title: Reduced endothelial NO-cGMP vascular relaxation pathway during TNF-alpha-induced hypertension in pregnant rats.
abstract: 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 x kg(-1) x day(-1) for 5 days) to increase plasma level twofold. Phenylephrine (Phe) increased active stress to a maximum of 4.2 +/- 0.4 x 10(3) and 9.9 +/- 0.7 x 10(3) 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 microM N(G)-nitro-L-arginine methyl ester, to inhibit nitric oxide (NO) synthase, or 1 microM 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.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Davis
authors.forename: Jena B
authors.initials: JB
authors.lastname: Giardina
authors.forename: Gachavis M
authors.initials: GM
authors.lastname: Green
authors.forename: Barbara T
authors.initials: BT
authors.lastname: Alexander
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
authors.forename: Raouf A
authors.initials: RA
authors.lastname: Khalil
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D006152:Cyclic GMP; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester