W Wienen1, M Entzeroth. 1. Department of Pharma Research, Dr Karl Thomae GmbH, Biberach, Germany.
Abstract
OBJECTIVE: To characterize the interaction of BIBR277, a new angiotensin II (Ang II) type 1 receptor (AT1)-selective antagonist, with rat renal Ang II receptors and to investigate its effects on renal function in vitro and in vivo. METHODS: The binding characteristics of BIBR277 in the rat kidney were evaluated in [125I]-Ang II displacement and autoradiographic studies. Renal function was assessed in vitro in the isolated, constant-pressure perfused rat kidney and in vivo in anaesthetized rats. RESULTS: In rat kidney cortical membrane preparations BIBR277 binds to a single population of Ang II receptors, which are of the AT1 subtype. In autoradiographic studies specific [125I]-(Sar1,Ile8)-Ang II binding to the rat kidney glomeruli, renal cortex and medulla was completely inhibited by 1 mumol/l BIBR277. In isolated rat kidneys BIBR277 (0.01, 0.1 and 1 mumol/l) increased perfusate flow, urinary flow and glomerular filtration rate concentration-dependently by 115, 130 and 112% of the control value, respectively. This effect was not blocked in the presence of indomethacin (10 mumol/l). Frusemide (10 mumol/l) increased urinary flow in the isolated kidney to about 140% of the control value. The diuretic effect of frusemide was significantly increased to 180 and 200% of the control value in the presence of 0.1 and 1.0 mumol/l BIBR277, respectively. Captopril (10 mumol/l) had no effect on perfusate flow, urinary flow or glomerular filtration rate, and did not increase frusemide-induced diuresis in this preparation. BIBR277 was also administered intravenously to anaesthetized rats at doses of 0.1, 0.3 and 1 mg/kg. BIBR277 had no effect on the heart rate, but decreased the blood pressure significantly at both higher doses. At the 0.3 mg/kg dose, the urinary flow and sodium excretion increased significantly (twofold and 2.47-fold, respectively) compared with the vehicle-treated group, but not increase in the urinary flow and sodium excretion was observed at the highest dose. Urinary potassium excretion was not significantly affected at all doses. CONCLUSIONS: These results show that BIBR277 potently interacts with rat renal AT1 receptors. BIBR277 shows diuretic effects both in vitro and in vivo. In anaesthetized rats BIBR277 also promotes sodium excretion without affecting potassium excretion.
OBJECTIVE: To characterize the interaction of BIBR277, a new angiotensin II (Ang II) type 1 receptor (AT1)-selective antagonist, with rat renal Ang II receptors and to investigate its effects on renal function in vitro and in vivo. METHODS: The binding characteristics of BIBR277 in the rat kidney were evaluated in [125I]-Ang II displacement and autoradiographic studies. Renal function was assessed in vitro in the isolated, constant-pressure perfused rat kidney and in vivo in anaesthetized rats. RESULTS: In rat kidney cortical membrane preparations BIBR277 binds to a single population of Ang II receptors, which are of the AT1 subtype. In autoradiographic studies specific [125I]-(Sar1,Ile8)-Ang II binding to the rat kidney glomeruli, renal cortex and medulla was completely inhibited by 1 mumol/l BIBR277. In isolated rat kidneys BIBR277 (0.01, 0.1 and 1 mumol/l) increased perfusate flow, urinary flow and glomerular filtration rate concentration-dependently by 115, 130 and 112% of the control value, respectively. This effect was not blocked in the presence of indomethacin (10 mumol/l). Frusemide (10 mumol/l) increased urinary flow in the isolated kidney to about 140% of the control value. The diuretic effect of frusemide was significantly increased to 180 and 200% of the control value in the presence of 0.1 and 1.0 mumol/l BIBR277, respectively. Captopril (10 mumol/l) had no effect on perfusate flow, urinary flow or glomerular filtration rate, and did not increase frusemide-induced diuresis in this preparation. BIBR277 was also administered intravenously to anaesthetized rats at doses of 0.1, 0.3 and 1 mg/kg. BIBR277 had no effect on the heart rate, but decreased the blood pressure significantly at both higher doses. At the 0.3 mg/kg dose, the urinary flow and sodium excretion increased significantly (twofold and 2.47-fold, respectively) compared with the vehicle-treated group, but not increase in the urinary flow and sodium excretion was observed at the highest dose. Urinary potassium excretion was not significantly affected at all doses. CONCLUSIONS: These results show that BIBR277 potently interacts with rat renal AT1 receptors. BIBR277 shows diuretic effects both in vitro and in vivo. In anaesthetized ratsBIBR277 also promotes sodium excretion without affecting potassium excretion.