Oxidative stress induced by tert-butyl hydroperoxide causes vasoconstriction in the aorta from hypertensive and aged rats: Role of cyclooxygenase-2 isoform

We analyzed the mechanisms involved in the effect of tert-butyl hydroperoxi de (t-BOOH) in isolated aortic rings with and without endothelium from norm otensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at 6, 18, and 24 months of age. t-BOOH (1 mu M-10 mM) induced concentration -dependent contractions that were scarcely modified by aging and potentiate d in SHR and by endothelium removal. The nitric oxide synthase and prostacy clin synthase inhibitors N-G-nitro-L-arginine methyl ester (100 mu M) and t ranylcypromine (100 mu M), 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 mu M), a nonspecific cyclooxygenase inhibitor, and SQ 29,548 (10 mu M), a prostaglandin H-2/thromboxane A(2) re ceptor 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 mu M). The cy clooxygenase-2 inhibitor NS-398 (10 mu M) abolished or markedly reduced the t-BOOH-induced contractions in segments with or without endothelium, respe ctively. In addition, expression of cyclooxygenase-2 protein was detected i n aorta from WKY and SHR in either basal condition or after stimulation wit h t-BOOH. These results suggest that (1) t-BOOH-induced vasoconstriction in the aorta from WKY and SHR is essentially mediated by cyclooxygenase-2 met abolites, different from thromboxane-A(2), probably prostaglandin-H-2, and/ or isoprostanes; (2) aging scarcely modifies, whereas endothelium negativel y modulates, these contractions in both strains; and (3) nitric oxide and p rostacyclin exert a negative modulator role on the t-BOOH-induced vasoconst riction in WKY, with this modulator role lost in SHR.