Hypolipidemic effect of NK-104, a potent HMG-CoA reductase inhibitor, in guinea pigs
Hypolipidemic effect of NK-104, a potent HMG-CoA reductase inhibitor, in guinea pigs
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DOI：
10.1016/s0021-9150(99)00146-x
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发表时间：
1999-10-01
期刊：
影响因子：
5.3
通讯作者：
Saito, Y
中科院分区：
文献类型：
--
作者：
Suzuki, H;Aoki, T;Saito, Y
使用辛伐他汀作为参比物质，在豚鼠中研究了NK-104的降血脂作用及其作用机制（对肝固醇合成、低密度脂蛋白（LDL）受体表达和极低密度脂蛋白（VLDL）分泌的影响）。两种血浆总胆固醇均呈剂量依赖性显著降低（0.3. 1和3 mg/kg）和甘油三酯（1和3 mg/kg分别为21.1和32.2%）。30 mg/kg辛伐他汀降低血浆总胆固醇（25.0%），但不降低甘油三酯水平。NK-104（3 mg/kg）和辛伐他汀（30 mg/kg）在给药后3 h抑制肝固醇合成约80%，并在给药14天后增强肝膜LDL受体结合能力1.5倍。前者比后者更明显地加速LDL清除，并使分解率增加1.8倍（vs. 1.4倍）。此外，仅NK-104（3 mg/kg）抑制VLDL分泌到肝灌注液中（甘油三酯，19.9%; apoB，24.2%），并且长期作用导致肝固醇合成的广泛减少。这些结果表明，NK-104和辛伐他汀在前者的10倍剂量下，类似地增强肝LDL受体;然而，只有NK-104具有延长的作用，抑制VLDL分泌，显示出更高的降低胆固醇的效力和降低胆固醇的效果。(C)1999爱思唯尔科学爱尔兰有限公司保留所有权利。
The hypolipidemic effect of NK-104 and its mechanisms of action (effects on hepatic sterol synthesis, low density lipoprotein (LDL)-receptor expression and very low density lipoprotein (VLDL) secretion) were studied in guinea pigs using simvastatin as a reference substance. There was a dose-dependent and significant reduction of both plasma total cholesterol (17.4, 24.5 and 45.3% at 0.3. 1 and 3 mg/kg, respectively) and triglycerides (21.1 and 32.2% at 1 and 3 mg/kg, respectively) after 14-day administration of NK-104. Simvastatin at 30 mg/kg lowered plasma total cholesterol (25.0%) but not triglyceride levels. NK-104 (3 mg/kg) and simvastatin (30 mg/kg) inhibited hepatic sterol synthesis by approximately 80%, 3 h after dosing, and enhanced LDL receptor binding-capacity of liver membranes 1.5-fold after 14-day dosing. The former group accelerated LDL clearance somewhat more markedly than the latter, and increased fractional catabolic rate 1.8-fold (vs. 1.4-fold). Furthermore, only the NK-104 (3 mg/kg) suppressed VLDL secretion into the liver perfusate (triglyceride, 19.9%; apoB, 24.2%) with extensive reduction of hepatic sterol synthesis caused by prolonged action. These results indicate that NK-104 and simvastatin at 10 times the dosage of the former, similarly enhances hepatic LDL receptor; however, only NK-104 with prolonged action suppresses VLDL secretion to show higher cholesterol-lowering potency and triglyceride-reducing effect. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.