PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

Abstract

Peroxisome proliferator activated receptors (PPARs) are nuclear transcription factors that regulate numerous genes influencing blood pressure. The aim of this study was to examine the effects of clofibrate, a PPARα ligand, on blood pressure in spontaneously hypertensive rats (SHR). Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), 8-9 weeks old, were randomly allocated into groups treated with vehicle or clofibrate (250 mg·kg(-1)·d(-1), ip for 21 d). Systolic blood pressure (SBP) was measured before and after the study period using tail-cuff plethysmography. Rats were sacrificed under anesthesia and blood, urine and tissue samples were processed for subsequent analysis. SHR rats showed significantly higher SBP compared with WKY rats (198±6 mmHg vs 93±7 mmHg), and a 3-fold increase in urinary protein excretion. Clofibrate treatment reduced SBP by 26%±2% and proteinuria by 43%±9% in SHR but not in WKY rats. The urinary nitrite/nitrate excretion in SHR rats was nearly 2-fold greater than that in WKY, and was further increased by 30%±4% and 48%±3%, respectively, following clofibrate treatment. In addition, PPARα protein expression and PPARα activity were significantly lower in SHR than that in WKY rats. Clofibrate treatment significantly increased PPARα protein expression and PPARα activity in SHR rats, but not in WKY rats. Moreover, the vasoconstrictor response of aortic ring was markedly increased in SHRs, which was blunted after clofibrate treatment. PPARα contributes to regulation of blood pressure and vascular reactivity in SHR, and clofibrate-mediated reduction in blood pressure and proteinuria is probably through increased NO production.