Effects of the ETA/ETB antagonist, TAK-044, on blood pressure and renal excretory function after unclipping of conscious one-kidney-one-clip hypertensive rats

Background Restoring renal perfusion pressure (unclipping) of one-kidney-on e-clip renal hypertensive (1K1C) rats normalizes mean arterial pressure (MA P) rapidly, This has been attributed to salt/volume losses or release of th e putative renal medullary depressor hormone (RMDH), Objective To investigate the effects of endothelin receptor A and B (ETA/ET B) antagonism on unclipping. Design and methods Telemetric devices were implanted in male Wistar 1K1C ra ts for measurement of conscious MAP. Hypertension was reversed by unclippin g with the animal under brief anaesthesia, Seven rats were treated with the ETA/ETB antagonist, TAK-044 (two doses of 10 mg/kg intraperitoneally in 24 h), and eight rats received its vehicle. In order to investigate whether e ndothelin receptor antagonism could release RMDH under resting conditions, TAK-044 was administered to telemetered nonclipped intact and chemically re nal medullectomized rats (BEA treatment). Results TAK-044 did not affect resting MAP, urine flow or sodium excretion in 1K1C rats. However, after unclipping, the TAK-044-treated group showed a more marked reduction in MAP during the first 24 h after unclipping (P < 0 .01). TAK-044 also reduced urine flow and sodium excretion during the first 8 h after unclipping (P < 0.05), TAK-044 reduced resting MAP (P < 0.05) to a similar extent in intact and BEA rats. Conclusions TAK-044 potentiated the reduction in MAP after unclipping, inde pendently of changes in urine flow and sodium excretion. it also reduced MA P in normotensive rats - an effect that was not dependent on an intact rena l medulla, Potentiation of the depressor response to unclipping by TAK-044 could be the result of an interaction of endogenous endothelin receptors wi th renal depressor mechanisms - possibly, the release, actions, or both, of the putative RMDH.