Abstract
We analyzed the mechanisms involved in the effect oftert-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 μM-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 inhibitorsNG-nitro-l-arginine methyl ester (100 μM) and tranylcypromine (100 μM), 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 μM), a nonspecific cyclooxygenase inhibitor, and SQ 29,548 (10 μM), a prostaglandin H2/thromboxane A2receptor 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 μM). The cyclooxygenase-2 inhibitor NS-398 (10 μM) abolished or markedly reduced thet-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-A2, probably prostaglandin-H2, 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 thet-BOOH-induced vasoconstriction in WKY, with this modulator role lost in SHR.
Footnotes
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Send reprint requests to: Dr. Jesús Marı́n, Departamento de Farmacologı́a, Facultad de Medicina, U.A.M., C/Arzobispo Morcillo 4, 28029 Madrid, Spain. E-mail:jesus.marin{at}uam.es
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↵1 This work was supported by grants from Fondo de Investigaciones Sanitarias (98/0074-02), Dirección General de Investigación Científica y Técnica (PM97-0008), Comunidad de Madrid (08.3/0003/1998), and Bayer España.
- Abbreviations:
- WKY
- Wistar-Kyoto rats
- SHR
- spontaneously hypertensive rats
- MAP
- mean arterial pressure
- KHS
- Krebs-Henseleit solution
- COX
- cyclooxygenase
- H2O2
- hydrogen peroxide
- l-NAME
- NG-nitro-l-arginine methyl ester
- NO
- nitric oxide
- PG
- prostaglandin
- t-BOOH
- tert-butyl hydroperoxide
- TX
- thromboxane
- Received July 23, 1999.
- Accepted January 4, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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