A thromboxane synthetase antagonist ameliorates progressive renal disease of Dahl-S rats.

Recent studies have suggested a role for thromboxane in the progression of renal disease. The current study evaluated the role of this arachidonic acid metabolite in a model of renal disease which bears many biologic similarities to that in the kidneys of patients with chronic progressive renal failure. The model is that induced by ferritin-anti-ferritin immune complex nephritis in Dahl-salt sensitive rats rendered hypertensive by a high salt intake. Rats with this model of renal disease were chronically given a thromboxane synthetase antagonist OKY-046 or a placebo treatment from 16 to 29 weeks of age. Sequential observations of serum creatinine and 24-hour urinary protein excretion showed an ameliorating effect of OKY-046 on these renal parameters. Histologic examination of the kidneys also showed significantly less glomerular sclerosis in OKY-046 treated animals. The efficacy of OKY-046 was monitored by measurements of serum TXB2 levels and of glomerular production of TXB2 (and other prostaglandins); amounts of TXB2 were significantly reduced in the OKY-046 group. It is concluded that blockade of thromboxane generation has been successful in ameliorating the functional and structural lesions in this model of renal disease, providing further support to the thesis that thromboxane is an important mediator in events leading to eventual chronic renal failure and sclerosis.