Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that regulate β-oxidation of fatty acids in various tissues. PPARα ligands also protect against pathological damage especially resulting from angiotensin II hypertension. The modulating effect of PPARα on hemodynamic effects elicited by angiotensin II under normal conditions, however, is not fully known.Method
We therefore evaluated renal and systemic hemodynamic effects of angiotensin II in normal animals treated with PPARα ligands.Results
PPARα ligands clofibrate (250 mg/kg), fenofibrate (100 mg/kg), or pirixinic acid (WY14643; 45 mg/kg) each elicited an increase in renal peroxisomal β-oxidation, accompanied by increased renal nitric oxide production. Clofibrate blunted the angiotensin II (3–100 ng/kg)-induced increase in mean arterial blood pressure (P < 0.05) but attenuated the reduction in renal cortical blood flow (laser Doppler flowmetry; P < 0.05). Nω-nitro-L-arginine methyl ester (L-NAME) but not D-NAME (100 mg/l) blunted clofibrate-induced inhibition of angiotensin II responses. In the presence of the angiotensin type 1 (AT1)-antagonist losartan (3 mg/kg), clofibrate uncovered a hypotensive effect of angiotensin II and further blunted the residual renal vasoconstriction. L-NAME or the angiotensin type 2 (AT2)-antagonist (S-[+]-1-[(4-dimethylamino]-3-methylphenyl)methyl]-5-[diphenylacetyl]-4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxilic acid; PD123319), but not D-NAME, blunted the effects of losartan and blocked the hypotensive effects of angiotensin II in losartan-treated rats. Except in rats treated for 7 days with WY14643, AT1-receptor expression was downregulated (P < 0.05) while AT2-receptor expression was upregulated (P < 0.05) in renal cortical homogenates from rats treated with clofibrate or WY14643.Conclusion
These data suggest that PPARα activation counters AT1-mediated pressor and vasoconstrictor effects and that, during AT1 receptor blockade, PPARα activation leads to hypotension coupled to AT2-receptor activation by a mechanism probably involving nitric oxide production.