title: L-arginine supplementation abolishes the blood pressure and endothelin response to chronic increases in plasma sFlt-1 in pregnant rats.
abstract: While soluble fms-like tyrosine kinase-1 (sFlt-1) and endothelin-1 (ET-1) have been implicated in the pathogenesis of preeclampsia (PE), the mechanisms whereby increased sFlt-1 leads to enhanced ET-1 production and hypertension remain unclear. It is well documented that nitric oxide (NO) production is reduced in PE; however, whether a reduction in NO synthesis plays a role in increasing ET-1 and blood pressure in response to chronic increases in plasma sFlt-1 remains unclear. The purpose of this study was to determine the role of reduced NO synthesis in the increase in blood pressure and ET-1 in response to sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg(-1)·day(-1) for 6 days beginning on day 13 of gestation) treated with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (100 mg/l for 4 days) or supplemented with 2% L-Arg (in drinking water for 6 days beginning on day 15 of gestation). Infusion of sFlt-1 into NP rats significantly elevated mean arterial pressure compared with control NP rats: 116 ± 2 vs. 103 ± 1 mmHg (P < 0.05). NO synthase inhibition had no effect on the blood pressure response in sFlt-1 hypertensive pregnant rats (121 ± 3 vs. 116 ± 2 mmHg), while it significantly increased mean arterial pressure in NP rats (128 ± 4 mmHg, P < 0.05). In addition, NO production was reduced ∼70% in isolated glomeruli from sFlt-1 hypertensive pregnant rats compared with NP rats (P < 0.05). Furthermore, prepro-ET-1 in the renal cortex was increased ∼3.5-fold in sFlt-1 hypertensive pregnant rats compared with NP rats. Supplementation with L-Arg decreased the sFlt-1 hypertension (109 ± 3 mmHg, P < 0.05) but had no effect on the blood pressure response in NP rats (109 ± 3 mmHg) and abolished the enhanced sFlt-1-induced renal cortical prepro-ET expression. In conclusion, a reduction in NO synthesis may play an important role in the enhanced ET-1 production in response to sFlt-1 hypertension in pregnant rats.
authors.affiliation: Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Murphy
authors.forename: Babbette
authors.initials: B
authors.lastname: LaMarca
authors.forename: Kathy
authors.initials: K
authors.lastname: Cockrell
authors.forename: Marietta
authors.initials: M
authors.lastname: Arany
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007668:Kidney / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D019331:NG-Nitroarginine Methyl Ester
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