title: Cytochrome P-450 2C9 signaling does not contribute to age-associated vascular endothelial dysfunction in humans.
abstract: Oxidative stress impairs endothelium-dependent dilation (EDD) with aging in healthy sedentary adults. Increased cytochrome P-450 2C9 (CYP 2C9) signaling can contribute to oxidative stress-mediated suppression of EDD, but its role in aging is unknown. We hypothesized that inhibition of CYP 2C9 signaling with sulfaphenazole would improve EDD in older, but not young, healthy sedentary adults. At baseline, increases in forearm blood flow (FBF; venous occlusion plethysmography) in response to brachial artery infusions of ACh (1, 2, 4, and 8 microg.100 ml forearm volume(-1).min(-1)), an endothelium-dependent dilator, were smaller in older [n = 14, 63 +/- 1 (SE) yr] than in young (n = 11, 23 +/- 2 yr) adults (P < 0.05), with a reduction in peak FBF of 32% (11.8 +/- 1.7 vs. 17.3 +/- 2.3 ml.100 ml tissue(-1).min(-1)). Infusion of sulfaphenazole at doses that block CYP 2C9 signaling in humans did not affect the FBF responses to ACh in the older (peak FBF = 13.0 +/- 4.3 ml.100 ml tissue(-1).min(-1), P = 0.41) or the young (peak FBF = 17.1 +/- 1.9 ml.100 ml tissue(-1).min(-1), P = 0.55) adults. Coadministration of the nitric oxide inhibitor l-NMMA and sulfaphenazole decreased the FBF response to ACh in young and older subjects (P < 0.05); the effect was smaller in the older subjects, but group differences in EDD remained (P < 0.05). Endothelium-independent dilation assessed with sodium nitroprusside was not different in the young and older subjects. These results provide the first support for the concept that increased CYP 2C9 signaling does not contribute to impairments in EDD with aging in healthy adults.
authors.affiliation: Department of Integrative Physiology, Universty of Colorado at Boulder, 354 UCB, Boulder, CO 80309, USA. tony.donato@colorado.edu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
authors.forename: Iratxe
authors.initials: I
authors.lastname: Eskurza
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Jablonski
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Gano
authors.forename: Gary L
authors.initials: GL
authors.lastname: Pierce
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001916:Brachial Artery / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D013426:Sulfaphenazole / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D013426:Sulfaphenazole; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019001:Nitric Oxide Synthase; D001189:Aryl Hydrocarbon Hydroxylases; D000109:Acetylcholine