Effects of lipid-lowering agents in the Dahl salt-sensitive rat
Effects of lipid-lowering agents in the Dahl salt-sensitive rat
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DOI：
10.1161/01.hyp.31.1.225
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发表时间：
1998-01-01
期刊：
影响因子：
8.3
通讯作者：
Roman, RJ
中科院分区：
文献类型：
--
作者：
Wilson, TW;Alonso-Galicia, M;Roman, RJ
氯贝特诱导肾细胞色素P4504A （P4504A）活性可防止Dahl盐敏感（Dahl S）大鼠高血压的发生。为了确定其他降脂药物是否也会出现这种情况，我们比较了相关药物非诺贝特和非相关药物普伐他汀对血压、肾脏组织学和P4504A活性的影响。将Dahl S大鼠从低盐（0.1% NaCl）改为高盐（8.0% NaCl）饮食前后分别用非诺贝特（95 mg/kg /天）、普伐他汀（70 mg/kg /天）或对照剂预处理7天。高盐饮食3周后，给药组、非诺贝特组和普伐他汀组动物的平均动脉压分别为183+/-13 （n=9）、126+/-10 （n=9）和148+/-11 mmhg （n=8）。两种药物均可减轻蛋白尿和肾小球损伤程度。非诺贝特处理的大鼠肝脏和肾脏中P4504A蛋白水平和20-羟基糖-5,8,11,14-四烯酸（20-HETE）的合成增加，而普伐他汀处理的大鼠则没有增加。我们也给高盐饮食引起高血压的Dahl S大鼠施用这些药物。给药、非诺贝特或普伐他汀治疗3周的大鼠平均动脉压为164+/-10、113+/-23和160+/-15 mm Hg。非诺贝特治疗的大鼠出现尿钠。普伐他汀可减少蛋白尿和肾小球损伤，非诺贝特则不能。这些结果表明，非诺贝特预防了Dahl S大鼠高血压的发展，并减少了随后的肾小球损伤，可能是继发于肾脏生成20-HETE的增加。尽管普伐他汀在这些动物中没有诱导肾脏P4504A活性，但它通过其他机制降低了高血压的严重程度和肾损害。
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.