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PPAR Research
Volume 2009, Article ID 237865, 13 pages
Research Article

Effects of Chronic PPAR-Agonist Treatment on Cardiac Structure and Function, Blood Pressure, and Kidney in Healthy Sprague-Dawley Rats

1Safety Pharmacology, Pfizer, 10777 Science Center Drive CB4/2100, San Diego, CA 92121, USA
2Department of Medicine, Georgetown University, 4000 Reservoir Rd. NW, Washington, DC, 20057, USA

Received 4 December 2008; Revised 25 February 2009; Accepted 23 March 2009

Academic Editor: Francine M. Gregoire

Copyright © 2009 Eileen R. Blasi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


PPAR- agonists have been associated with heart failure (HF) in diabetic patients. These incidences have been reported mostly in patient populations who were at high risk for HF or had pre-existing impaired cardiovascular function. However, whether there are similar effects of these agents in subjects with no or reduced cardiovascular pathophysiology is not clear. In this study, the effects of chronic treatment with PD168, a potent peroxisome proliferator activated receptor (PPAR) subtype- agonist with weak activity at PPAR- , and rosiglitazone (RGZ), a less potent PPAR- agonist with no PPAR- activity, were evaluated on the cardiovascular-renal system in healthy male Sprague-Dawley (SD) rats by serial echocardiography and radiotelemetry. Rats were treated with vehicle (VEH), PD168, @ 10 or 50 mg/kg⋅bw/day (PD-10 or PD-50, resp.) or RGZ @ 180 mg/kg⋅bw/day for 28 days ( /group). Relative to VEH, RGZ, and both doses of PD168 resulted in a significant fall in blood pressure. Furthermore, RGZ and PD168 increased plasma volume (% increase from baseline) 18%, 22%, and 48% for RGZ, PD-10, and PD-50, respectively. PD168 and RGZ significantly increased urinary aldosterone excretion and heart-to-body weight ratio relative to VEH. In addition, PD168 significantly decreased (10–16%) cardiac ejection fraction (EF) and increased left ventricular area (LVA) in systole (s) and diastole (d) in PD-10 and -50 rats. RGZ significantly increased LVAd; however, it did not affect EF relative to VEH. In conclusion, chronic PPAR- therapy may predispose the cardiorenal system to a potential sequela of structural and/or functional changes that may be deleterious with regard to morbidity and mortality.