TNF- enhances contraction and inhibits endothelial NO-cGMP relaxation in systemic vessels of pregnant rats

Giardina, Jena B., Gachavis M. Green, Kathy L. Cockrell, Joey P. Granger, and Raouf A. Khalil. TNFenhances contraction and inhibits endothelial NO-cGMP relaxation in systemic vessels of pregnant rats. Am J Physiol Regulatory Integrative Comp Physiol 283: R130–R143, 2002. First published February 28, 2002; 10.1152/ajpregu.00704. 2001.—Tumor necrosis factor(TNF) is elevated in the plasma of preeclamptic women and may have a role in pregnancy-induced hypertension. However, whether the hemodynamic effects of TNFreflect the direct effects on vascular reactivity is unclear. We tested the hypothesis that TNFimpairs endothelium-dependent relaxation and enhances vascular contraction in systemic vessels of pregnant rats. We measured isometric contraction in aortic strips isolated from virgin and pregnant Sprague-Dawley rats (nontreated vs. treated for 2 h with 10–1,000 pg/ml TNF). In endotheliumintact vascular strips, TNFcaused greater enhancement of phenylephrine (Phe) contraction in pregnant than virgin rats. TNFcaused significant inhibition of AChand bradykinin-induced vascular relaxation and nitrite/nitrate production that were more prominent in pregnant than virgin rats. NG-nitro-L-arginine methyl ester [L-NAME, 100 M, an inhibitor of nitric oxide (NO) synthase] or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 1 M, an inhibitor of cGMP production in smooth muscle) inhibited ACh relaxation and enhanced Phe contraction in nontreated but to a lesser extent in TNF-treated vessels, particularly those of pregnant rats. Endothelium removal enhanced Phe contraction in nontreated but not TNF-treated vessels, especially those of pregnant rats. Relaxation of Phe contraction with the NO donor sodium nitroprusside was not different between nontreated and TNF-treated vessels. Thus TNFenhances vascular contraction and inhibits endothelium-dependent NO-cGMP-mediated vascular relaxation in systemic vessels, particularly those of pregnant rats. The results support a direct role for TNFas a possible mediator of increased vascular resistance associated with pregnancy-induced hypertension.