icatibant and Pleurisy

The present study investigates some of the mechanisms underlying the inflammatory responses caused by the selective B1 kinin receptor agonist, des-Arg9-bradykinin (des-Arg9-BK), in the rat pleural cavity.. Male Wistar rats were used (N = 4-10 per group).. A fixed volume (100 microl) of PBS or des-Arg9-BK (10-60 nmol) was injected into the rat pleural cavity. Animals were treated with the B1 des-Arg9[Leu8]-BK (60 nmol/cav.) and R715 (65 nmol/cav.), B2 HOE 140 (3 nmol/cav.), NK1 FK888 (1 nmol/cav.), NK2 SR 48968 (20 nmol/cav) or NK3 SR142801 (10 nmol/cav.) receptor antagonists, or with either cyproheptadine (40 mg/kg, i.p.) or compound 48/80 (0.6 mg/kg, i.p., twice a day/3 days, 1.2 mg/kg/4th day).. des-Arg9-BK (30 nmol/cavity) induced a time-dependent leukocyte migration. The increase in total leukocytes was not significantly reduced by the treatment with any of the B1, B2, NK1, NK2 or NK3 receptor antagonists. Treatment of animals with cyproheptadine or with compound 48/80 markedly inhibited des-Arg9-BK-induced cell migration (77 +/- 7 and 82 +/- 4%, respectively).. These findings suggest that inflammatory responses caused by the B1 agonist des-Arg9-BK in the rat pleural cavity are mediated by a receptor-independent mechanism, being largely dependent on the activation of resident mast cells and release of histamine and/or serotonin.

Topics: Animals; Bradykinin; Dose-Response Relationship, Drug; Interleukin-1; Lipopolysaccharides; Male; Mast Cells; Pleurisy; Rats; Rats, Wistar; Receptors, Bradykinin

1. Bradykinin is suggested to play a role in the pathophysiology of several acute and chronic diseases, including allergic disorders such as asthma. In the present study, we have investigated the importance of bradykinin in mediating allergic inflammation in rats. 2. To this end we have tested the effects of the B2 receptor antagonists Hoe 140, FR173657 or FR172357 on the pleural inflammatory response triggered by intrapleural (i.pl.) injection of allergen (ovalbumin, 12 microg cavity(-1)) in 14 day-actively sensitized Wistar rats. Analysis of the pleural fluid effluent revealed a sequence of mast cell-dependent inflammatory events, including early protein exudation and neutrophilia and late pleural eosinophil influx. 3. Local treatment with Hoe 140 (0.1 and 1 microg cavity(-1)), FR173657 (1 and 10 microg cavity(-1)) or FR172357 (1 and 10 microg cavity(-1)) inhibited dose-dependently allergen-induced mast cell activation with impairment of pleural plasma leakage, neutrophil accumulation and late eosinophil influx. 4. Moreover, the B2 receptor antagonists also dose-dependently inhibited the allergic like inflammatory pleurisy triggered by bradykinin (50 microg cavity(-1)), which is characterized by acute mast cell degranulation, protein leakage and pleural eosinophil infiltration. 5. Taken together, our findings provide substantial evidence to suggest that bradykinin acting on its B2 receptors play a critical role in mediating allergic mast cell-dependent inflammation in rats, and suggest that B2 receptor antagonists may be useful therapeutically to control allergic dysfunction.

Topics: Allergens; Animals; Anti-Allergic Agents; Bradykinin; Bradykinin Receptor Antagonists; Cell Degranulation; Exudates and Transudates; Female; Histamine Release; Leukocytes; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Platelet Activating Factor; Pleurisy; Proteins; Quinolines; Rats; Receptor, Bradykinin B2

Bradykinin caused a dose-related increase in cell influx 4 h after its administration into the mouse pleural cavity (ED50 = 3.2 nmol/cav., 95% confidence limits = 0.6-15.5). Cell influx peaked at 4 h and remained elevated for up to 72 h, whereas exudation was detected between 2 and 6 h after bradykinin administration. Both HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7, Oic8]bradykinin) and NPC 17731 (D-Arg0-[Hyp3 D-HypE(transpropyl7)Oic8]bradykinin) inhibited bradykinin-induced cell influx (ID50 0.028 (0.05-0.16) and 0.4 (0.3-0.7) pmol/cav., respectively). Des-Arg9-[Leu8]bradykinin (0.1 and 3.0 nmol/cav., 30 min before) did not inhibit the effects of bradykinin. Pre-treatment of animals with either indomethacin, terfenadine, dexamethasone, N(omega)-nitro-L-arginine benzyl ester, cromolyn, theophylline, salbutamol, FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]N-met hyl-N-phenyl-methyl-3-(2-naphthyl)-L-alaninamide) or SR 142801 ((N)-(1-[3-[1-benzoyl-3-(3,4-dichloro-phenyl)-piperidin-3-yl]pr opy l]-4-phenyl-piperidin-4-yl)-N-methyl-acetamide) significantly inhibited cell migration (P < 0.01). These results indicate that bradykinin had a significant pro-inflammatory effect on the pleural cavity of the mice. This effect seems to be primarily mediated via activation bradykinin B2 receptors which trigger the release of other mediators.

Topics: Animals; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Cell Movement; Dipeptides; Dose-Response Relationship, Drug; Female; Indoles; Inflammation; Leukocyte Count; Male; Mice; Neutrophils; Oligopeptides; Piperidines; Pleura; Pleurisy; Receptor, Bradykinin B2; Time Factors