(Hypertension. 1998;31:232.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Induction of P4504A Activity Improves Pressure-Natriuresis in Dahl S Rats
From the Department of Physiology (M.A.-G., B.F., R.J.R.) Medical College of Wisconsin, Milwaukee, Wisc.
Correspondence to Dr. Richard J. Roman, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226-0509. E-mail: rroman{at}post.its.mcw.edu
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 µmol/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 µmol/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 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.
Key Words: cytochrome P450 • eicosanoids • antilipidemic agents • hypertension • pressure-natriuresis • renal hemodynamics • arachidonic acid
Abbreviations: AII = angiotensin II • Dahl R rats = Dahl salt-resistant rats • Dahl S rats = Dahl salt-sensitive rats • FENa = fractional sodium excretion • GFR = glomerular filtration rate • 20-HETE = 20-hydroxyeicosatetraenoic acid • P4504A = cytochrome P450 4A enzymes • PMSF = phenylmethylsulfonyl fluoride • PPAR = peroxisome proliferator action receptor • PTH = parathyroid hormone • RPP = renal perfusion pressure • SDS = sodium dodecyl sulfate • TALH = thick ascending limb of the loop of Henle • TBS = Tris buffered saline • UNaV = sodium excretion
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