Effects of B-1 and B-2 kinin receptor antagonists in diabetic mice

Streptozotocin (STZ) has been extensively used to produce type I diabetes in animals. This experimental disease is characterized by a mild inflammatory reaction in the Langerhans islets. Because kinins have been proposed as prominent inflammatory mediators in the pathogenesis of several diseases, we decided to evaluate the role of kinins and their receptors in the evolution of insulitis. Male C57BL/Ks mdb mice were injected with STZ (40 mg/kg) for 5 consecutive days. The kinin B-1 receptor antagonist [Leu(8)]des-Arg(9)-bradykinin or the B-2 antagonist d-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykinin (HOE-140) was injected subcutaneously into STZ mice at 300 mu g/kg body weight twice a day and 500 mu g/kg per day, respectively. Treatment with antagonists was started 3 days after STZ and lasted for 10 days. Plasma glucose was determined by the glucose oxidase method, and urine samples collected on day 13 were assayed for proteins, nitrites, and kallikreins. Diabetic mice showed hyperglycemia and increased diuresis, marked proteinuria, and increased excretion of nitrites and kallikreins. The treatment with the B-2 receptor antagonist did not show any effect on glycemia, but it significantly reduced water and protein excretion, compared with the STZ group. STZ mice treated with the B-1 receptor antagonist showed normal glycemia and complete normalization of diuresis and protein, nitrite, and kallikrein excretion. The results obtained in the present investigation support the assumption that the kallikrein-kinin system intervenes in the maintenance of diabetic lesions, and they also indicate that B-1 kinin receptors play a significant role in this experimental disease.