Russell J C, Dolphin P J, Graham S E, Amy R M
Department of Surgery, University of Alberta, Edmonton, Canada.
J Cardiovasc Pharmacol. 1997 May;29(5):586-92. doi: 10.1097/00005344-199705000-00004.
The JCR:LA-cp rat exhibits the obesity/insulin resistance/hypertriglyceridemia syndrome in an extreme form. These normotensive rats spontaneously develop advanced atherosclerosis and ischemic myocardial lesions. The calcium channel antagonist, nisoldipine, was administered to obese rats of the JCR:LA-cp strain in drinking water at a dose of 1 mg/kg from age 6 weeks. Nisoldipine-treated rats showed no change in food consumption or body weight compared with control animals. Plasma glucose and insulin levels also were unchanged in the nisoldipine-treated rats. Insulin-mediated total glucose turnover, an index of insulin sensitivity as measured by euglycemic insulin clamp, was similarly not improved. Serum triglyceride levels in obese male rats were markedly reduced (57%; p < 0.001, at age 12 weeks), whereas obese female rats showed no significant change in triglyceride levels and an increase in esterified cholesterol in response to nisoldipine treatment. The impaired endothelium-dependent (nitric oxide-mediated) vascular relaxation of the male cp/cp rats was not improved by nisoldipine treatment. The severity of atherosclerotic raised lesions in the aortic arch of male cp/cp rats was significantly reduced (p < 0.01) by nisoldipine treatment, and this was accompanied by a major reduction in the incidence of ischemic myocardial lesions (85%; p < 0.01). Thus nisoldipine treatment ameliorates atherosclerotic damage and myocardial injury even in the presence of gross obesity, hyperinsulinemia, and significant hyperlipidemia. This effect appears to involve protection of the vascular wall from atherogenesis and probably antivasocontractile effects at the smooth muscle level as well.
LA-cp大鼠呈现出极端形式的肥胖/胰岛素抵抗/高甘油三酯血症综合征。这些血压正常的大鼠会自发发展为晚期动脉粥样硬化和缺血性心肌病变。从6周龄起，以1 mg/kg的剂量将钙通道拮抗剂尼索地平添加到JCR:LA-cp品系肥胖大鼠的饮用水中。与对照动物相比，接受尼索地平治疗的大鼠在食物摄入量或体重方面没有变化。接受尼索地平治疗的大鼠血浆葡萄糖和胰岛素水平也未改变。通过正常血糖胰岛素钳夹测量的胰岛素介导的总葡萄糖周转率（胰岛素敏感性指标）同样没有改善。肥胖雄性大鼠的血清甘油三酯水平显著降低（12周龄时降低57%；p<0.001），而肥胖雌性大鼠的甘油三酯水平没有显著变化，且对尼索地平治疗有反应，酯化胆固醇增加。尼索地平治疗并未改善雄性cp/cp大鼠内皮依赖性（一氧化氮介导）血管舒张功能受损的情况。尼索地平治疗显著降低了雄性cp/cp大鼠主动脉弓动脉粥样硬化隆起病变的严重程度（p<0.01），同时缺血性心肌病变的发生率大幅降低（85%；p<0.01）。因此，即使在存在严重肥胖、高胰岛素血症和显著高脂血症的情况下，尼索地平治疗也能改善动脉粥样硬化损伤和心肌损伤。这种作用似乎涉及保护血管壁免受动脉粥样硬化的影响，并且可能在平滑肌水平上具有抗血管收缩作用。
