ABSTRACT
BACKGROUND AND PURPOSE: Bradykinin, through its B(2) receptor, is involved in inflammatory processes related to arthropathies. In carrageenan and lipopolysaccharide (LPS)-induced arthritis in rat, the anti-inflammatory activity of MEN16132, a potent and selective kinin B(2) receptor antagonist, was compared with that of steroidal and nonsteroidal anti-inflammatory drugs. The interaction between MEN16132 and dexamethasone was also investigated. EXPERIMENTAL APPROACH: Drugs, alone or in combination, were injected into the knee joint 30min before intra-articular administration of carrageenan or LPS, in pentobarbital anaesthetized rats. Effects on incapacitation, oedema, neutrophil recruitment and kallikrein system activation, in the knee joint, were assessed. KEY RESULTS: MEN16132 and dexamethasone (10-300µg per knee) dose-dependently reduced carrageenan-induced joint pain, oedema and neutrophil infiltration, reaching a maximal inhibition of about 50%. Dexketoprofen exerted a similar analgesic activity, whereas it did not affect the other inflammatory responses. MEN16132 showed a partial inhibition of LPS-induced joint pain, whereas dexamethasone produced a full analgesic effect. Combination of MEN16132 and dexamethasone showed a strong synergistic interaction in inhibiting both carrageenan and LPS-induced knee joint inflammation. Dexamethasone did not prevent the contact activation of prekallikrein by carrageenan and the subsequent release of kallikreins and bradykinin in the synovium. CONCLUSIONS AND IMPLICATIONS: Steroids and kinin B(2) receptor antagonists appear to relieve arthritic symptoms induced by carrageenan or LPS and act synergistically to inhibit joint inflammation. This could have interesting therapeutic implications, possibly opening the way for combination therapies in the control of inflammatory arthropathies.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Bradykinin B2 Receptor Antagonists , Dexamethasone/pharmacology , Ornithine/analogs & derivatives , Sulfonamides/pharmacology , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/metabolism , Bradykinin/metabolism , Carrageenan , Drug Synergism , Injections, Intra-Articular , Kallikreins/blood , Knee Joint , Lipopolysaccharides , Male , Ornithine/pharmacology , Peroxidase/metabolism , Rats , Rats, Wistar , Receptor, Bradykinin B2/metabolismABSTRACT
1. The effect of montelukast or MEN91507, selective leucotriene CysLT1 receptor antagonists, on antigen-induced airway inflammation and bronchoconstriction were compared in anaesthetized guinea-pigs. 2. In sensitized animals, ovalbumin (0.3 mg kg(-1), i.v.)-induced microvascular leakage in trachea, intrapulmonary airways, total lung (parenchyma and intrapulmonary airways) and urinary bladder was reduced by MEN91507 (0.01-1 micromol kg(-1), i.v.), whereas montelukast (0.01-1 micromol kg(-1), i.v.) antagonized the effect of the antigen only in the lung and urinary bladder. 3. Ovalbumin (1 mg kg(-1), i.v.)-induced bronchoconstriction was dose dependently antagonized by MEN91507 (10-30 micromol kg(-1), i.v.), whereas the effect of montelukast (0.1-30 micromol kg(-1), i.v.) was marginal (15-30% inhibition). Neither MEN91507 nor montelukast (30 micromol kg(-1), i.v.) affected the bronchoconstrictor response induced by acetylcholine (0.3 micromol kg(-1), i.v.) in sensitized animals. 4. It is concluded that montelukast and MEN91507 display a differential activity against the effect of endogenous leucotrienes, despite the fact that both compounds show a similar antagonist profile against exogenous leucotrienes acting through CysLT1 receptors.
