D'Eletto R D, Javitt N B
Division of Hepatic Diseases, New York University Medical Center, New York 10016.
J Cardiovasc Pharmacol. 1989;13 Suppl 2:S1-4; discussion S4. doi: 10.1097/00005344-198900132-00002.
The effect of doxazosin on cholesterol synthesis was determined by measuring the content of deuterium-enriched cholesterol in rabbit fibroblasts with and without receptors for low-density lipoproteins (LDL) and in hepatoma (Hep G2 cells). Doxazosin, at concentrations of 5-20 mumol/L, increased LDL binding to hepatic cells in a dose-related manner. Also, in these hepatic cells, doxazosin produced dose-related decreases in both newly synthesized cholesterol and cholesterol ester. In rabbit fibroblasts that were LDL receptor negative, de novo cholesterol synthesis was markedly reduced by increasing concentrations of doxazosin. Taken together, these results suggest that doxazosin may have a direct inhibitory effect on cholesterol synthesis independent of the LDL receptor. The inhibition of cholesterol synthesis by doxazosin may cause cells to compensate by upregulating the LDL receptor, thereby increasing the importation of lipoprotein cholesterol and reducing LDL cholesterol in the medium. This hypothesis supports findings in the clinical setting whereby doxazosin has a beneficial effect on the lipid profile, and suggests a useful additional property for this antihypertensive agent.
通过测量有和没有低密度脂蛋白（LDL）受体的兔成纤维细胞以及肝癌（Hep G2细胞）中富含氘的胆固醇含量，来确定多沙唑嗪对胆固醇合成的影响。浓度为5-20μmol/L的多沙唑嗪以剂量相关的方式增加LDL与肝细胞的结合。此外，在这些肝细胞中，多沙唑嗪使新合成的胆固醇和胆固醇酯均呈剂量相关的减少。在LDL受体阴性的兔成纤维细胞中，随着多沙唑嗪浓度增加，从头合成胆固醇显著减少。综合这些结果表明，多沙唑嗪可能对胆固醇合成具有直接抑制作用，且独立于LDL受体。多沙唑嗪对胆固醇合成的抑制作用可能导致细胞通过上调LDL受体进行代偿，从而增加脂蛋白胆固醇的摄入并降低培养基中的LDL胆固醇。这一假设支持了临床研究结果，即多沙唑嗪对血脂状况具有有益作用，并提示了这种抗高血压药物的一项有用的附加特性。
