title: Involvement of cytochrome epoxygenase metabolites in cutaneous postocclusive hyperemia in humans.
abstract: Several mediators contribute to postocclusive reactive hyperemia (PORH) of the skin, including sensory nerves and endothelium-derived hyperpolarizing factors. The main objective of our study was to investigate the specific contribution of epoxyeicosatrienoic acids in human skin PORH. Eight healthy volunteers were enrolled in two placebo-controlled experiments. In the first experiment we studied the separate and combined effects of 6.5 mM fluconazole, infused through microdialysis fibers, and lidocaine/prilocaine cream on skin PORH following 5 min arterial occlusion. In the second experiment we studied the separate and combined effects of 6.5 mM fluconazole and 10 mM N(G)-monomethyl-l-arginine (l-NMMA). Skin blood flux was recorded using two-dimensional laser speckle contrast imaging. Maximal cutaneous vascular conductance (CVC(max)) was obtained following 29 mM sodium nitroprusside perfusion. The PORH peak at the placebo site averaged 66 ± 11%CVC(max). Compared with the placebo site, the peak was significantly lower at the fluconazole (47 ± 10%CVC(max); P < 0.001), lidocaine (29 ± 10%CVC(max); P < 0.001), and fluconazole + lidocaine (30 ± 10%CVC(max); P < 0.001) sites. The effect of fluconazole on the area under the curve was more pronounced. In the second experiment, the PORH peak was significantly lower at the fluconazole site, but not at the l-NMMA or combination site, compared with the placebo site. In addition to sensory nerves cytochrome epoxygenase metabolites, putatively epoxyeicosatrienoic acids, play a major role in healthy skin PORH, their role being more important in the time course rather than the peak.
authors.affiliation: Clinical Pharmacology Department, Institut National de la Santé et de la Recherche Médicale CIC3, University Hospital, Grenoble, France. Jean-Luc.Cracowski@ujf-grenoble.fr
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
authors.forename: Florence
authors.initials: F
authors.lastname: Gaillard-Bigot
authors.forename: Claire
authors.initials: C
authors.lastname: Cracowski
authors.forename: Claire
authors.initials: C
authors.lastname: Sors
authors.forename: Matthieu
authors.initials: M
authors.lastname: Roustit
authors.forename: Claire
authors.initials: C
authors.lastname: Millet
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000328:Adult; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D006940:Hyperemia / Q000378:metabolism* / Q000503:physiopathology; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000201:enzymology*; D012867:Skin / Q000098:blood supply* / Q000378:metabolism; D012871:Skin Diseases / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D009599:Nitroprusside; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid; D019331:NG-Nitroarginine Methyl Ester