Impact of esomeprazole on the nitric oxide bioavailability in Gestational Hypertension in rats

• Grant number: 20/03135-8
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): November 01, 2020
• Effective date (End): February 28, 2026
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Carlos Alan Candido Dias Junior
• Grantee: Maria Luiza Santos da Silva
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

During the gestational period, several cardiovascular adaptations must take place to maintain a healthy pregnancy. Preeclampsia (PE) is a disorder that occurs in pregnancy and is characterized by elevated maternal blood pressure (140x90mmHg) accompanied by 24-hour proteinuria after the 20th gestational week. Its pathogenesis is still unclear, however, the placenta seems to play a fundamental role. In PE there is an increase in oxidative stress, an increase in antiangiogenic factors and a decrease in vasodilatory mediators. During pregnancy, many women use medications to relieve symptoms of symptomatic gastric reflux. Among these drugs are Proton Pump Inhibitors (PPIs). Research reveals that PPIs can compromise bioavailability in a pH-dependent manner and also the synthesis of Nitric Oxide (NO) through the inhibition of the activity of the enzyme dimethylarginine dimethylaminohydrolase (ADHD), indispensable for the cardiovascular system. DDAH metabolizes the endogenous ADHD inhibitor, asymmetric dimethylarginine (ADMA), which competes with NO synthase (NOS). Through inhibition, there is a decrease in NO production favoring the risk of cardiovascular diseases, inflammation and mainly leading to health problems during pregnancy. The experimental model of Gestational Hypertension and PE induced by L-nitro-arginine-methyl ester (LNAME) has been shown to be very promising for manifesting many of the responses found in human PE. Our main hypothesis is that the impairment of NO production caused by use of PPI can be an aggravation to gestational health. In addition, we will also evaluate circulating concentrations of antiangiogenic factors, the soluble fms-like tyrosine kinase-1 (sFlt-1), the angiogenic factor PlGF (Placental Growth Factor), DDHA and ADMA in this experimental model. This study seeks to evaluate the impact of the use of PPIs on the bioavailability of NO and on the control of experimentally induced Gestational Hypertension, as well as contributing to the understanding and development of possible future therapies. (AU)