Abstract 198: Oral Administration of the Mas Agonist A-1317 Produces Beneficial Cardiometabolic Effects in Rats

Abstract

The beneficial effects of the Mas/Ang-(1-7) pathway prompted us to develop novel Ang-(1-7) analogues and ligands for Mas. In the present study, we evaluated the cardiometabolic effects of a pharmacological formulation developed by including the Mas agonist A-1317 in hydroxypropyl β-cyclodextrin (HPβCD). The inclusion compound was given orally (10 μg/Kg body weight) to Spontaneously hypertensive rat (SHR) and fructose-fed rats. Mean arterial pressure (MAP) and heart rate (HR) were monitored for 5 hours after administration of a single dose of A-1317-HPβCD in conscious SHR. Seven-weeks-old male Sprague-Dawley rats were fed with either normal rat chow (CTL) or the same diet plus 10% fructose in the drinking water (FFR). For the last 4 wk of a 9-wk period of each diet, a subgroup of each group of animals was treated daily with the oral A-1317 (CTL-A or FFR-A) or with vehicle (CTL-V or FFR-V). Rats were subjected to oral glucose tolerance test (2 g/Kg body weight) concomitantly with the evaluation of plasma insulin levels. A-1317 reduced MAP with the maximum change occurring after 4 hours of administration (Δ=-23±2mmHg). There was no significant effect of A-1317 on HR of SHR. Once a day administration of A-1317 ameliorated all metabolic conditions altered by fructose-feed, including the glucose tolerance with less release of insulin and the decreased in the basal insulinemia. However no change in glycemia was observed. Regarding the lipidic metabolism, there was a decrease in the hepatic and serum tryacilglicerol levels (CTL-V=51±3; CTL-A=44±4; FFR-V=74±6; FFR-A=45±5 mg/dl serum levels), the body weight gain and the epididymal and mesenteric adipose tissue mass. Moreover hepatic and serum cholesterol levels were surprisingly diminished in both treated groups. These data suggest that A-1317 inclusion compound is an innovative therapeutic tool for treatment the cardiovascular and metabolic diseases.