title: Chronic in vivo or acute in vitro resveratrol attenuates endothelium-dependent cyclooxygenase-mediated contractile signaling in hypertensive rat carotid artery.
abstract: Exaggerated cyclooxygenase (COX) and thromboxane-prostanoid (TP) receptor-mediated endothelium-dependent contraction can contribute to endothelial dysfunction. This study examined the effect of resveratrol (RSV) on endothelium-dependent contraction and cell signaling in the common carotid artery (CCA) from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Acetylcholine (Ach)-stimulated endothelium-dependent nitric oxide synthase (NOS)-mediated relaxation in precontracted SHR CCA was impaired (maximum 73 ± 6% vs. 87 ± 5% in WKY) (P < 0.05) by competitive COX-mediated contraction. Chronic (28-day) treatment in vivo (drinking water) with a ∼0.075 mg·kg(-1)·day(-1) RSV dose affected neither endothelium-dependent relaxation nor endothelium-dependent contraction and associated prostaglandin (PG) production evaluated in non-precontracted NOS-blocked CCA. In contrast, a chronic ∼7.5 mg·kg(-1)·day(-1) RSV dose improved endothelium-dependent relaxation (94 ± 6%) and attenuated endothelium-dependent contraction (58 ± 4% vs. 73 ± 5% in No-RSV) and PG production (183 ± 43 vs. 519 ± 93 pg/ml) in SHR CCA, while U46619-stimulated TP receptor-mediated contraction was unaffected. In separate acute in vitro experiments, 20-μM RSV preincubation attenuated endothelium-dependent contraction (6 ± 4% vs. 62 ± 2% in No Drug) and PG production (121 ± 15 vs. 491 ± 93 pg/ml) and attenuated U46619-stimulated contraction (134 ± 5% vs. 171 ± 4%) in non-precontracted NOS-blocked SHR CCA. Compound C, a known AMP-activated protein kinase (AMPK) inhibitor, did not prevent the RSV attenuating effect on Ach- and U46619-stimulated contraction but did prevent the RSV attenuating effect on PG production (414 ± 58 pg/ml). These data demonstrate that RSV can attenuate endothelium-dependent contraction both by suppressing arterial wall PG production, which may be partially mediated by AMPK, and by TP receptor hyporesponsiveness, which does not appear to be mediated by AMPK.
authors.affiliation: 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.affiliation: Integrative Vascular Biology Laboratory, Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Integrative Vascular Biology Laboratory, Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Smith
authors.affiliation: Integrative Vascular Biology Laboratory, Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Jeffery
authors.affiliation: Integrative Vascular Biology Laboratory, Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada jwerush@uwaterloo.ca.
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; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017482:Receptors, Thromboxane / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D011453:Prostaglandins; D017482:Receptors, Thromboxane; D013267:Stilbenes; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases; D055372:AMP-Activated Protein Kinases; D000109:Acetylcholine; D000077185:Resveratrol
keywords: AMP-activated protein kinase; cyclooxygenase; endothelium-dependent contraction; prostaglandin; resveratrol; thromboxane-prostanoid receptor