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Am J Physiol Regul Integr Comp Physiol 282: R390-R399, 2002; doi:10.1152/ajpregu.00270.2001
0363-6119/02 $5.00
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Vol. 282, Issue 2, R390-R399, February 2002

Reduced endothelial NO-cGMP vascular relaxation pathway during TNF-alpha -induced hypertension in pregnant rats

Justin R. Davis, Jena B. Giardina, Gachavis M. Green, Barbara T. Alexander, Joey P. Granger, and Raouf A. Khalil

Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505

Placental ischemia during pregnancy is thought to release cytokines such as tumor necrosis factor-alpha (TNF-alpha ), which may contribute to the increased vascular resistance associated with pregnancy-induced hypertension. We have reported that a chronic twofold elevation in plasma TNF-alpha increases blood pressure in pregnant but not in virgin rats; however, the vascular mechanisms are unclear. We tested the hypothesis that increasing plasma TNF-alpha during pregnancy impairs endothelium-dependent vascular relaxation and enhances vascular reactivity. Active stress was measured in aortic strips of virgin and late-pregnant Sprague-Dawley rats untreated or infused with TNF-alpha (200 ng · kg-1 · day-1 for 5 days) to increase plasma level twofold. Phenylephrine (Phe) increased active stress to a maximum of 4.2 ± 0.4 × 103 and 9.9 ± 0.7 × 103 N/m2 in control pregnant and TNF-alpha -infused pregnant rats, respectively. Removal of the endothelium enhanced Phe-induced stress in control but not in TNF-alpha -infused pregnant rats. In endothelium-intact strips, ACh caused greater relaxation of Phe contraction in control than in TNF-alpha -infused pregnant rats. Basal and ACh-induced nitrite/nitrate production was less in TNF-alpha -infused than in control pregnant rats. Pretreatment of vascular strips with 100 µM NG-nitro-L-arginine methyl ester, to inhibit nitric oxide (NO) synthase, or 1 µM 1H-[1,2,4]oxadiazolo[4,3-]quinoxalin-1-one, to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in control but not in TNF-alpha -infused pregnant rats. Phe contraction and ACh relaxation were not significantly different between control and TNF-alpha -infused virgin rats. Thus an endothelium-dependent NO-cGMP-mediated vascular relaxation pathway is inhibited in late-pregnant rats infused with TNF-alpha . The results support a role for TNF-alpha as one possible mediator of the increased vascular resistance associated with pregnancy-induced hypertension.

nitric oxide; cytokines; pregnancy


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