Suppressive effect of distinct bradykinin B2 receptor antagonist on allergen-evoked exudation and leukocyte infiltration in sensitized rats

Abstract

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.

Figure 1

Inhibition by Hoe 140 (0.1 and 1 μg cavity⁻¹), FR173657 or FR172357 (1 and 10 μg cavity⁻¹) of pleural eosinophil accumulation observed 24 h after allergen (ovalbumin, 12 μg cavity⁻¹) in actively sensitized rats. The antagonists were injected locally 5 min before challenge, as described in Methods. Non-sensitized ovalbumin challenged control group is represented by the dashed line. Results were expressed as the mean±s.e.mean from at least six animals. ^*P<0.001 compared to the allergen-challenged sensitized group.

Figure 2

Effect of Hoe 140 (0.1 and 1 μg cavity⁻¹), FR173657 or FR172357 (1 and 10 μg cavity⁻¹) on reduction in intact mast cell numbers evoked by intrapleural injection of bradykinin (50 μg cavity⁻¹) in naive rats. The analysis was performed 30 min post-challenge and the antagonists were injected locally just 5 min before stimulation. Saline challenged control group is represented by the dashed line. Results were expressed as the mean±s.e.mean from at least six animals. ^*P<0.001 compared to the bradykinin-injected group.

Figure 3

(A) effect of Hoe 140, FR173657 or FR172357 on plasma leakage evoked by intrapleural injection of bradykinin (50 μg cavity⁻¹). Saline challenged control group is represented by the dashed line. (B) effect of Hoe 140 (1 μg cavity⁻¹), FR173657 or FR172357 (10 μg cavity⁻¹) on plasma leakage evoked by intrapleural injection of compound 48/80 (25 μg cavity⁻¹). The analyses were performed 30 min post-challenge and the antagonists locally injected just 5 min before stimulation. Results were expressed as the mean±s.e.mean from at least six animals. ^*P<0.001 compared to the Bradykinin-injected group. †P<0.001 compared to saline-injected group.

Figure 4

Effect of Hoe 140 (1 μg cavity⁻¹), FR173657 or FR172357 (10 μg cavity⁻¹) on eosinophil infiltration induced by intrapleural injection of (A) bradykinin (50 μg cavity⁻¹) or (B) PAF (1 μg cavity⁻¹). The analyses were performed 24 h post-challenge and the antagonists locally injected just 5 min before stimulation. Results were expressed as the mean±s.e.mean from at least six animals. ^*P<0.001 compared to the saline injected group. ⁺P<0.001 compared to the bradykinin injected group.