Involvement of Thromboxane A₂ in Antigen-Induced Nasal Blockage in Guinea Pigs

Abstract

To estimate the involvement of thromboxane (Tx) A₂ in the onset of nasal blockage, we examined the effect of the selective TxA₂ receptor antagonist, S-1452, as well as an H₁-antihistamine, diphenhydramine, on the antigen-induced increase in intranasal pressure, as an index of nasal blockage, in anesthetized guinea pigs actively sensitized by inhalation of aerosolized ovalbumin (OA). Oral administration of S-1452 or intravenous administration of diphenhydramine significantly but incompletely reduced the increase in intranasal pressure following exposure of the nasal cavity of guinea pigs to aerosolized OA. In combination, the two agents were more effective than either alone, but there was no significant difference between them. The TxB₂ level was significantly elevated in nasal lavage fluid 15 and 30 min after antigen challenge. Exposure of the nasal cavity of guinea pigs to aerosolized U-46619, a TxA₂ mimetic, also resulted in a marked increase in intranasal pressure, and this could be almost completely suppressed by S-1452. These findings suggest that TxA₂ contributes to antigen-induced nasal blockage in guinea pigs.

Inhibitory Effect of a TP-Receptor Antagonist, S-1452, on Antigen-Induced Nasal Plasma Exudation in Guinea Pig Model for Allergic Rhinitis

“…When orally administered to guinea pigs 2 h before antigen exposure, S-1452 significantly inhibited antigeninduced plasma exudation into both the nasal mucosa and nasal airway lumen. In this model, we have reported that the level of TxB 2 was significantly elevated in nasal lavage fluid after antigen exposure [11]. These findings suggest that TxA 2 is involved in antigen-induced nasal plasma exudation in this model.…”

“…Therefore, we examined the involvement of histamine in antigen-induced nasal plasma exudation, using an H 1 -antihistamine, diphenhydramine. Intravenous administration of diphenhydramine (5 mg/kg) 5 min before antigen exposure markedly suppressed dye exudation into the nasal mucosa and nasal lavage fluid with the percent inhibition of about 80-90%, indicating that histamine, as well as TxA 2 , acts as a major mediator for inducing nasal plasma exudation, but does not for increasing intranasal pressure [11], following antigen challenge in this guinea pig model. These pharmacological studies showing the marked suppression of the antigen-induced nasal plasma exudation by either S-1452 or diphenhydramine further suggest that TxA 2 and histamine synergistically cause increase in vascular permeability, i.e., TxA 2 may contribute to nasal plasma exudation via enhancing vascular permeability caused by histamine as well as via directly inducing plasma exudation.…”

“…The present animal study was approved by Shionogi Animal Use and Care Committee. The animals were sensitized to ovalbumin (OA) twice, 1 week apart, by inhalation of an aerosolized solution of 1% OA dissolved in sterile 0.9% saline as described previously [11]. The OA aerosol was generated with an ultrasonic nebulizer (NE-U12; Omron, Tokyo, Japan), and guinea pigs were made to inhale it by being placed in an exposure chamber for 10 min.…”

“…The nasal challenge was performed according to our previous report [11]. Briefly, 7-10 days after the second sensitization, guinea pigs were anesthetized with sodium pentobarbital (30 mg/kg, i.p.)…”

“…Recently, we demonstrated that the selective TP-receptor antagonist S-1452 [8][9][10] inhibited antigen-induced increase in intranasal pressure, which was used as an index of nasal blockage [11]. In addition, U-46619, a TxA 2 mimetic, could induce an increase in intranasal pressure in actively sensitized guinea pigs and this response was completely suppressed by S-1452 [11]. These results sug-gest that TxA 2 is involved in antigen-induced nasal blockage in actively sensitized guinea pigs.…”