This study was designed to investigate the role of
eicosanoids,
thromboxane A2 (TXA2) and
prostacyclin (PGI2) 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 TXA2 (TXB2) and PGI2 (6-keto-PGF1alpha) 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 TXA2 in the progression of
hypertension and
renal failure, a group of uremic rats were treated with
ridogrel (25 mg/kg/day), a TXA2 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). TXB2 and ET-1 concentrations were increased in blood vessels, the renal cortex and in urine (P < 0.05). 6-keto-PGF1alpha 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 TXA2 concentrations, while ET-1 and 6-keto-PGF1alpha 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 TXA2 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.