title: NS-398, a selective cyclooxygenase-2 blocker, acutely inhibits receptor-mediated contractions of rat aorta: role of endothelium.
abstract: NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)-methane sulfonamide) is a selective inhibitor of the cyclooxygenase-2 isozyme in vitro and in vivo. This study reports on acute inhibition of receptor-mediated contractions of isolated rat aorta by NS-398 and its modulation by endothelium-derived nitric oxide. NS-398 (1-10 microM) blocked norepinephrine, and 5-hydroxytryptamine (5-HT) evoked contractions and suppressed E(max) responses for both agonists. E(max) changes occurred in endothelium-intact vessel rings and in the absence, as well as in the presence of cycloheximide or dexamethasone in the physiological salt solution (PSS) bathing the tissues. NS-398 altered contractions to these receptor agonists in denuded rings only at 10 microM, and did not significantly alter contractions to KCl and sodium fluoride in all situations. NS-398 (3 and 10 microM) reduced aortic contractions initiated by cyclopiazonic acid (CPA), a sarcoplasmic reticulum Ca(2+)-ATPase blocker, in endothelium intact rings bathed with PSS with/without nitro-D-arginine methyl ester (D-NAME; 100 microM), but did not alter contractions to the compound in endothelium-denuded aortic rings and in vessel rings bathed with PSS+L-NAME (100 microM). Western blot analyses reveal significantly denser cyclooxygenase-2 protein expressions in freshly isolated endothelium-intact, compared to, denuded vessel segments. We conclude that: (1) cyclooxygenase-2 is constitutively expressed in rat aortic endothelial and smooth muscle cells, and (2) NS-398 modulates aortic contractions principally through an action on endothelial cyclooxygenase-2. Our data strongly suggest that cyclooxygenase-2 and/or its product(s), in concert with endothelium-derived nitric oxide, regulates the sarcoplasmic reticulum Ca(2+) pump activity in rat aorta.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40292, USA. asadea01@louisville.edu
authors.forename: Ayotunde S O
authors.initials: AS
authors.lastname: Adeagbo
authors.forename: Darshana
authors.initials: D
authors.lastname: Patel
authors.forename: Abdallah
authors.initials: A
authors.lastname: Iddrissu
authors.forename: John
authors.initials: J
authors.lastname: Walker
authors.forename: Sridhar
authors.initials: S
authors.lastname: Thirumalai
authors.forename: Irving G
authors.initials: IG
authors.lastname: Joshua
authors.forename: Dale
authors.initials: D
authors.lastname: Schuschke
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D007527:Isoenzymes; D009578:Nitrobenzenes; D011956:Receptors, Cell Surface; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D012701:Serotonin; D003907:Dexamethasone; D003513:Cycloheximide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium; D009638:Norepinephrine; C000543:cyclopiazonic acid