Song Dongzhe, Kuo Kuo-Hsing, Yao Reina, Hutchings Simon R, Pang Catherine C Y
Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, B.C., Canada V6T 1Z3.
Eur J Pharmacol. 2008 Jan 28;579(1-3):253-9. doi: 10.1016/j.ejphar.2007.09.043. Epub 2007 Oct 12.
Cardiac contractile dysfunction is a common occurrence in type 2 diabetes. The aim was to examine if inducible nitric oxide synthase (iNOS) causes cardiac dysfunction in Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. ZDF and Zucker lean control rats (20 week old) were studied at 6 h after recovery from halothane anaesthesia and surgery that involved insertions of catheters into the iliac arteries, iliac veins and the left ventricle via the right carotid artery. Protein expression and activity of iNOS in the hearts were measured by immunostaining and arginine-citrulline conversion assay, respectively. Both groups had similar baseline left ventricular developed pressure and maximum rate of rise of left ventricular pressure (+dP/dt), but heart rate and rate pressure product were lower in the ZDF than control rats. Dobutamine dose-dependently increased left ventricular developed pressure, +dP/dt, heart rate and rate pressure product in both groups, but the responses were less in the diabetic than control rats. The activity and protein expression of iNOS and nitrotyrosine were higher in the hearts of the diabetic than control rats. Selective inhibition of iNOS by 1400 W (N-3-aminomethyl-benzyl-acetamidine) did not alter responses to dobutamine in the control rats, but augmented the effects of dobutamine on left ventricular developed pressure and rate pressure product in the diabetic rats. The results indicate that activation of iNOS contributed to left ventricular contractile dysfunction in the ZDF rats, and this was partially reversed by selective inhibition of the activity of iNOS.
心脏收缩功能障碍在2型糖尿病中很常见。本研究旨在探讨诱导型一氧化氮合酶（iNOS）是否会导致2型糖尿病模型——Zucker糖尿病肥胖（ZDF）大鼠出现心脏功能障碍。对ZDF大鼠和Zucker瘦素对照大鼠（20周龄）在从氟烷麻醉和手术中恢复6小时后进行研究，手术包括通过右颈动脉将导管插入髂动脉、髂静脉和左心室。分别通过免疫染色和精氨酸 - 瓜氨酸转化试验测量心脏中iNOS的蛋白表达和活性。两组的基线左心室舒张末压和左心室压力最大上升速率（+dP/dt）相似，但ZDF大鼠的心率和心率血压乘积低于对照大鼠。多巴酚丁胺剂量依赖性地增加两组的左心室舒张末压、+dP/dt、心率和心率血压乘积，但糖尿病大鼠的反应低于对照大鼠。糖尿病大鼠心脏中iNOS和硝基酪氨酸的活性及蛋白表达高于对照大鼠。用1400W（N - 3 - 氨基甲基 - 苄基 - 脒）选择性抑制iNOS对对照大鼠对多巴酚丁胺的反应无影响，但增强了多巴酚丁胺对糖尿病大鼠左心室舒张末压和心率血压乘积的作用。结果表明，iNOS的激活导致ZDF大鼠左心室收缩功能障碍，而选择性抑制iNOS的活性可部分逆转这种情况。
