Cytochrome P-450 2C9 signaling does not contribute to age-associated vascular endothelial dysfunction in humans

Anthony J Donato; Iratxe Eskurza; Kristen L Jablonski; Lindsey B Gano; Gary L Pierce; Douglas R Seals

doi:10.1152/japplphysiol.90629.2008

Back

Cytochrome P-450 2C9 signaling does not contribute to age-associated vascular endothelial dysfunction in humans

Journal article

Open access

Peer reviewed

Cytochrome P-450 2C9 signaling does not contribute to age-associated vascular endothelial dysfunction in humans

Anthony J Donato, Iratxe Eskurza, Kristen L Jablonski, Lindsey B Gano, Gary L Pierce and Douglas R Seals

Journal of applied physiology (1985), Vol.105(4), pp.1359-1363

10/2008

DOI: 10.1152/japplphysiol.90629.2008

PMCID: PMC2576044

PMID: 18669935

Files and links (1)

url

https://doi.org/10.1152/japplphysiol.90629.2008View

Published (Version of record) Open Access

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.

Cytochrome P-450 CYP2C9

Age Factors

Oxidative Stress

Humans

Middle Aged

Nitric Oxide Synthase - antagonists & inhibitors

Endothelium, Vascular - drug effects

Male

omega-N-Methylarginine - pharmacology

Nitroprusside - pharmacology

Endothelium, Vascular - enzymology

Sulfaphenazole - pharmacology

Brachial Artery - enzymology

Dose-Response Relationship, Drug

Forearm - blood supply

Adult

Brachial Artery - physiopathology

Female

Brachial Artery - drug effects

Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors

Vasodilator Agents - pharmacology

Acetylcholine - pharmacology

Endothelium, Vascular - physiopathology

Enzyme Inhibitors - pharmacology

Regional Blood Flow

Aryl Hydrocarbon Hydroxylases - metabolism

Signal Transduction - drug effects

Aged

Nitric Oxide Synthase - metabolism

Vasodilation - drug effects

Nitric Oxide - metabolism

Aging - metabolism

Details

Title: Subtitle: Cytochrome P-450 2C9 signaling does not contribute to age-associated vascular endothelial dysfunction in humans
Creators: Anthony J Donato - Department of Integrative Physiology, Universty of Colorado at Boulder, 354 UCB, Boulder, CO 80309, USA. tony.donato@colorado.edu
Iratxe Eskurza
Kristen L Jablonski
Lindsey B Gano
Gary L Pierce
Douglas R Seals
Resource Type: Journal article
Publication Details: Journal of applied physiology (1985), Vol.105(4), pp.1359-1363
DOI: 10.1152/japplphysiol.90629.2008
PMID: 18669935
PMCID: PMC2576044
NLM abbreviation: J Appl Physiol (1985)
ISSN: 8750-7587
eISSN: 1522-1601
Publisher: United States
Grant note: R01 AG022241 / NIA NIH HHS AG 006537 / NIA NIH HHS AG 029337 / NIA NIH HHS R01 AG006537 / NIA NIH HHS K01 AG029337 / NIA NIH HHS AG 013038 / NIA NIH HHS AG 000279 / NIA NIH HHS HL 007851 / NHLBI NIH HHS R01 AG013038 / NIA NIH HHS RR 00051 / NCRR NIH HHS AG 022241 / NIA NIH HHS
Language: English
Date published: 10/2008
Academic Unit: Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984002349302771

Metrics

27 Record Views

23 Times Cited - Web of Science