PPARα agonist protects against salt‐mediated increases in endogenous carbon monoxide production and blood pressure in Dahl salt‐sensitive rats

Abstract

Heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme-derived CO inhibits nitric oxide synthase and promotes hypertension in Dahl salt-sensitive rats (DS). Peroxisome proliferator-activated receptor α (PPARα) agonists confer cardiovascular protection during hypertension and lower blood pressure in DS. The current study tests the hypothesis that the PPARα agonist fenofibrate prevents the high salt (HS)-diet induced increase in endogenous CO production and blood pressure in DS. Male DS were placed on low (0.3% NaCl, LS) or HS (8% NaCl) diets and some received 90mg/kg/day fenofibrate in the drinking water. Respiratory CO excretion and blood pressure were measured weekly via solid-phase gas chromatography and tail-cuff plethysmography. CO excretion (HS: Δ +0.57±0.07 μmol/hr per kg) and systolic blood pressure (HS: 132±4 to 251±5 mmHg) increased markedly in HS rats. Fenofibrate treatment attenuated the HS diet induced increase in CO excretion (Δ+0.07±0.01 μmol/hr per kg) and blood pressure (145±4 to 172±8 mmHg). These data show that a PPARα agonist protects from HS diet-induced increases in CO production and blood pressure in DS. These results suggest that PPARα agonists might exert their blood pressure lowering effect by “normalizing” endogenous CO production in DS. Supported by NIH/NCRR grant P20 RR017659 (FKJ), NIH/NHLBI RO1 grants HL76187 (RAJ), HL59976 (WD) and HL74966 (WD).