title: Effects of glutathione-depleting drug buthionine sulfoximine and aging on activity of endothelium-derived relaxing and contracting factors in carotid artery of Sprague-Dawley rats.
abstract: The role of the antioxidant glutathione (GSH) in mediating endothelial (dys)function, and how that role may depend on age, is unclear. The main purpose of the current study was to investigate the effect of 10-day treatment with the GSH-depleting drug l-buthionine sulfoximine (BSO) on endothelium-derived relaxing factor and endothelium-derived contracting factor activities in the isolated common carotid artery (CCA) of Adult and Aging animals. CCA blood pressure and flow were unaffected by age or BSO. Endothelium-derived relaxing factor activity, examined in precontracted CCA as relaxation to cumulative acetylcholine (ACh), was largely nitric oxide synthase (NOS) mediated and was not different between Adult and Aging animals at lower ACh; however, at higher ACh, relaxation was blunted in Aging CCA, an effect abolished by cyclooxygenase (COX) inhibition but not by NOS inhibition nor by the reactive oxygen species (ROS) inhibitors 4-hydroxy-TEMPO or Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin,tetratosylate,hydroxide. Specific examination of endothelium-derived contracting factor activity in quiescent NOS-inhibited CCA established that higher ACh elicited a contractile response, ∼3.5-fold greater in Aging versus Adult CCA, which was abolished by COX-1-specific inhibition but unaffected by ROS inhibitors. Aging was unrelated to changes in liver or vascular tissue GSH or ROS content. BSO was effective in significantly decreasing GSH and increasing ROS content in both animal cohorts. However, NOS-mediated endothelium-derived relaxing factor activity was well preserved and age-related COX-mediated endothelium-derived contracting factor activity was unaffected in response to these BSO-induced perturbations, as were exogenous H2O2-stimulated NOS/non-NOS-mediated relaxation and COX-mediated contractile activities. These data suggest that, regardless of age, chronic partial depletion of GSH in vivo does not necessarily cause endothelium-dependent vasomotor dysfunction.
authors.affiliation: From the Integrative Vascular Biology Laboratory, Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Denniss
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levy
authors.forename: James W E
authors.initials: JW
authors.lastname: Rush
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000375:Aging; D000818:Animals; D001794:Blood Pressure; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000378:metabolism; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006339:Heart Rate; D006439:Hemodynamics; D008297:Male; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism; D015398:Signal Transduction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D019328:Buthionine Sulfoximine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005978:Glutathione