Effects of sodium nitrite and its association with sildenafil in experimental models of preeclampsia

• Grant number: 14/14336-3
• Support Opportunities: Scholarships abroad - Research
• Effective date (Start): July 01, 2015
• Effective date (End): June 30, 2016
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Alan Candido Dias Junior
• Grantee: Carlos Alan Candido Dias Junior
• Host Investigator: Raouf Khalil
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Research place: Harvard University, Boston, United States

Abstract

Preeclampsia affects 5-8% of pregnancies and is characterized by increased blood pressure and proteinuria from 20 weeks of gestation. These changes appear to be initially related to placental ischemia, causing insufficient uteroplacental oxygenation followed by increased release of anti-angiogenic factors such as sFlt-1 (soluble fms-like tyrosine kinase-1, which is a soluble VEGF receptor) along with the reduction of angiogenic factors such as VEGF (vascular endothelial growth factor-). Experimentally, some models assume the major pathophysiological changes in pregnant rats. This project is proposed to use the model of preeclampsia induced by (1) RUPP (of reduced uteroplacental perfusion pressure), as well as (2) controlled infusion of anti-angiogenic factor, sFlt-1, via "mini-osmotic pump "; both animal models exhibiting the main clinical condition of pre-eclampsia: increased blood pressure accompanied by proteinuria. In these two models increases oxidative stress and impaired bioavailability of nitric oxide (NO) have been observed. Recent studies have shown that reducing the bioavailability of NO aggravate endothelial dysfunction during the course of pre-eclampsia and some time, new pharmacological strategies have shown promise in re-establish the physiological levels of NO. In this context, it was demonstrated that oral administration of sodium nitrite (NaNO2) increases NO bioavailability by promoting vasodilatation via formation of the second messenger cGMP (cyclic guanosine monophosphate). However, the actions of intracellular cGMP are terminated by phosphodiesterase type 5 (PDE5) that can be inhibited by sildenafil. Therefore, we will investigate (1) the hemodynamic effects of sodium nitrite (NaNO2) or (2) of sildenafil, as well as (3) sildenafil potentiate the effects of sodium nitrite in both experimental models of preeclampsia. The concentrations of nitrite, proteinuria of angiogenic factors (VEGF and PLGF, placental growth factor), anti-angiogenic factor (sFlt-1), the second messenger of vasodilation (cGMP), biomarkers of oxidative stress (8-isoprostane) and of tissue hypoxia (hypoxia-inducible factor-1±, HIF-1±) will be determined, aiming biochemically evaluations of hemodynamic effects observed. (AU)