Effects of FR173657, a non‐peptide B 2 antagonist, on kinin‐induced hypotension, visceral and peripheral oedema formation and bronchoconstriction
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‐...
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Published in | British journal of pharmacology Vol. 120; no. 5; pp. 933 - 939 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
03.02.2009
|
Online Access | Get full text |
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Summary: | 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 |
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ISSN: | 0007-1188 1476-5381 |
DOI: | 10.1038/sj.bjp.0700966 |