211: Effects of Rho-kinase pathway inhibition by fasudil on growth and metabolic parameters in a rat model of intrauterine growth retardation

fasudil on growth and metabolic parameters in a rat model of intrauterine growth retardation Laura Butruille, Jean Lesage, Sylvain Mayeur, Laurent Storme, Philippe Deruelle EA 4489, Perinatal Environment and Growth, Research, Lille, France, EA 4489, Universite de Lille 1, Research, Villeneuve d’Ascq, France, EA 4489, Universite de Lille 2, Neonatalogy, Lille, France, EA 4489, Universite de Lille 2, Obstetrics, Lille, France OBJECTIVE: In humans, epidemiology studies have found an inverse relationship between birth weight and adult diseases. The fetal programming hypothesis suggests that low birth weight is associated with increased risk of coronary heart disease, stroke, high blood pressure, insulin resistance, type 2-diabetes or obesity. Fasudil inhibits Rhokinase pathway, which induces vasodilatation and may prevent diabetes and obesity complications. Antenatal maternal treatment by Fasudil improved fetal growth in a rat model of intrauterine growth retardation -IUGR(Le Roch A. et al Am J Obstet Gynecol Dec 2009). In the present study, we investigated whether administration of Fasudil during pregnancy could alter long-term outcome in a rat model of IUGR induced by NO synthase inhibition. STUDY DESIGN: Osmotic mini pumps were implanted in pregnant rats on day 17th of pregnancy, and diffused saline, L-NAME (50 mg/day), Fasudil (10 mg/day) or L-NAME Fasudil. Growth, feeding behavior, glucose tolerance were evaluated at 3 and 9 months postnatally. RESULTS: L-NAME exposure reduced fetal growth (6.160.26 g for control vs. 5.110.16 g L-NAME on P2). Offspring of L-NAME mother had reduced kidney weight (4779 vs 4469 mg/100g body weight) and increased epididymal white adipose tissue compared to control (2748 117 vs 3267150 mg/100g body weight). Furthermore, Fasudil treatment attenuated IUGR-induced LNAME effects (5.110.16 g for LNAME vs. 5.750.10 g for L-NAME Fasudil) but was consistently associated with overweight, hyperphagia and partial glucose intolerance. CONCLUSION: We found that Fasudil improves fetal growth but induces adverse effects on long-term outcome. Our results indicate that Rho-kinase inhibition may alter appetite regulation, lipid and glucose metabolism, suggesting a role of this pathway in energy balance.