TNF-alpha enhances contraction and inhibits endothelial NO-cGMP relaxation in systemic vessels of pregnant rats.
Tumor necrosis factor-alpha (TNF-alpha) is elevated in the plasma of preeclamptic women and may have a role in pregnancy-induced hypertension. However, whether the hemodynamic effects of TNF-alpha reflect the direct effects on vascular reactivity is unclear. We tested the hypothesis that TNF-alpha impairs 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-alpha). In endothelium-intact vascular strips, TNF-alpha caused greater enhancement of phenylephrine (Phe) contraction in pregnant than virgin rats. TNF-alpha caused significant inhibition of ACh- and bradykinin-induced vascular relaxation and nitrite/nitrate production that were more prominent in pregnant than virgin rats. N(G)-nitro-L-arginine methyl ester [L-NAME, 100 microM, an inhibitor of nitric oxide (NO) synthase] or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 1 microM, an inhibitor of cGMP production in smooth muscle) inhibited ACh relaxation and enhanced Phe contraction in nontreated but to a lesser extent in TNF-alpha-treated vessels, particularly those of pregnant rats. Endothelium removal enhanced Phe contraction in nontreated but not TNF-alpha-treated vessels, especially those of pregnant rats. Relaxation of Phe contraction with the NO donor sodium nitroprusside was not different between nontreated and TNF-alpha-treated vessels. Thus TNF-alpha enhances 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 TNF-alpha as a possible mediator of increased vascular resistance associated with pregnancy-induced hypertension.
Giardina
Jena B
JB
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
Green
Gachavis M
GM
Cockrell
Kathy L
KL
Granger
Joey P
JP
Khalil
Raouf A
RA
D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000502:physiology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D006152:Cyclic GMP