Effects of endothelin in radiocontrast-induced nephropathy in rats are mediated through endothelin-A receptors.

Abstract

A role for endothelin in the pathogenesis of radiocontrast-induced nephropathy has been suggested by several studies, but the specific contributions of endothelin-A and endothelin-B receptors to the changes in renal function induced by endothelin in this form of renal failure have not been defined. This study examined the effects of the nonselective endothelin receptor antagonist SB-209,670, and the less potent, but selective, endothelin-A receptor antagonist BMS-182,874 in radiocontrast-induced nephropathy in rats. The doses used in this study were chosen from pressor testing data. BMS-182,874 (100 mumol/kg, iv) and SB-209,670 (30 mumol/kg, iv) maximally inhibited the endothelin-1-induced pressor response in rats. BMS-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 BMS-182,874, and an endothelin-A/B inhibitory dose of SB-209,670. Radiocontrast-induced nephropathy was produced in anesthetized rats (N = 6/group) by intravenous injection of indomethacin (5.0 mg/kg), the nitric oxide synthesis inhibitor N-nitro-L-arginine methyl ester (10.0 mg/kg), vehicle or antagonist, and the radiocontrast agent lopamidol (2,9 g iodine/kg). GFR was partially protected (P < 0.05) by BMS-182,874 (-43 +/- 3.0% change from baseline) compared with vehicle (-65 +/- 6.0%). The decrease in GFR in SB-209,670-treated rats that received lopamidol was intermediate between the other two groups. The fall in RPF induced by lopamidol was unchanged by either antagonist. The marked diuresis in lopamidol treated rats (630 +/- 125.1%) was reduced (P < 0.01) by BMS-182,874 (176 +/- 77.1%) or SB-209,670 (173 +/- 60.1%). Kidneys were collected for histopathologic evaluation approximately 1 h after lopamidol 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 significantly decreased in the BMS-182,874- or SB-209,670-treated rats (P < 0.01) compared with vehicle plus lopamidol-treated animals. In summary, endothelin-A receptor blockade with a highly selective, well-characterized endothelin-A receptor antagonist partly protected GFR, and reduced the marked diuresis and mTAL necrosis in radiocontrast-induced nephropathy in rats. Administration of a nonselective endothelin receptor antagonist provided essentially equivalent ameliorative effects in this model, suggesting that blockade of endothelin-B receptors did not yield any additional protection. These results are consistent with the hypothesis that endothelin-A receptors mediate endothelin-induced changes in renal function and structure in this acute model of radiocontrast-induced nephropathy.