Onozato Maristela Lika, Tojo Akihiro, Goto Atsuo, Fujita Toshiro
Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Japan.
Diabetes Res Clin Pract. 2003 Feb;59(2):83-92. doi: 10.1016/s0168-8227(02)00154-7.
BACKGROUND/AIMS: Dipyridamole stimulates nitric oxide action via inhibition of phosphodiesterase and also has an antioxidant effect. ACE inhibitor reduces glomerular pressure and enhances NO action via increased bradykinin. Thus, we evaluated the effect of the combination of dipyridamole and ACE inhibitor in diabetic nephropathy.
Streptozotocin-induced diabetic rats at 2 weeks were treated with dipyridamole, quinapril or both. The expression of NOS and NAD(P)H oxidase p47phox was investigated using immunohistochemistry and western blot, and urinary albumin, cGMP and lipid peroxidation products (LPO) were measured at 4 weeks.
NAD(P)H oxidase and urinary LPO were significantly enhanced in diabetes, and suppressed by each treatment to the same extent. The nNOS expression in macula densa and eNOS increased significantly with combination therapy compared to quinapril treatment alone contributing to an enhanced urinary excretion of cGMP and to maintain the creatinine clearance. Increased albuminuria in diabetes was reduced more effectively with combination therapy to the control level than with single treatments.
Combination therapy with dipyridamole and quinapril suppressed urinary LPO via reduction of NAD(P)H oxidase increase in diabetes. The combination therapy reduced microalbuminuria to the control level and maintained creatinine clearance with enhanced nNOS and eNOS expression compared to quinapril alone.
背景/目的：双嘧达莫通过抑制磷酸二酯酶刺激一氧化氮的作用，并且还具有抗氧化作用。血管紧张素转换酶抑制剂可降低肾小球压力，并通过增加缓激肽增强一氧化氮的作用。因此，我们评估了双嘧达莫与血管紧张素转换酶抑制剂联合应用对糖尿病肾病的影响。
对链脲佐菌素诱导的糖尿病2周龄大鼠分别给予双嘧达莫、喹那普利或两者联合治疗。使用免疫组织化学和蛋白质印迹法研究一氧化氮合酶和烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）氧化酶p47phox的表达，并在4周时测量尿白蛋白、环磷酸鸟苷（cGMP）和脂质过氧化产物（LPO）。
糖尿病时NAD(P)H氧化酶和尿LPO显著升高，每种治疗均能同等程度地抑制它们。与单独使用喹那普利治疗相比，联合治疗组致密斑处神经元型一氧化氮合酶（nNOS）表达和内皮型一氧化氮合酶（eNOS）显著增加，导致尿cGMP排泄增加，并维持肌酐清除率。与单一治疗相比，联合治疗能更有效地将糖尿病时增加的蛋白尿降低至对照水平。
双嘧达莫与喹那普利联合治疗通过降低糖尿病时NAD(P)H氧化酶的增加来抑制尿LPO。与单独使用喹那普利相比，联合治疗可将微量白蛋白尿降低至对照水平，并通过增强nNOS和eNOS的表达维持肌酐清除率。
