The Selective TP Receptor Antagonist, S18886 (Terutroban), Attenuates Renal Damage in the Double Transgenic Rat Model of Hypertension

BACKGROUND/AIMS: Thromboxane receptors play a decisive role in the renovascular actions of angiotensin II. We studied the efficacy of the selective thromboxane receptor antagonist, S18886, in the retardation of renal damage in the double transgenic rats (dTGR), harboring human renin and angiotensinogen genes. METHODS: dTGR were gavaged daily with either S18886 (30 mg/kg/day, n = 12), or placebo (dTGR-Plac, tap water, n = 14) for 3 weeks. Matched Sprague-Dawley rats (n = 10) served as controls. RESULTS: The dTGR-Plac had higher systolic blood pressure (1.7-fold) than controls, and developed profound renal damage with significantly higher proteinuria (6.9-fold), polyuria (2.3-fold), index of glomerulosclerosis (+58%), and tubulointerstitial (+47%) and vascular damage scores (+19%). Creatinine concentration and the mesangiolysis index remained unchanged. In dTGR, S18886 slightly lowered the blood pressure (162 +/- 15 vs. 149 +/- 13 mm Hg, not significant) and improved proteinuria (558 +/- 218 vs. 136 +/- 71 mg/micromol creatinine, p < 0.01), polyuria and renal morphology (glomerulosclerosis index: 0.79 +/- 0.05 vs. 0.66 +/- 0.13, p < 0.01; tubulointerstitial damage index: 1.82 +/- 0.22 vs. 1.49 +/- 0.27, p < 0.05; mesangiolysis index: 1.31 +/- 0.18 vs. 0.36 +/- 0.09, p < 0.01). Vascular damage score and plasma creatinine were not influenced. S18886 did not alter measured markers of oxidative stress. CONCLUSION: The data present the first evidence that thromboxane receptor inhibition ameliorates angiotensin II-induced nephropathy.