Effects of FR173657, a non‐peptide B 2 antagonist, on kinin‐induced hypotension, visceral and peripheral oedema formation and bronchoconstriction

• Published in: British journal of pharmacology Vol. 120; no. 5; pp. 933 - 939
• Main Authors: Griesbacher, Thomas, Legat, Franz J
• Format: Journal Article
• Language: English
• Published: 03.02.2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0700966

Kinins are believed to play a key role in many inflammatory conditions. Therefore, bradykinin antagonists are being developed for potential therapeutic applications. In the present investigation we describe the pharmacology, in vivo , of (E)‐3‐(6‐ acetamido‐ 3‐pyridyl)‐ N‐[N‐ [2,4‐ dichloro‐ 3‐[(2‐ methyl‐8‐ quinolinyl)oxymethyl]phenyl]‐ N‐methylaminocarbonylmethyl]acrylamide (FR173657), a novel, non‐peptide bradykinin antagonist. The hypotensive effects of i.v. injections of bradykinin (50 pmol) in captopril‐pre‐treated anaesthetized rats were significantly inhibited by 100 nmol kg −1 FR173657 s.c., and completely abolished by 300 nmol kg −1 . The full inhibitory effect developed within 60 min and remained unchanged for at least 4 h. However, the effect was reversible, since 24 h after an injection of 300 nmol kg −1 FR173657 no inhibitory effect could be observed. The plasma protein extravasation into the pancreas and duodenum induced by an i.v. infusion of bradykinin (11 nmol kg −1 within 20 min) in captopril‐treated anaesthetized rats was completely abolished by FR173657 at doses of 30 nmol kg −1 s.c. and above, given 60 min before bradykinin. FR173657 3 nmol kg −1 was ineffective, while a dose of 10 nmol kg −1 produced an intermediate effect. The paw oedema induced by the subplantar injection of bradykinin (30 nmol) in anaesthetized rats was inhibited slightly by s.c. injection of FR173657 0.3 μmol kg −1 , whereas 1 and 3 μmol kg −1 produced significant inhibition of the bradykinin‐induced oedema. The maximum inhibition amounted to about 50% and could not be increased even when the dose of FR173657 was increased to 30 μmol kg −1 . FR173657 did not effect the oedema caused by histamine or 5‐hydroxytryptamine. Bradykinin (20 nmol kg −1 , i.v.) caused increases in pulmonary inflation pressure by 300–600 Pa in anaesthetized, respirated guinea‐pigs. The effect was reduced to 58±9% of the initial value 60 min after the s.c. injection of FR173657 1 μmol kg −1 , whereas only 9±7% remained after 10 μmol kg −1 . The bronchoconstrictor actions of histamine remained unaffected by FR173657. In summary, FR173657 is a highly potent and selective bradykinin antagonist. The inhibitory action in vivo lasts for longer than 4 h but is fully reversible. FR173657, or similar compounds, will be a useful tool for the pharmacological investigation of pathophysiological states and may possess a therapeutic potential in diseases involving the endogenous release of kinins. British Journal of Pharmacology (1997) 120 , 933–939; doi: 10.1038/sj.bjp.0700966