ACUTE AND CHRONIC EFFECTS OF THROMBOXANE A(2) INHIBITION ON THE RENAL HEMODYNAMICS IN STREPTOZOTOCIN-INDUCED DIABETIC RATS

We examined acute and chronic effects of thromboxane (TX) A(2) inhibition on the renal hemodynamics at early and late stage of untreated streptozotocin (STZ)-induced diabetic rats, Two weeks and 28 weeks after the induction of diabetes, renal blood flow (RBF) under anesthesia was measured with an electromagnetic flowmeter before and after TXA(2) inhibition. In two-week-old diabetic rats, a specific TXA(2) synthetase inhibitor, OKY-046, or a specific TXA(2) receptor antagonist, Sulotroban, increased renal vascular resistance (RVR) and ameliorated the hyperperfusion. The renal vasoconstrictive effect of OKY-046 was blunted by an angiotensin converting enzyme (ACE) inhibitor, MK422, or an angiotensin II receptor antagonist, Saralasin. On the contrary, OKY-046 ameliorated the renal hypoperfusion by decreasing RVR in 28-week-old diabetic rats. Chronic oral administration of OKY-046 ameliorated not only the renal hyperperfusion but increased urinary albumin excretion (UAE) at two weeks, but also the renal hypoperfusion, filtration fraction and UAE at 24 weeks. It is suggested that TXA(2) might, at least in part, play important roles in the hyperperfusion by modulating activity of the renin-angiotensin system at an early stage of untreated diabetic rats and in the hypoperfusion at the late stage of untreated diabetic rats, and that TXA(2) is also involved in the increase of UAE. These results support roles for TXA(2) in the progression of renal injury in STZ-induced diabetic rats.