thromboxane-a2 and azelastine

To identify the chemical mediators involved in the pathogenesis of allergic rhinitis, we studied the effects of the thromboxane (TX) A2 receptor antagonist seratrodast, the peptide leukotriene receptor antagonist pranlukast and the antihistamine azelastine using a guinea pig model of allergic rhinitis. In guinea pigs actively sensitized by aerosol inhalation of antigen, antigen challenge into the nasal cavity increased both the nasal vascular permeability and the intranasal pressure; it also induced swelling of the nasal mucosa, which was evaluated by magnetic resonance imaging. Both seratrodast and azelastine significantly inhibited these antigen-induced responses when the drugs were administered p.o. 1 hr before antigen challenge. Also, the TX synthetase inhibitor ozagrel reduced the antigen-induced increase in nasal vascular permeability. On the other hand, pranlukast had little effect on the antigen-induced increases in nasal vascular permeability and intranasal pressure. Perfusions and inhalations of U-46619, a stable TXA2 mimetic, or of histamine into the nasal cavity caused concentration-dependent increases in nasal vascular permeability and intranasal pressure in normal guinea pigs. Leukotriene C4 also induced these responses, but the maximal responses to leukotriene C4 were less than the maximal responses to U-46619 or histamine. On the other hand, these responses were not induced by prostaglandin D2 or prostaglandin F2alpha. Moreover, the U-46619- and histamine-induced increases in vascular permeability and intranasal pressure were significantly inhibited by seratrodast and azelastine, respectively. In addition, levels of TXB2, a stable breakdown product of TXA2, and histamine in nasal lavage fluid increased after antigen challenge in actively sensitized guinea pigs. These results suggest that TXA2 and histamine play important roles in the pathogenesis of experimental allergic rhinitis in guinea pigs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antigens; Benzoquinones; Capillary Permeability; Guinea Pigs; Heptanoic Acids; Histamine; Histamine H1 Antagonists; Male; Nasal Mucosa; Phthalazines; Prostaglandin Antagonists; Prostaglandin Endoperoxides, Synthetic; Rhinitis, Allergic, Seasonal; Thromboxane A2

The effect of the anti-allergic drug azelastine, 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1-(2H)-phth alazione), on airway hyperresponsiveness induced by immunologically stimulated pulmonary alveolar macrophages was investigated in canine bronchial segments under isometric conditions in vitro. Macrophages stimulated with anti-dinitrophenyl immunoglobulin E (IgE) antibody and dinitrophenyl-human serum albumin potentiated the contractile responses to electrical field stimulation at all frequencies, an effect that was abolished by azelastine (3 x 10(-5) M). In contrast, azelastine had no effect on the potentiation of the contractile responses to electrical stimulation by U46619, a thromboxane A2 mimetic. The IgE-mediated release of thromboxane A2 from macrophages was inhibited by azelastine in a concentration-dependent fashion, the maximal decrease and the concentration required to produce a half-maximal effect being 84 +/- 6% (P < 0.001) and 16 microM, respectively. These results suggest that azelastine may attenuate macrophage-induced parasympathetic airway hyperresponsiveness through an inhibition of the release of thromboxane A2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bronchial Hyperreactivity; Dogs; Electric Stimulation; Female; Histamine H1 Antagonists; Immunoglobulin E; In Vitro Techniques; Isometric Contraction; Macrophage Activation; Macrophages, Alveolar; Male; Parasympathetic Nervous System; Phthalazines; Prostaglandin Endoperoxides, Synthetic; Serum Albumin; Synaptic Transmission; Thromboxane A2; Vasoconstrictor Agents