920:Bradykinin