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.
Mamnoor
Prem K
PK
Discovery Biology, Dr. Reddy's Laboratories Ltd.-Discovery Research, 7-1-27 Ameerpet, Hyderabad 500016, India.
Hegde
Pragathi
P
Datla
Srinivas R
SR
Damarla
Ravi K B
RK
Rajagopalan
Ramanujam
R
Chakrabarti
Ranjan
R
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007333:Insulin Resistance; D008297:Male; D010078:Oxazines / Q000494:pharmacology* / Q000627:therapeutic use; D047493:PPAR alpha / Q000378:metabolism* / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism* / Q000502:physiology; D010666:Phenylpropionates / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D011924:Rats, Zucker; D012015:Reference Standards; D014280:Triglycerides / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D010078:Oxazines; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D014280:Triglycerides; D014665:Vasodilator Agents; D000109:Acetylcholine; C432703:ragaglitazar