Tumor necrosis factor-alpha impairs contraction but not relaxation in carotid arteries from iNOS-deficient mice

We used mice deficient in expression of inducible NO synthase (iNOS -/-) to directly examine the role of iNOS in impaired vasoconstrictor responses fo llowing tumor necrosis factor-alpha (TNF-alpha). In iNOS +/+ mice, contract ion of carotid arteries in response to prostaglandin F-2 alpha (PGF(2 alpha )) was impaired following TNF-alpha (100 mg/kg ip)( n = 10, P < 0.01). In c ontrast to responses in wild-type mice, contraction to low concentrations o f PGF(2<alpha>) were normal, but maximum contraction to PGF(2 alpha) was im paired in arteries from iNOS -/- mice treated with TNF-alpha [0.35 +/- .0.0 2 g (n = 8) following vehicle and 0.25 +/- 0.02 g (n = 7) following TNF-alp ha (P < 0.05)]. Aminoguanidine, a relatively selective inhibitor of iNOS, p artially restored contraction to PGF(2<alpha>) in vessels from iNOS +/+ mic e but had no effect in iNOS -/- mice injected with TNF-alpha, suggesting th at a mechanism(s) other than iNOS contributes to impaired responses. In con trast to contractile responses, relaxation of the carotid artery in respons e to acetylcholine and nitroprusside was not altered following TNF-alpha in iNOS +/+ or iNOS -/- mice. Responses of carotid arteries from iNOS -/- mic e and effects of aminoguanidine suggest that both iNOS-dependent and iNOS-i ndependent mechanisms contribute to impaired contractile responses followin g TNF-alpha.