BACKGROUND: Restoring renal perfusion pressure (unclipping) of one-kidney-one-clip renal hypertensive (1 K1C) rats normalizes mean arterial pressure (MAP) rapidly. This has been attributed to salt/volume losses or release of the putative renal medullary depressor hormone (RMDH). OBJECTIVE: To investigate the effects of endothelin receptor A and B (ET(A)/ET(B)) antagonism on unclipping. DESIGN AND METHODS: Telemetric devices were implanted in male Wistar 1K1C rats for measurement of conscious MAP. Hypertension was reversed by unclipping with the animal under brief anaesthesia. Seven rats were treated with the ET(A)/ET(B) antagonist, TAK-044 (two doses of 10 mg/kg intraperitoneally in 24 h), and eight rats received its vehicle. In order to investigate whether endothelin receptor antagonism could release RMDH under resting conditions, TAK-044 was administered to telemetered non-clipped intact and chemically renal 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, independently of changes in urine flow and sodium excretion. It also reduced MAP in normotensive rats--an effect that was not dependent on an intact renal medulla. Potentiation of the depressor response to unclipping by TAK-044 could be the result of an interaction of endogenous endothelin receptors with renal depressor mechanisms--possibly, the release, actions, or both, of the putative RMDH.
BACKGROUND: Restoring renal perfusion pressure (unclipping) of one-kidney-one-clip renal hypertensive (1 K1C) rats normalizes mean arterial pressure (MAP) rapidly. This has been attributed to salt/volume losses or release of the putative renal medullary depressor hormone (RMDH). OBJECTIVE: To investigate the effects of endothelin receptor A and B (ET(A)/ET(B)) antagonism on unclipping. DESIGN AND METHODS: Telemetric devices were implanted in male Wistar 1K1C rats for measurement of conscious MAP. Hypertension was reversed by unclipping with the animal under brief anaesthesia. Seven rats were treated with the ET(A)/ET(B) antagonist, TAK-044 (two doses of 10 mg/kg intraperitoneally in 24 h), and eight rats received its vehicle. In order to investigate whether endothelin receptor antagonism could release RMDH under resting conditions, TAK-044 was administered to telemetered non-clipped intact and chemically renal 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, independently of changes in urine flow and sodium excretion. It also reduced MAP in normotensive rats--an effect that was not dependent on an intact renal medulla. Potentiation of the depressor response to unclipping by TAK-044 could be the result of an interaction of endogenous endothelin receptors with renal depressor mechanisms--possibly, the release, actions, or both, of the putative RMDH.