Effects on binding characteristics and renal function of the novel, non-peptide angiotensin II antagonist BIBR277 in the rat. 1994

W Wienen, and M Entzeroth
Department of Pharma Research, Dr Karl Thomae GmbH, Biberach, Germany.

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.

UI MeSH Term Description Entries
D007213 Indomethacin A non-steroidal anti-inflammatory agent (NSAID) that inhibits CYCLOOXYGENASE, which is necessary for the formation of PROSTAGLANDINS and other AUTACOIDS. It also inhibits the motility of POLYMORPHONUCLEAR LEUKOCYTES. Amuno,Indocid,Indocin,Indomet 140,Indometacin,Indomethacin Hydrochloride,Metindol,Osmosin
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D008297 Male Males
D010477 Perfusion Treatment process involving the injection of fluid into an organ or tissue. Perfusions
D011945 Receptors, Angiotensin Cell surface proteins that bind ANGIOTENSINS and trigger intracellular changes influencing the behavior of cells. Angiotensin Receptor,Angiotensin Receptors,Angiotensin II Receptor,Angiotensin III Receptor,Receptor, Angiotensin II,Receptor, Angiotensin III,Receptor, Angiotensin
D001794 Blood Pressure PRESSURE of the BLOOD on the ARTERIES and other BLOOD VESSELS. Systolic Pressure,Diastolic Pressure,Pulse Pressure,Pressure, Blood,Pressure, Diastolic,Pressure, Pulse,Pressure, Systolic,Pressures, Systolic
D002216 Captopril A potent and specific inhibitor of PEPTIDYL-DIPEPTIDASE A. It blocks the conversion of ANGIOTENSIN I to ANGIOTENSIN II, a vasoconstrictor and important regulator of arterial blood pressure. Captopril acts to suppress the RENIN-ANGIOTENSIN SYSTEM and inhibits pressure responses to exogenous angiotensin. (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-L-proline,Capoten,Lopirin,SQ-14,225,SQ-14,534,SQ-14225,SQ-14534,SQ 14,225,SQ 14,534,SQ 14225,SQ 14534,SQ14,225,SQ14,534,SQ14225,SQ14534
D004231 Diuresis An increase in the excretion of URINE. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Diureses
D005665 Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for EDEMA and chronic RENAL INSUFFICIENCY. Frusemide,Fursemide,Errolon,Frusemid,Furanthril,Furantral,Furosemide Monohydrochloride,Furosemide Monosodium Salt,Fusid,Lasix
D005919 Glomerular Filtration Rate The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to INULIN clearance. Filtration Rate, Glomerular,Filtration Rates, Glomerular,Glomerular Filtration Rates,Rate, Glomerular Filtration,Rates, Glomerular Filtration

Related Publications

W Wienen, and M Entzeroth
March 1995, Hypertension research : official journal of the Japanese Society of Hypertension,
W Wienen, and M Entzeroth
January 1994, Blood pressure. Supplement,
W Wienen, and M Entzeroth
July 1995, European journal of pharmacology,
W Wienen, and M Entzeroth
October 1996, Biological & pharmaceutical bulletin,
W Wienen, and M Entzeroth
July 1993, Japanese journal of pharmacology,
W Wienen, and M Entzeroth
January 1992, Proceedings of the Western Pharmacology Society,
Copied contents to your clipboard!