EFFECTS ON BINDING CHARACTERISTICS AND VENAL FUNCTION OF THE NOVEL, NONPEPTIDE ANGIOTENSIN-II ANTAGONIST BIBR-277 IN THE RAT

Objective: To characterize the interaction of BIBR277, a new angiotens in II (Ang II) type 1 receptor (AT(1))-selective antagonist, with rat renal Ang II receptors and to investigate its effects on renal functio n in vitro and in vivo. Methods: The binding characteristics of BIBR27 7 in the rat kidney were evaluated in [I-125]-Ang II displacement and autoradiographic studies. Renal function was assessed in vitro in the isolated, constant-pressure perfused rat kidney and in vivo in anaesth etized rats. Results: In rat kidney cortical membrane preparations BIB R277 binds to a single population of Ang II receptors, which are of th e AT(1) subtype. in autoradiographic studies specific [I-125]-(Sar(1), Ile(8))-Ang II binding to the rat kidney glomeruli, renal cortex and m edulla was completely inhibited by 1 mu mol/l BIBR277. In isolated rat kidneys BIBR277 (0.01, 0.1 and 1 mu mol/l) increased perfusate flow, urinary flow and glomerular filtration rate concentration-dependently by 115, 130 and 112% of the control value, respectively. This effect w as not blocked in the presence of indomethacin (10 mu mol/l). Frusemid e (10 mu mol/l) increased urinary flow in the isolated kidney to about 140% of the control value. The diuretic effect of frusemide was signi ficantly increased to 180 and 200% of the control value in the presenc e of 0.1 and 1.0 mu mol/l BIBR277, respectively. Captopril (10 mu mol/ l) had no effect on perfusate flow, urinary flow or glomerular filtrat ion rate, and did not increase frusemide-induced diuresis in this prep aration. 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 he art rate, but decreased the blood pressure significantly at both highe r 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 no increase in the urinary flow a nd sodium excretion was observed at the highest dose. Urinary potassiu m excretion was not significantly affected at all doses. Conclusions: These results show that BIBR277 potently interacts with rat renal AT(1 ) receptors. BIBR277 shows diuretic effects both in vitro and in vivo. In anaesthetized rats BIBR277 also promotes sodium excretion without affecting potassium excretion.