Russell J C, Graham S E, Dolphin P J, Amy R M, Wood G O, Brindley D N
Department of Surgery, 275 Heritage Medical Research Centre, University of Alberta, Edmonton, Canada.
Atherosclerosis. 1997 Jul 25;132(2):187-97. doi: 10.1016/s0021-9150(97)00092-0.
The JCR:LA-corpulent rat is an animal model that, if homozygous for the cp gene (cp/cp), spontaneously exhibits obesity and a severe insulin resistance, with a resultant hyperinsulinemia and hypertriglyceridemia. The obese male rats show defective nitric oxide-mediated vascular relaxation, advanced atherosclerosis, and ischemic myocardial lesions. Benfluorex has both anorectic and metabolic effects that lower body weight and improve insulin sensitivity in obesity and type 2 diabetes. Male cp/cp rats that were treated with benfluorex (or pair-fed to the treated animals) from the time of weaning, at 3 weeks of age, showed a marked delay in the development of postprandial hyperinsulinemia. At 12 weeks of age benfluorex-treated cp/cp rats did not show the extreme insulin response to a test meal that was observed in untreated or pair-fed rats. Both benfluorex-treated and pair-fed rats had a significant increase in sensitivity to acetylcholine-induced (nitric oxide-mediated) vascular relaxation. Corpulent male rats were also treated from 6 to 39 weeks of age with benfluorex in the feed at a dose of approximately 36 mg/kg/day at 12 weeks of age and decreasing to 23 mg/kg/day at 39 weeks to determine the effects on cardiovascular outcomes. The rats showed a sustained decrease in food consumption and body weight, although they exhibited 50% of the excess body weight of the controls and were grossly obese. Both fasting insulin concentrations and the hyperplasia of the islets of Langerhans were decreased by approximately 50%. Serum triglyceride concentrations were decreased by 44%, and free cholesterol and cholesteryl esters by 30%. The severity of the atherosclerotic lesions on the aortic arch was decreased (P < 0.05). There was also a decrease in the size of early ischemic myocardial lesions that are characterized by cell lysis and chronic inflammatory cell infiltration. Mature, scarred myocardial lesions were essentially absent in the hearts of 39-week-old benfluorex-treated rats. Long-term major food restriction (18 g/day) decreased the body weights of obese rats to essentially those of lean control animals, with similar beneficial effects on the insulin resistance and hyperlipidemia. While myocardial lesion frequency was reduced in these much thinner animals, lesions remained and the apparent effect was not statistically significant. This evidence shows that the beneficial metabolic effects of benfluorex are associated with long-term effects on the vessel wall and delay the onset of insulin resistance and cardiovascular disease in an animal model.
LA肥胖大鼠是一种动物模型，若其cp基因纯合（cp/cp），会自发出现肥胖和严重的胰岛素抵抗，继而导致高胰岛素血症和高甘油三酯血症。肥胖雄性大鼠表现出一氧化氮介导的血管舒张功能缺陷、严重的动脉粥样硬化和缺血性心肌损伤。苯氟雷司具有抑制食欲和代谢作用，可降低肥胖和2型糖尿病患者的体重并提高胰岛素敏感性。从3周龄断奶时开始用苯氟雷司治疗（或与接受治疗的动物配对饲养）的雄性cp/cp大鼠，餐后高胰岛素血症的发展明显延迟。在12周龄时，接受苯氟雷司治疗的cp/cp大鼠对试验餐未表现出未治疗或配对饲养大鼠所观察到的极端胰岛素反应。接受苯氟雷司治疗的大鼠和配对饲养的大鼠对乙酰胆碱诱导的（一氧化氮介导的）血管舒张的敏感性均显著增加。肥胖雄性大鼠在6至39周龄时也在饲料中添加苯氟雷司进行治疗，12周龄时剂量约为36 mg/kg/天，39周龄时降至23 mg/kg/天，以确定对心血管结局的影响。大鼠的食物摄入量和体重持续下降，尽管它们仍有对照组50%的超重体重，且明显肥胖。空腹胰岛素浓度和胰岛增生均降低了约50%。血清甘油三酯浓度降低了44%，游离胆固醇和胆固醇酯降低了30%。主动脉弓上动脉粥样硬化病变的严重程度降低（P<0.05）。以细胞溶解和慢性炎症细胞浸润为特征的早期缺血性心肌损伤的大小也有所减小。在39周龄接受苯氟雷司治疗的大鼠心脏中，基本没有成熟的、有瘢痕的心肌损伤。长期严格限制食物摄入量（每天18克）可使肥胖大鼠的体重基本降至瘦对照动物的水平，对胰岛素抵抗和高脂血症有类似的有益作用。虽然在这些瘦得多的动物中心肌损伤频率降低，但损伤仍然存在，且明显效果无统计学意义。这一证据表明，苯氟雷司的有益代谢作用与对血管壁的长期影响相关，并可延缓动物模型中胰岛素抵抗和心血管疾病的发生。
