Effects of a selective thromboxane synthetase inhibitor OKY-046 on experimental diabetic nephropathy.
To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.
Hora
K
K
Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Oguchi
H
H
Furukawa
T
T
Hora
K
K
Tokunaga
S
S
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000502:physiology; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology / Q000652:urine*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000503:physiopathology / Q000652:urine*; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage / Q000494:pharmacology*; D008854:Microscopy, Electron; D010974:Platelet Aggregation / Q000502:physiology; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000502:physiology; D013929:Thromboxane B2 / Q000097:blood / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001786:Blood Glucose; D007328:Insulin; D008689:Methacrylates; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D013930:Thromboxane-A Synthase; C034364:ozagrel