Prevention of radiocontrast dye-induced renal hemodynamic changes using a novel endothelin-a receptor antagonist

Administration of radiocontrast agents increases endothelin-1 (ET-1) release and reduces renal blood flow (RBF). The current study examined the effect of a potent (IC50=3.1 nM, [ I]ET-1 binding) and highly selective (ETA/ETB=12,000) small non-peptide ETA receptor antagonist, TBC11241, on acute renal hemodynamic changes following sodium iodothalamate (SI, 5 ml/kg) infusion in the rat. Prior to infusing SI, pentobarbital-anesthetized, male Sprague-Dawley rats (350-400 g) were treated with indomethacin and L-nitroarginine methyl ester (LNAME) (10 mg/kg each) to block prostaglandin and nitric oxide formation, respectively. L-NAME increased mean arterial pressure (MAP, mm Hg) from 153 ±8 (n=9) to 165 ±3 (n=15) and reduced RBF (ml/min) from 4.0 ±0.3 to 2.0 ±0.3). Sixty min after SI infusion, values for MAP and RBF in L-NAME vs. L-NAME+SI groups were 147 ±3 vs. 151 ±3 and 1.7 ±0.3 vs. 1.0 ±0.1, respectively. TBC11241 (20 mg/kg, i.v.) prevented the Si-induced decrease in RBF (1.6 ±0.2) and induced a further fall in MAP (138 ±9). These data indicate that ETA receptors are involved predominantly in mediating decreased RBF following radiocontrast dye infusion in the rat and that highly selective ET_A receptor antagonists may have therapeutic benefit.