Renal haemodynamic effects of endothelin-1 and the ET(A)/ET(B) antagonist TAK-044 in anaesthetized rabbits

Objective. The aim of this study was to test the effects of exogenous endothelin-1 (ET-1) on regional kidney blood flow and renal function, and the renal haemodynamic effects of endogenous ET, in anaesthetized rabbits. Methods. ET-1 was infused into the left renal artery at 2 ng/kg/min for 30 min, then at 1 ng/kg/min. Cumulative doses of TAK-044 (0.1-3 mg/kg, i.v.) or its vehicle were given at 30-min intervals. In other rabbits, an extracorporeal circuit was established to adjust renal arterial pressure (RAP) independently of systemic arterial pressure (MAP). RAP was set at 65 mmHg, and either TAK-044 (3 mg/kg, i.v.) or its vehicle was administered. Results. In the infused kidney ET-1 (2 ng/kg/min) reduced renal blood flow (RBF(probe); 52 ± 8%), cortical perfusion (37 ± 7%), glomerular filtration rate (GFR; 49 ± 8%), urine flow (47 ± 14%) and sodium excretion (49 ± 13%), but not medullary perfusion (5 ± 6%). No effects of ET-1 on MAP or on the contralateral kidney were observed. TAK-044 dose-dependently reversed the effects of ET-1 on RBF(probe) and cortical perfusion. TAK-044 also reduced MAP (by up to 11 ± 3%) and increased effective renal blood flow in the contralateral kidney (by up to 46 ± 27%). In the extracorporeal circuit model, TAK-044 decreased MAP by 12 ± 2% and RAP by 10 ± 3%, and increased RBF by 9 ± 3%. Conclusion. Exogenous ET-1 reduces cortical more than medullary perfusion, and reduces GFR without affecting net tubular sodium and fluid reabsorption. TAK-044 antagonizes local renal vascular responses to ET-1. Endogenous ETs appear to contribute markedly to resting renal vasomotor tone and MAP.