Capuzzi D M, Cevallos W H
J Cardiovasc Pharmacol. 1984;6 Suppl 5:S847-52. doi: 10.1097/00005344-198400065-00024.
Abundant evidence exists for the cumulative adverse effects of hypertension and hypercholesterolemia on the progression of coronary heart disease. The antihypertensive drug guanabenz acetate has been shown to lower serum cholesterol levels, but the mechanism for this effect is unclear. To explore this problem, suspensions of rat liver cells were incubated with guanabenz and labeled lipogenic precursors. Guanabenz produced an inhibition of cholesterol production from [14C]acetate that ranged from 10% at 0.005 mM guanabenz to 90% at 0.20 mM guanabenz. Inhibition of cholesterol production from [14C]mevalonate was half as great as inhibition from [14C]acetate. Thus, guanabenz inhibits hepatic cholesterol production at both pre- and postmevalonic sites in the sterol pathway. Synthesis of triglycerides from [14C]palmitate also was inhibited by guanabenz, whereas oxidation of [14C]palmitate to 14CO2 was stimulated. Therefore, the inhibition of triglyceride formation from fatty acid produced by guanabenz may be due to the stimulation of fatty acid oxidation. The clinical effects of guanabenz on serum lipid levels may relate to its direct actions on hepatic cholesterol and triglyceride biosynthesis.
有充分证据表明高血压和高胆固醇血症对冠心病进展具有累积不良影响。抗高血压药物胍那苄乙酸盐已被证明可降低血清胆固醇水平，但其作用机制尚不清楚。为探究此问题，将大鼠肝细胞悬液与胍那苄及标记的脂肪生成前体一起孵育。胍那苄对[14C]乙酸盐生成胆固醇有抑制作用，在0.005 mM胍那苄时抑制率为10%，在0.20 mM胍那苄时抑制率达90%。对[14C]甲羟戊酸生成胆固醇的抑制作用是对[14C]乙酸盐抑制作用的一半。因此，胍那苄在固醇途径的甲羟戊酸前和甲羟戊酸后位点均抑制肝脏胆固醇生成。胍那苄也抑制[14C]棕榈酸生成甘油三酯，而刺激[14C]棕榈酸氧化为14CO2。因此，胍那苄对脂肪酸生成甘油三酯的抑制作用可能是由于脂肪酸氧化受刺激。胍那苄对血清脂质水平的临床作用可能与其对肝脏胆固醇和甘油三酯生物合成的直接作用有关。
