PPARα activation attenuated AT1‐ but enhanced AT2‐mediated hemodynamic effects to Angiotensin II in the rat

PPARs are ligand‐dependent nuclear transcription factors that regulate β oxidation of fatty acids in various tissues. PPARα ligands are also known to protect against pathological damage especially resulting from angiotensin II (AII) hypertension. However, the role of PPARα in regulation of hemodynamics under physiological conditions is not fully known. In this study, we evaluated the modulation by PPARα of the renal and systemic hemodynamic effects of AII. Clofibrate (250 mg/kg), fenofibrate (100 mg/kg), or WY14643 (45 mg/kg), PPARα ligands, each elicited a 3–4‐fold increase in renal peroxisomal β‐oxidation that was accompanied by increased renal NO production – 92±7, 73±5, or 59±6%, respectively. Clofibrate blunted AII (3–100 ng/kg)‐induced increase in mean arterial blood pressure (MABP; 46±6%, p<0.05) and the reduction in renal cortical blood flow (CBF, laser Doppler flowmetry, 29±4%, p<0.05). L‐NAME but not D‐NAME (100 mg/L) attenuated clofibrate‐induced inhibition of AII responses. In the presence of losartan (5 mg/kg), clofibrate uncovered a hypotensive effect of AII and further blunted the residual renal vasoconstriction. L‐NAME but not D‐NAME blunted the effects of losartan and blocked the hypotensive effects of AII in losartan‐treated rats. Except for WY14643, AT 1 ‐receptor expression was down regulated (44±6%) while AT 2 receptor expression was upregulated (6‐fold, p<0.05) in whole kidney homogenates from rats treated with PPARα ligands. These data suggest that PPARα activation counters AT 1 ‐mediated pressor and vasoconstrictor effects and that during AT 1 receptor blockade, PPARα activation leads to hypotension that is coupled to AT 2 receptor activation by a mechanism probably involving NO production.