L-Arginine supplementation abolishes the blood pressure and endothelin response to chronic increases in plasma sFlt-1 in pregnant rats

Murphy SR, LaMarca B, Cockrell K, Arany M, Granger JP. L-Arginine supplementation abolishes the blood pressure and endothelin response to chronic increases in plasma sFlt-1 in pregnant rats. Am J Physiol Regul Integr Comp Physiol 302: R259-R263, 2012. First published November 9, 2011; doi:10.1152/ajpregu.00319.2011.-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 mu g.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 similar to 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 similar to 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.