Prostaglandins Contribute to Impaired Angiotensin II–Induced Cerebral Vasodilation after Brain Injury

Abstract

This study characterized the effects of fluid percussion brain injury (FPI) on angiotensin II (AII)–induced cerebral vasodilation, determined the role of prostaglandins in such changes and evaluated the contribution of two subtypes of AII receptors (AT₁ and AT₂) to the effects of AII on cerebrovascular regulation. Topical AII (10^-8, 10^-6, 10^-4 M) elicited vasodilation, which was attenuated by FPI (10 ± 1; 18 ± 2; 27 ± 1% vs. 2 ± 1; 4 ± 1; 7 ± 1%). Such changes in diameter were associated with increases in CSF 6-keto-PGF_1α, the stable breakdown product of PGI₂ (1.5 ± 0.1; 2.1 ± 0.1; 4.0 ± 0.3 fold) and TXB₂, the stable breakdown product of TXA₂ (1.2 ± 0.1; 1.4 ± 0.1; 1.6 ± 0.1 fold). However, after FPI, increases in 6-keto PGF_1α were blocked (1.0 ± 0.1; 1.0 ± 0.1; 1.1 ± 0.1 fold) whereas TXB₂ release was enhanced (1.5 ± 0.1; 1.8 ± 0.1; 1.9 ± 0.1 fold). Pretreatment with the cyclooxygenase inhibitor indomethacin (5 mg/kg i.v.) in FPI animals partially protected AII vasodilation(8 ± 1; 14 ± 2; 19 ± 3%). CGP 42112A, a putative AT₂ agonist, elicited vasodilation, which was also blunted by FPI. Such dilation was not associated with CSF prostaglandin changes, and indomethacin did not protect responses altered by FPI. Vasodilatation caused by low concentrations of AII was blunted by an AT₁ antagonist ZD 7155 but unchanged by an AT₂ antagonist PD 123,319. The high AII concentration produced dilation that was blunted by both antagonists. These data show that FPI impairs AII-mediated vasodilation. These data suggest that FPI causes these changes via alteration in an AT₁-mediated production of prostaglandins. These data additionally suggest that FPI induced impairment of AT₂ mediated vasodilation is independent of an altered production of prostaglandins.