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(Hypertension. 1998;31:225.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Effects of Lipid-Lowering Agents in the Dahl Salt-Sensitive Rat
From the Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada; and the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wis.
Correspondence to Dr. Thomas W. Wilson, Cardiovascular Risk Factor Reduction Unit, Department of Pharmacology, Health Sciences Building, Room A120, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5. E-mail wilsont{at}duke.usask.ca
Inducing renal cytochrome P4504A (P4504A) activity with clofibrate prevents the development of hypertension in Dahl salt-sensitive (Dahl S) rats. To determine if this also occurs with other antilipidemic agents, we compared the effects of a related drug, fenofibrate, with those of an unrelated agent, pravastatin, on blood pressure, renal histology, and P4504A activity. Dahl S rats were pretreated with fenofibrate (95 mg/kg per day), pravastatin (70 mg/kg per day), or vehicle for 7 days before and after being switched from a low-salt (0.1% NaCl) to a high-salt (8.0% NaCl) diet. After 3 weeks on the high-salt diet, mean arterial pressures averaged 183±13 (n=9), 126±10 (n=9), and 148±11 mm Hg (n=8), respectively, in vehicle-, fenofibrate-, and pravastatin-treated animals. Both drugs reduced the degree of proteinuria and glomerular injury. P4504A protein levels and the synthesis of 20-hydroxyeicosa-5,8,11,14-tetraenoic acid (20-HETE) were increased in the liver and kidney of fenofibrate-treated, but not pravastatin-treated rats. We also administered these agents to Dahl S rats in which hypertension had previously been induced by a high-salt diet. Mean arterial pressures averaged 164±10, 113±23, and 160±15 mm Hg in rats treated with vehicle, fenofibrate, or pravastatin for 3 weeks. Fenofibrate-treated rats exhibited a natriuresis. Proteinuria and glomerular injury were reduced by pravastatin but not by fenofibrate. These results indicate that fenofibrate prevented the development of hypertension and reduced subsequent glomerular injury in Dahl S rats, probably secondary to increased renal production of 20-HETE. Although pravastatin did not induce renal P4504A activity in these animals, it reduced the severity of hypertension and renal damage through some other mechanism.
Key Words: salt sensitivity • cytochrome P450 • hydroxyeicosatetraenoic acids • glomerulosclerosis • antilipidemic drugs • pravastatin • fenofibrate
Abbreviations: Dahl S rat = Dahl salt-sensitive rat • HDL = high-density lipoprotein • 20-HETE = 20-hydroxyeicosa-5,6,11,14-tetraenoic acid • LDL = low-density lipoprotein • P4504A = cytochrome P4504A • PAS = periodic acid-Schiff
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