Tumor necrosis factor-alpha-induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression.
BACKGROUND
Preeclampsia is associated with increases in plasma levels of tumor necrosis factor-alpha (TNF-alpha), a cytokine known to contribute to endothelial dysfunction. We recently reported that a twofold elevation in plasma TNF-alpha produces significant reductions in renal function and hypertension in pregnant rats. The purpose of this study was to determine the role of the nitric oxide (NO) system in TNF-alpha-induced hypertension in pregnant rats.


METHODS
Tumor necrosis factor-alpha (50 ng/day) was chronically infused starting at day 14 of gestation. Mean arterial pressure, 24-h urinary nitrite/nitrate excretion, and renal nitric oxide synthase (NOS) protein expression by Western blot analysis was measured at day 19 of gestation.


RESULTS
A twofold increase in plasma TNF-alpha levels in pregnant rats resulted in a significant increase in arterial pressure (97 +/- 3.6 v 116 +/- 2.1 mm Hg, pregnant versus TNF-alpha pregnant, respectively, P < .05), but no significant change in urinary nitrite/nitrate excretion (22.0 +/- 1.9 v 20.8 +/- 2.5 micromol/24 h, pregnant versus TNF-alpha pregnant, respectively), a measure of whole body NO production. As abnormalities in renal production of NO would not be reflected in the measure of whole body NO production, changes in renal NOS protein levels were determined. The protein expression of both neuronal (nNOS) and inducible (iNOS) nitric oxide synthase were significantly decreased in the medulla of TNF-alpha pregnant rats (nNOS: 10.6 +/- 0.7 v 8.2 +/- 0.8 densitometric units, P < .05; and iNOS: 19.2 +/- 0.9 v 15.4 +/- 0.8 densitometric units, P < .05, pregnant versus TNF-alpha pregnant, respectively).


CONCLUSIONS
The hypertension associated with a chronic twofold increase in TNF-alpha in pregnant rats is associated with significant decreases in renal nNOS and iNOS protein production.
Alexander
Barbara T
BT
Department of Physiology, Center for Excellence in Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Cockrell
Kathy L
KL
Massey
Matthew B
MB
Bennett
William A
WA
Granger
Joey P
JP
D000818:Animals; D001794:Blood Pressure; D005260:Female; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D007668:Kidney / Q000294:innervation*; D009474:Neurons / Q000201:enzymology*; D009566:Nitrates / Q000652:urine; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000652:urine; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat