Article date: June 1997
By: Masataka Majima, Noriko Kawashima, Ito Hiroshi, Makoto Katori, in Volume 121, Issue 4, pages 723-730
Effects of an orally active non‐peptide (BK) B2 receptor antagonist, FR173657 ((E)‐3‐(6‐acetamido‐3‐pyridyl)‐ N‐[N‐[2,4‐dichloro‐3‐[(2‐methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl] acrylamide) on the plasma exudation in rat carrageenin‐induced pleurisy were investigated.
Plasma exudation induced by intrapleural injection of bradykinin (BK, 3 nmol per rat) into male SD strain rats (SPF, 8 weeks old) were significantly inhibited by oral administration of novel B2 receptor antagonist FR173657 (3–30 mg kg−1, 1 h before BK injection) in a dose‐dependent manner, whereas that induced by histamine was not.
The inhibitory effect of 30 mg kg−1 FR173657 persisted for more than 4 h.
Intrapleural injection of λ‐carrageenin (2% (w/v), 0.1 ml per rat) caused marked plasma exudation and accumulation of exudates from 1 h after carrageenin injection. The maximum plasma exudation response was observed 5 h after carrageenin. The oral administration of FR173657 to rats (30 mg kg−1, 1 h before carrageenin) significantly (by 50–77%) blunted the plasma exudation 1, 3, 5, and 7 h after carrageenin, causing a significant parallel reduction (by 42–57%) in the volume of exudates.
The anti‐inflammatory effect of FR173657 on rat carrageenin‐induced pleurisy was almost equipotent with that of the peptide B2 antagonist Hoe140 (1 mg kg−1, i.v.), a plasma kallikrein inhibitor, soy bean trypsin inhibitor (0.3 mg per rat, intrapleural injection) and bromelain (10 mg kg−1, i.v.).
In pleurisy induced by intrapleural injection of a histamine releaser, compound 48/80, the plasma exudation was observed only within 20 min after the injection. This plasma exudation was not affected by FR173657, although it was completely inhibited by a mixture of pyrilamine (5 mg kg−1, i.v.) and methysergide (3 mg kg−1, i.v.).
These results indicate that FR173657 is an orally active, promising anti‐inflammatory agent for kinin‐dependent inflammation.
Effects of an orally active non‐peptide (BK) B2 receptor antagonist, FR173657 ((E)‐3‐(6‐acetamido‐3‐pyridyl)‐ N‐[N‐[2,4‐dichloro‐3‐[(2‐methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl] acrylamide) on the plasma exudation in rat carrageenin‐induced pleurisy were investigated.
Plasma exudation induced by intrapleural injection of bradykinin (BK, 3 nmol per rat) into male SD strain rats (SPF, 8 weeks old) were significantly inhibited by oral administration of novel B2 receptor antagonist FR173657 (3–30 mg kg−1, 1 h before BK injection) in a dose‐dependent manner, whereas that induced by histamine was not.
The inhibitory effect of 30 mg kg−1 FR173657 persisted for more than 4 h.
Intrapleural injection of λ‐carrageenin (2% (w/v), 0.1 ml per rat) caused marked plasma exudation and accumulation of exudates from 1 h after carrageenin injection. The maximum plasma exudation response was observed 5 h after carrageenin. The oral administration of FR173657 to rats (30 mg kg−1, 1 h before carrageenin) significantly (by 50–77%) blunted the plasma exudation 1, 3, 5, and 7 h after carrageenin, causing a significant parallel reduction (by 42–57%) in the volume of exudates.
The anti‐inflammatory effect of FR173657 on rat carrageenin‐induced pleurisy was almost equipotent with that of the peptide B2 antagonist Hoe140 (1 mg kg−1, i.v.), a plasma kallikrein inhibitor, soy bean trypsin inhibitor (0.3 mg per rat, intrapleural injection) and bromelain (10 mg kg−1, i.v.).
In pleurisy induced by intrapleural injection of a histamine releaser, compound 48/80, the plasma exudation was observed only within 20 min after the injection. This plasma exudation was not affected by FR173657, although it was completely inhibited by a mixture of pyrilamine (5 mg kg−1, i.v.) and methysergide (3 mg kg−1, i.v.).
These results indicate that FR173657 is an orally active, promising anti‐inflammatory agent for kinin‐dependent inflammation.
British Journal of Pharmacology (1997) 121, 723–730; doi:10.1038/sj.bjp.0701194
DOI: 10.1038/sj.bjp.0701194
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