Induction of P4504A Activity Improves Pressure-Natriuresis in Dahl S Rats

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Abstract
Clofibrate has been reported to prevent the development of hypertension in Dahl S rats, but its mechanism of action remains to be determined. The present study examined the effects of clofibrate on renal P4504A activity and the pressure natriuresis relationship in Dahl S rats. Dahl S and R rats fed a low-salt diet (0.4% NaCl) were given either clofibrate (240 mg/kg/d) or vehicle (20 mmol/L Na 2 CO 3 ) in their drinking water for 1 week and then switched to a high salt diet (8% NaCl) while continuing drug treatment. After 3 weeks, mean arterial pressure in ketamine-Inactin anesthetized rats averaged 121±2 (n=8) in Dahl R, 173±8 (n=6) in Dahl S, and 139±4 mm Hg (n=7) in clofibrate-treated Dahl S rats. Increasing renal perfusion pressure (RPP) from 100 to 150 mm Hg in Dahl R rats increased sodium excretion (U Na V) from 2.9±0.7 to 9.7±3.2 μmol/min/g kwt. In contrast, the pressure natriuresis relation was blunted in Dahl S rats and U Na V only increased from 2.7±0.9 to 6.1±1.3 μmol/min/g kwt. The pressure natriuresis relation was improved in clofibrate-treated Dahl S rats and U Na V increased from 5.1±1.3 to 16.7±2.6 μmol/min/g kwt. At similar levels of RPP, the fractional excretion of sodium tended to be higher in clofibrate-treated than in vehicle-treated Dahl S rats, but not significantly. Glomerular filtration rate (GFR) was 40% higher in clofibrate-compared to vehicle-treated Dahl S rats (0.9±0.2 versus 0.6±0.2 mL/min/g kwt), and was not significantly different from the values seen in Dahl R rats (0.9±0.1 mL/min/g kwt). Clofibrate induced the expression of P4504A protein in the renal cortex and outer medulla of Dahl S rats. These data suggest that induction of renal P4504A activity with clofibrate improves the pressure natriuresis relation in Dahl S rats by primarily increasing GFR.