Acute Renal Effects of Endothelin-A Blockade: Interspecies Differences

The acute renal effects of LU135252 (LU), a selective endothelin-A (ETA) receptor antagonist, were studied in conscious rats after i.p. administration of 1-10 mg/kg LU, and in clearance studies in anesthetized dogs during left intrarenal infusion of 0.01-0.1 mg/kg/min. In the rat (n = 12), LU (10 mg/kg i.p.) decreased diuresis (-36%), excretion of Na (-55%) and Cl (-38%) but not of K and creatinine, as measured in 8-h collections in metabolic cages. Excretion of oral NaCl load (5% of body weight) during 4 h decreased from 68 +/- 2% (vehicle) to 50.5 +/- 5% (LU; n = 12, p < 0.01). Blood pressure was not affected. In contrast, left intrarenal LU infusion at 0.01, 0.03 and 0.1 mg/kg/min in the dog (n = 4) had no effect on renal hemodynamics or excretory function, whereas it mildly decreased blood pressure. In addition, intrarenal LU (0.03 mg/kg/ min; n = 6) had no effect on the renal response to volume expansion (7% bw) by 0.9% NaCl i.v. These markedly different effects of acute ETA blockade were observed at similar systemic plasma levels of LU in the two species. It is concluded that in the rat, but not in the dog, acute blockade of ETA receptors can impair renal excretory function, most likely at the tubule level. This interspecies difference in the role of endogenous ET in the regulation of renal function is probably due to a different ET receptor profile and distribution in rat and dog kidneys.