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

被引:24
作者
Griesbacher, T [1 ]
Legat, FJ [1 ]
机构
[1] DEPT DERMATOL & VENEROL,A-8036 GRAZ,AUSTRIA
关键词
bradykinin antagonists; FR173657; blood pressure; hypotension; inflammation; plasma protein extravasation; paw oedema; bronchoconstriction;
D O I
10.1038/sj.bjp.0700966
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 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)oxymethy]phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657), a novel, nonpeptide bradykinin antagonist. 2 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. 3 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. 4 The paw oedema induced by the subplantar injection of bradykinin (30 mmol) in anaesthetized rats was inhibited slightly by s.c. injection of FR173657 0.3 mu mol kg(-1), whereas 1 and 3 mu mol 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 mu mol kg(-1). FR173657 did not effect the oedema caused by histamine or 5-hydroxytryptamine. 5 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 mu mol kg(-1), whereas only 9+/-7% remained after 10 mu mol kg(-1). The bronchoconstrictor actions of histamine remained unaffected by FR173657. 6 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.
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页码:933 / 939
页数:7
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