Vascular effects of the 21-aminosteroid tirilazad mesylate: protection against oxidant stress.

The vascular effects of tirilazad mesylate (U-74006F), a 21-aminosteroid antioxidant under development for the treatment of acute CNS trauma and ischemia, have been investigated using isolated rings of rabbit aorta. Endothelium-dependent relaxation was measured in rings contracted with 0.25 μM phenylephrine. Acetylcholine produced a dose-dependent relaxation that was slightly attenuated by the addition of U-74006F (0.1-10.0 μM). At a concentration of 10.0 μM, U-74006F shifted the EC 50 for acetylcholine relaxation from 60 ± 10 to 150 ± 20 nMand reduced the maximum response by 20%. U-74006F (0.1-10.0 μM), didnotreduce relaxation to the endothelium-independent vasodilator nitroglycerin nor did it affect the tone of either resting or phenylephrine contracted rings. ACh relaxation was abolished by a 40 min treatment with the superoxide generating system xanthine oxidase (XO ; 0.1 U/ml) plus xanthine (0.4 mM), Relaxation to nitroglycerin was not impaired by XO, nor were the phenylephrine-induced contractions. U-74006F at doses of 0.05-10 μM, protected against XO mediated damage to endothelium-dependent relaxation. These results demonstrate that tirilazad mesylate can protect endothelial function from damage by reactive oxygen species. Preservation of endothelial function might represent an important component of the activity of tirilazad mesylate in vivo.