title: Aging increases PGHS-2-dependent vasoconstriction in rat mesenteric arteries.
abstract: During aging, the vascular endothelium changes functionally and morphologically. Although previous studies have shown that endothelium-derived eicosanoids increase vessel tone in aging, the precise mechanism(s) has not been fully determined. We hypothesized that aging would increase prostaglandin H synthase (PGHS)-dependent vasoconstriction as well as decrease nitric oxide-dependent relaxation. Mesenteric arteries from 3-month-old (n=9) and 12-month-old (n=14) female Sprague-Dawley rats were studied in a myograph system. Aging significantly blunted the endothelium-dependent relaxation response to methacholine compared with young rats (EC(50)=7.77x10(-8) versus 2.68x10(-8) mol/L, P<0. 05). Nitric oxide synthase inhibition reduced methacholine-induced relaxation in the young (P<0.05) but had no effect in the aging group. Specific inhibition of the PGHS-1 isoform did not significantly affect methacholine-mediated relaxation in the young or aged groups. However, PGHS-2 inhibition greatly enhanced relaxation to methacholine (1.59x10(-8) versus 7.77x10(-8) mol/L, P<0.01) in the aged group only, restoring vessel function to that of the young. In the aged group, inhibition of the prostaglandin H(2)/thromboxane A(2) receptor enhanced methacholine-dependent relaxation similar to that of PGHS-2 inhibition. Moreover, arterial expression of PGHS-2 protein increased with age. In summary, nitric oxide-dependent modulation of vessel function decreased with age, PGHS-1 did not significantly affect vessel tone in either the young or aging group, and PGHS-2 greatly increased vasoconstriction in aging. Thus, we have identified enhanced PGHS-2-mediated vasoconstriction in aging and therefore suggest that inhibition of this isoform is potentially a new target for therapeutic intervention to improve vascular function.
authors.affiliation: Departments of Obstetrics/Gynecology and Physiology, Perinatal Research Centre, University of Alberta, Edmonton, Canada.
authors.forename: K G
authors.initials: KG
authors.lastname: Stewart
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: S T
authors.initials: ST
authors.lastname: Davidge
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D005260:Female; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D016210:Methacholine Chloride / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007527:Isoenzymes; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016210:Methacholine Chloride; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C045749:SQ 29548; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases