Schäfer A, Pfrang J, Neumüller J, Fiedler S, Ertl G, Bauersachs J
Department of Internal Medicine I-Cardiology, University Hospital Würzburg, Julius-Maximilians-University, Würzburg, Germany.
Br J Pharmacol. 2008 Jul;154(5):1047-54. doi: 10.1038/bjp.2008.158. Epub 2008 May 12.
We investigated the effect of rimonabant on inflammation and enhanced platelet reactivity in type 2 diabetic Zucker rats, an experimental model of impaired glucose tolerance and the metabolic syndrome.
Rimonabant (10 mg kg(-1) by gavage) was fed for 2 weeks to 3-month-old male obese Zucker rats as an impaired glucose tolerance model and for 10 weeks to 6-month-old male obese Zucker rats as a model of the metabolic syndrome. RANTES (Regulated upon Activation, Normal T cell Expressed, and Secreted) and MCP-1 (monocyte chemotactic protein-1) serum levels were determined by ELISA. Leukocyte populations were quantitatively assessed using a veterinary differential blood cell counter. Platelet activation was assessed by flow-cytometry, platelet aggregation, and adhesion of isolated platelets to immobilized fibrinogen.
RANTES and MCP-1 serum levels were increased in obese vs lean Zucker rats and significantly reduced by long-term treatment with rimonabant, which slowed weight gain in rats with the metabolic syndrome. Neutrophils and monocytes were significantly increased in young and old obese vs lean Zucker rats and lowered by rimonabant. Platelet-bound fibrinogen was significantly enhanced in obese vs lean Zucker rats of both age, and was reduced by rimonabant. Platelets from obese rats were more sensitive to thrombin-induced aggregation and adhesion to fibrinogen, which were both attenuated by rimonabant therapy.
We demonstrate positive modulation of circulating neutrophil and monocyte numbers, reduced platelet activation and lower RANTES and MCP-1 levels by rimonabant in Zucker rats. This may potentially contribute to a reduction of cardiovascular risk.
我们研究了利莫那班对2型糖尿病Zucker大鼠炎症及血小板反应性增强的影响，该大鼠是糖耐量受损和代谢综合征的实验模型。
将利莫那班（10毫克/千克，经口灌胃）给予3月龄雄性肥胖Zucker大鼠作为糖耐量受损模型，连续给药2周；给予6月龄雄性肥胖Zucker大鼠作为代谢综合征模型，连续给药10周。通过酶联免疫吸附测定法（ELISA）测定调节激活正常T细胞表达和分泌因子（RANTES）及单核细胞趋化蛋白-1（MCP-1）的血清水平。使用兽用血细胞分类计数器对白细胞群体进行定量评估。通过流式细胞术、血小板聚集以及分离的血小板与固定化纤维蛋白原的黏附来评估血小板激活情况。
与瘦Zucker大鼠相比，肥胖大鼠的RANTES和MCP-1血清水平升高，长期使用利莫那班可显著降低这些水平，利莫那班还减缓了代谢综合征大鼠的体重增加。与瘦Zucker大鼠相比，年轻和老年肥胖大鼠的中性粒细胞和单核细胞显著增加，而利莫那班可使其减少。在两个年龄段的肥胖与瘦Zucker大鼠中，血小板结合的纤维蛋白原均显著增强，而利莫那班可使其降低。肥胖大鼠的血小板对凝血酶诱导的聚集和与纤维蛋白原的黏附更敏感，而利莫那班治疗可减弱这些反应。
我们证明利莫那班可对Zucker大鼠循环中的中性粒细胞和单核细胞数量产生正向调节作用，降低血小板激活，并降低RANTES和MCP-1水平。这可能有助于降低心血管疾病风险。
