EFFECTS OF ENDOTHELIN IN RADIOCONTRAST-INDUCED NEPHROPATHY IN RATS ARE MEDIATED THROUGH ENDOTHELIN-A RECEPTORS

A role for endothelin in the pathogenesis of radiocontrast-induced nep hropathy has been suggested by several studies, but the specific contr ibutions of endothelin-A and endothelin-B receptors to the changes in renal function induced by endothelin in this form of renal failure hav e not been defined. This study examined the effects of the nonselectiv e endothelin receptor antagonist SB-209,670, and the less potent, but selective, endothelin-A receptor antagonist BMS-182,874 in radiocontra st-induced nephropathy in rats. The doses used in this study were chos en from presser testing data. EMS-182,874 (100 mu mol/kg, iv) and SB-2 09,670 (30 mu mol/kg, iv) maximally inhibited the endothelin-l-induced presser response in rats. EMS 182,874 had no effect on the endothelin -B-mediated depressor response, whereas SB-209,670 abolished it. These results suggest that this is an endothelin-A selective dose of BEMS-1 82,874, and an endothelin-A/B inhibitory dose of SB-209,670. Radiocont rast-induced nephropathy was produced in anesthetized rats (N = 6/grou p) by intravenous injection of indomethacin (5.0 mg/kg), the nitric ox ide synthesis inhibitor N-nitro-L-arginine methyl ester (10.0 mg/kg), vehicle or antagonist, and the radiocontrast agent iopamidol (2.9 g io dine/kg). GFR was partially protected (P < 0.05) by BMS-182,874 (-43 /- 3.0% change from baseline) compared with vehicle (-65 +/- 6.0%). Th e decrease in GFR in SB-209,670-treated rats that received iopamidol w as intermediate between the other two groups. The fall in RPF induced by iopamidol was unchanged by either antagonist. The marked diuresis i n lopamidol-treated rats (630 +/- 125.1%) was reduced (P < 0.01) by BM S-182,874 (176 +/- 77.1%) or SB-209,670 (173 +/- 60.1%). Kidneys were collected for histopathologic evaluation approximately 1 h after iopam idol administration, and the percentage of medullary tubular ascending limbs (mTAL) with morphologic features of necrosis were enumerated by semiquantitative analysis. The percentage of mTAL necrosis was signif icantly decreased in the BMS-182,874- or SB-209,670-treated rats (P < 0.01) compared with vehicle plus iopamidol-treated animals. In summary , endothelin-A receptor blockade with a highly selective, well-charact erized endothelin-A receptor antagonist partly protected GFR, and redu ced the marked diuresis and mTAL necrosis in radiocontrast-induced nep hropathy in rats. Administration of a nonselective endothelin receptor antagonist provided essentially equivalent ameliorative effects in th is model, suggesting that blockade of endothelin-B receptors did not y ield any additional protection. These results are consistent with the hypothesis that endothelin-A receptors mediate endothelin-induced chan ges in renal function and structure in this acute model of radiocontra st-induced nephropathy.