Vol. 280, Issue 3, 1471-1479, 1997

Involvement of Thromboxane A₂ and Histamine in Experimental Allergic Rhinitis of Guinea Pigs

M. Yamasaki, T. Matsumoto, S. Fukuda, T. Nakayama, H. Nagaya and Y. Ashida

Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan

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 F₂. 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.