Induction of P4504A activity improves pressure-natriuresis in Dahl S rats

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 Na2CO3) 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 (UNaV) from 2.9+/-0.7 to 9.7+/-3.2 mu mol/min/g kwt. In contrast, the pressure natriuresis relation was blunted in Dahl S rats and UNaV only increased from 2.7+/-0.9 to 6.1+/-1.3 mu mol/min/g kwt. The pressure natriuresis relation was improved in clofibrate-treated Dahl S rats and UNaV increased from 5.1+/-1.3 to 16.7+/-2.6 mu mol/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 sim 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.