Effects of an orally active non‐peptide bradykinin B2 receptor antagonist, FR173657, on plasma exudation in rat carrageenin‐induced pleurisy

Abstract

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