Impact of Insulin or Tolbutamide Treatment on 14C-Arachidonic Acid Conversion to Prostacyclin and/or Thromboxane in Lungs, Aortas, and Platelets of Streptozotocin-induced Diabetic Rats

Abstract

Diabetes is associated with a dramatic increase in the risk of thrombotic and atherosclerotic disease. The underlying factors responsible for this predisposition as well as the mechanisms involved have yet to be elucidated. Two endogenous substances, prostacyclin (PGI2) and thromboxane (TXA2), have recently been shown to possess significant vascular and thrombotic activity and are known to be altered in atherosclerosis, thrombotic conditions, and diabetes. We determined the conversion of 14C-arachidonic acid (AA) to PGI2 and TXA2 by lungs, aortas, and platelets obtained from chemically induced diabetic rats. In addition, we investigated the ability of insulin or tolbutamide to reverse these changes. Streptozotocin (STZ)-injected rats developed blood glucose levels 2–4 times that seen in normoglycemic controls. Intact perfused lungs isolated from rats beginning 7 days after STZ treatment synthesized 22–30% less PGI2 from 14C-AA. The ratio of PGI2/ TXA2 was decreased in the diabetic rat lungs and was inversely proportional to plasma glucose levels at the time of death. Platelet TXA2 generation was increased 67% above control in diabetic rats while aortic PGI2 generation was decreased 28% below normoglycemic controls. Ten-day treatment with NPH insulin 20 U/kg s.c. in STZ-pretreated rats lowered plasma glucose toward normoglycemia more effectively than tolbutamide 200 mg/kg orally. Partial correction of the decreased pulmonary PGI2/TXA2 ratio seen in diabetic rats was produced by insulin and tolbutamide in proportion to their ability to lower blood glucose. At the doses employed, insulin caused aortic PGI2 and platelet TXA2 generation from 14C-AA to approach that seen in normoglycemic controls more effectively than tolbutamide. An inverse correlation with plasma glucose levels was observed for pulmonary PGI2/TXA2 ratios as well as aortic PGI2 generation, r = −0.72 and −0.74, respectively. Platelet TXA2 generation correlated posi-tively with plasma glucose, r = 0.69. This study indicates that metabolism of 14C-AA by pulmonary tissue, platelets, and aortas is altered by experimentally induced diabetes. Furthermore, these findings suggest that such alterations can be partially reversed by regulation Of the diabetic condition.