Effect of combination therapy with dipyridamole and quinapril in diabetic nephropathy.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Onozato
Maristela Lika
ML
Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Japan.
Tojo
Akihiro
A
Goto
Atsuo
A
Fujita
Toshiro
T
D000419:Albuminuria / Q000652:urine; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood / Q000652:urine; D006152:Cyclic GMP / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D004176:Dipyridamole / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008054:Lipid Peroxides / Q000096:biosynthesis / Q000652:urine; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D000077583:Quinapril; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D007546:Isoquinolines; D008054:Lipid Peroxides; D010726:Phosphodiesterase Inhibitors; D010750:Phosphoproteins; D044005:Tetrahydroisoquinolines; D004176:Dipyridamole; D003404:Creatinine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D006152:Cyclic GMP; D000077583:Quinapril