title: Oxidative stress induced by tert-butyl hydroperoxide causes vasoconstriction in the aorta from hypertensive and aged rats: role of cyclooxygenase-2 isoform.
abstract: We analyzed the mechanisms involved in the effect of tert-butyl hydroperoxide (t-BOOH) in isolated aortic rings with and without endothelium from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at 6, 18, and 24 months of age. t-BOOH (1 microM-10 mM) induced concentration-dependent contractions that were scarcely modified by aging and potentiated in SHR and by endothelium removal. The nitric oxide synthase and prostacyclin synthase inhibitors N(G)-nitro-L-arginine methyl ester (100 microM) and tranylcypromine (100 microM), respectively, increased both basal tone and the t-BOOH-induced contractions in intact segments from WKY, with these effects not observed in SHR. Indomethacin (10 microM), a nonspecific cyclooxygenase inhibitor, and SQ 29,548 (10 microM), a prostaglandin H(2)/thromboxane A(2) receptor blocker, abolished the t-BOOH-induced vasoconstriction, independent of age and hypertension. In both strains, these contractile responses were unaltered by the thromboxane synthase inhibitor imidazole (10 microM). The cyclooxygenase-2 inhibitor NS-398 (10 microM) abolished or markedly reduced the t-BOOH-induced contractions in segments with or without endothelium, respectively. In addition, expression of cyclooxygenase-2 protein was detected in aorta from WKY and SHR in either basal condition or after stimulation with t-BOOH. These results suggest that (1) t-BOOH-induced vasoconstriction in the aorta from WKY and SHR is essentially mediated by cyclooxygenase-2 metabolites, different from thromboxane-A(2), probably prostaglandin-H(2), and/or isoprostanes; (2) aging scarcely modifies, whereas endothelium negatively modulates, these contractions in both strains; and (3) nitric oxide and prostacyclin exert a negative modulator role on the t-BOOH-induced vasoconstriction in WKY, with this modulator role lost in SHR.
authors.affiliation: Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: E C
authors.initials: EC
authors.lastname: Garcia-Cohen
authors.forename: J
authors.initials: J
authors.lastname: Marin
authors.forename: L D
authors.initials: LD
authors.lastname: Diez-Picazo
authors.forename: A B
authors.initials: AB
authors.lastname: Baena
authors.forename: M
authors.initials: M
authors.lastname: Salaices
authors.forename: M A
authors.initials: MA
authors.lastname: Rodriguez-Martinez
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D020122:tert-Butylhydroperoxide / Q000633:toxicity*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020122:tert-Butylhydroperoxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin