Thromboxane blockade reduces blood pressure and progression of renal failure independent of endothelin-1 in uremic rats

Abstract

This study was designed to investigate the role of eicosanoids, thromboxane A 2 (TXA 2) and prostacyclin (PGI 2) as well as their relationship with endothelin-1 (ET-1) in the pathogenesis of renal parenchymal hypertension. Uremic rats were prepared by renal mass ablation and compared with sham-operated controls. The stable metabolites of TXA 2 (TXB 2) and PGI 2 (6-keto-PGF 1α) and immunoreactive ET-1 concentrations were measured by specific RIAs in biological fluids and in vascular and renal tissues. To investigate the functional role of TXA 2 in the progression of hypertension and renal failure, a group of uremic rats were treated with ridogrel (25 mg/kg/day), a TXA 2 synthase inhibitor and receptor antagonist. Renal preproET-1 expression was assessed by Northern blot analysis. Systolic blood pressure (SBP), serum creatinine and proteinuria were found to be higher in uremic rats as compared to sham-operated controls ( P<0.01). TXB 2 and ET-1 concentrations were increased in blood vessels, the renal cortex and in urine ( P<0.05). 6-keto-PGF 1 α concentrations were also increased in blood vessels and the renal cortex but decreased in urine ( P<0.05). Ridogrel significantly lowered SBP and proteinuria ( P<0.05) and blunted the increase of serum creatinine. Treatment with ridogrel resulted in a marked fall in vascular, renal and urine TXA 2 concentrations, while ET-1 and 6-keto-PGF 1 α concentrations remained unchanged. The preproET-1 expression was higher in uremic rats than in the controls and was unaffected by ridogrel. These results suggest that TXA 2 is involved in the pathogenesis of hypertension and renal failure progression in rats with subtotal 5/6 nephrectomy and that this effect is independent of the ET-1 system.