Tumor necrosis factor-α 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 following tumor necrosis factor-α (TNF-α). In iNOS +/+ mice, contraction of carotid arteries in response to prostaglandin F2α(PGF2α) was impaired following TNF-α (100 μg/kg ip)( n = 10, P < 0.01). In contrast to responses in wild-type mice, contraction to low concentrations of PGF2αwere normal, but maximum contraction to PGF2αwas impaired in arteries from iNOS −/− mice treated with TNF-α [0.35 ± .0.02 g ( n = 8) following vehicle and 0.25 ± 0.02 g ( n = 7) following TNF-α ( P < 0.05)]. Aminoguanidine, a relatively selective inhibitor of iNOS, partially restored contraction to PGF2αin vessels from iNOS +/+ mice but had no effect in iNOS −/− mice injected with TNF-α, suggesting that a mechanism(s) other than iNOS contributes to impaired responses. In contrast to contractile responses, relaxation of the carotid artery in response to acetylcholine and nitroprusside was not altered following TNF-α in iNOS +/+ or iNOS −/−mice. Responses of carotid arteries from iNOS −/− mice and effects of aminoguanidine suggest that both iNOS-dependent and iNOS-independent mechanisms contribute to impaired contractile responses following TNF-α.