thromboxane-a2 and Nasal-Obstruction

Although thromboxane (TX)A2 is involved in allergic rhinitis, the mechanisms inducing nasal blockage have not been elucidated. We evaluated the roles of nasal mucosal vascular changes following intranasal instillation of the TXA2 analog U-46619 or leukotriene (LT)D4 to induce nasal blockage in a guinea pig model of allergic rhinitis. Both U-46619- and LTD4-induced nasal blockages in sensitized animals were swiftly and completely suppressed by a vasoconstrictor, naphazoline. The nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester relieved LTD4-induced nasal blockage, but not U-46619-induced nasal blockage. Although both agonists produced vasodilatation of nasal mucosa in vivo, LTD4 caused vasodilatation while U-46619 caused vasoconstriction in vitro. Both LTD4- and U-46619-induced nasal blockages in vivo should depend on vasodilatation of nasal mucosa. LTD4-induced nasal blockage is induced by direct vasodilatation via nitric oxide. In contrast, U-46619-induced nasal blockage may be associated with contraction of a certain vein that should exist at the exit of capacitance vessels, leading to congestion of the nasal mucosa.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Blood Vessels; Disease Models, Animal; Drug Synergism; Guinea Pigs; Leukotriene D4; Male; Models, Biological; Naphazoline; Nasal Mucosa; Nasal Obstruction; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phenylephrine; Pollen; Rhinitis, Allergic, Seasonal; Thromboxane A2

We investigated the effects of the thromboxane (TX) A2 antagonist seratrodast, the peptide leukotriene (p-LT) antagonist pranlukast, the antihistaminic drug terfenadine and the glucocorticoid dexamethasone on antigen-induced sneezing, biphasic nasal blockage and nasal hyperresponsiveness to histamine using a guinea pig model of allergic rhinitis.. Male Hartley guinea pigs were used.. Intranasally sensitized guinea pigs were challenged once every week for 13 weeks by inhalation of Japanese cedar pollen as the antigen. Dexamethasone and other agents were administered orally 3 and 1 h, respectively, before the 4th, 6th and 13th challenge.. Sneezing frequency and the change in specific airway resistance (sRaw) were measured at these challenges. Two days after the 13th challenge, nasal responsiveness to histamine was evaluated by measuring sRaw after intranasal instillation of increasing doses of histamine. Moreover, the levels of TXB2, p-LTs and histamine were estimated in nasal cavity lavage fluid (NCLF) collected at the 13th challenge.. Only terfenadine (10 mg/kg) significantly inhibited sneezing at any challenge time. Seratrodast (3 and 10 mg/ kg), pranlukast (30 mg/kg) and dexamethasone (10 mg/kg), but not terfenadine, suppressed both the early and late phase elevation of sRaw (biphasic nasal blockage), although the degree of inhibition on the early phase response varied with the challenge time. In contrast, the development of nasal hyperresponsiveness to histamine was inhibited by only dexamethasone. Furthermore, biphasic increases in TXB2, p-LTs and histamine in NCLF were observed after the challenge in sensitized animals.. These results suggest that TXA2 and p-LTs, but not histamine, play important roles in both the early and the late phase nasal blockage in this model of allergic rhinitis.

Topics: Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Benzoquinones; Chromones; Dexamethasone; Guinea Pigs; Heptanoic Acids; Histamine; Histamine Release; Leukotrienes; Male; Nasal Cavity; Nasal Obstruction; Rhinitis, Allergic, Seasonal; Sneezing; Terfenadine; Therapeutic Irrigation; Thromboxane A2

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Antigens; Bridged Bicyclo Compounds; Diphenhydramine; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Male; Nasal Obstruction; Ovalbumin; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Thromboxane B2

Thromboxane A2 (TxA2) seems to play an important role in bronchial constriction and hypersensitivity in asthmatics. To study the role of TxA2 in allergic rhinitis, we investigated the levels of thromboxane B2 (TxB2), a stable metabolite of TxA2, in nasal lavage fluid from patients with allergic rhinitis and from actively sensitized guinea pigs after antigen challenge by radioimmunoassay (RIA). There was a significant (p < 0.05) rise in TxB2 levels soon after antigen challenge in nasal lavage fluid from both patients (36.4 +/- 7.5 pg/ml, mean +/- SE) and models (55.6 +/- 21.8 pg/ml). In some of the patients and models, there was an dual rise in TxB2 in the 10 hours after antigen challenge. There was a significant (p < 0.03) correlation between the patients whose levels of TxB2 were re-elevated and them whose nasal airway resistance showed dual rises. These results suggest that TxA2 may contribute to the nasal obstruction in later phase in allergic rhinitis.

Topics: Adult; Animals; Antigens; Disease Models, Animal; Female; Guinea Pigs; Humans; Male; Nasal Lavage Fluid; Nasal Obstruction; Radioimmunoassay; Rhinitis, Allergic, Perennial; Thromboxane A2; Thromboxane B2