Effects of an orally active non-peptide bradykinin B2 receptor antagonist, FR173657, on plasma exudation in rat carrageenin-induced pleurisy.
1. 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-quinoli nyl) oxymethyl]phenyl]-N-methylaminocarbonylmethyl] acrylamide) on the plasma exudation in rat carrageenin-induced pleurisy were investigated. 2. 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. 3. The inhibitory effect of 30 mg kg-1 FR173657 persisted for more than 4 h. 4. Intrapleural injection of lambda-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. 5. 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.). 6. 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.). 7. These results indicate that FR173657 is an orally active, promising anti-inflammatory agent for kinin-dependent inflammation.
Majima
M
M
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
Kawashima
N
N
Hiroshi
I
I
Katori
M
M
D000818:Animals; D065168:Bradykinin Receptor Antagonists; D002351:Carrageenan; D005079:Excipients; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D010996:Pleural Effusion / Q000517:prevention & control; D010998:Pleurisy / Q000139:chemically induced / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2
D065168:Bradykinin Receptor Antagonists; D005079:Excipients; C105311:FR 173657; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D002351:Carrageenan