Antihypertensive effect of ragaglitazar: a novel PPARalpha and gamma dual activator.

Ragaglitazar is a novel and potent dual peroxisome proliferators activated receptor (PPAR) alpha and gamma activator. The aim of this study is to investigate the effect of ragaglitazar on blood pressure and endothelial function in insulin resistant animal model and non-insulin resistant hypertensive models. The effects ragaglitazar were tested in Zucker fa/fa, spontaneously hypertensive rats (SHR), 2 kidney 1clip rat (2K1C) and Wistar Kyoto rats (WKY). Pioglitazone was taken as a comparative standard. Ragaglitazar showed significant reduction (P<0.001) of systolic blood pressure (SBP) in insulin resistant fa/fa rats, with concomitant reduction in plasma triglycerides (TG) and insulin levels while pioglitazone (10 mg kg(-1)) showed significant (P<0.05) but comparatively less reduction. Ragaglitazar in contrast to pioglitazone showed significant reduction (P<0.05) of SBP in SHR, 2K1C while the same dose did not have any effect on normotensive WKY. Ragaglitazar also showed significant improvement in acetylcholine-induced relaxation in isolated aorta of Zucker fa/fa, SHR, 2K1C and also potentiated the insulin-induced vasorelaxation in Zucker fa/fa rats. These findings summarize that ragaglitazar shows significant reduction of BP and improvement in endothelial function not only in insulin resistant but also in non-insulin resistant hypertensive models where standard thiazolidinediones are ineffective. These data indicates that dual PPARalpha and gamma activator ragaglitazar can be beneficial for the treatment of hypertension and vascular disease commonly associated with type 2 diabetes.

Antidiabetic and hypolipidemic potential of DRF 2519--a dual activator of PPAR-alpha and PPAR-gamma.

We investigated the biological activity of Dr. Reddy's Research Foundation (DRF) 2519, a benzoxazinone analogue of the thiazolidinedione class of compounds. In the in vitro transactivation assay, DRF 2519 showed interesting dual activation of Peroxisome Proliferator Activated Receptor (PPAR) alpha and gamma. In insulin-resistant ob/ob mouse model, DRF 2519 showed significant alleviation of insulin resistance and dyslipidemia, which is better than rosiglitazone. Fatty Zucker rats treated with DRF 2519 showed better reduction of plasma insulin, triglyceride and free fatty acid levels than those treated with rosiglitazone. In addition, these rats were able to clear plasma lipids better when challenged with exogenous lipid (i.v.). DRF 2519 treatment resulted in improved plasma lipid profiles in high-fat-fed Sprague-Dawley rats. Treated rats showed better plasma lipid clearance and hepatic triglyceride secretion. When compared to DRF 2519, fenofibrate was comparatively less efficacious while rosigltiazone showed no activity in these models. In ex vivo studies, DRF 2519 showed induction of liver acyl CoA oxidase mRNA and increase in lipoprotein lipase (LPL) protein expression and activity in adipose tissue. In the in vitro studies, DRF 2519 inhibited the lipid biosynthesis and secretion of apolipoprotein B from human hepatoma (Hep)G2 cells. It also enhanced insulin-induced relaxation of rat aortic smooth muscle. These results indicate that DRF 2519, a dual activator of PPAR-alpha and gamma, could be an interesting development candidate in the management of metabolic disorders and associated complications.