Involvement of thromboxane A2 and peptide leukotrienes in early and late phase nasal blockage in a guinea pig model of allergic rhinitis.
OBJECTIVE
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.


METHODS
Male Hartley guinea pigs were used.


METHODS
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Yamasaki
M
M
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Osaka, Japan. Yamasaki_Masashi@takeda.co.jp
Mizutani
N
N
Sasaki
K
K
Nabe
T
T
Matsumoto
T
T
Ashida
Y
Y
Kohno
S
S
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D015289:Leukotrienes / Q000502:physiology*; D008297:Male; D009296:Nasal Cavity / Q000473:pathology; D015508:Nasal Obstruction / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy / Q000503:physiopathology*; D012912:Sneezing; D016593:Terfenadine / Q000494:pharmacology; D007507:Therapeutic Irrigation; D013928:Thromboxane A2 / Q000502:physiology*
D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D002867:Chromones; D006538:Heptanoic Acids; D015289:Leukotrienes; C060230:seratrodast; D013928:Thromboxane A2; D016593:Terfenadine; D003907:Dexamethasone; D006632:Histamine; C047681:pranlukast