Renal haemodynamic effects of endothelin-1 and the ETA/ETB antagonist TAK-044 in anaesthetized rabbits

Objective The aim of this study was to test the effects of exogenous endoth elin-1 (ET-1) on regional kidney blood flow and renal function, and the ren al 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 m in, 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 extracorp oreal circuit was established to adjust renal arterial pressure (RAP) indep endently of systemic arterial pressure (MAP). RAP was set at 65 mmHg, and e ither 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 ( RBFprobe; 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 o r on the contralateral kidney were observed. TAK-044 dose-dependently rever sed the effects of ET-1 on RBFprobe end cortical perfusion. TAK-044 also re duced MAP (by up to 11 +/- 3%) and increased effective renal blood flow in the contralateral kidney (by up to 46 +/- 27%). In the extracorporeal circu it model, TAK-044 decreased MAP by 12 +/- 2% and RAP by 10 +/- 3%, and incr eased RBF by 9 +/- 3%. Conclusion Exogenous ET-1 reduces cortical more than medullary perfusion, a nd 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. J H ypertens 1998, 16:1897-1905 (C) 1998 Lippincott Williams & Wilkins.