Elevated nasal mucosal G protein levels and histamine receptor affinity in a guinea pig model of nasal hyperresponsiveness.
BACKGROUND
Nasal hyperresponsiveness is a common feature of allergic rhinitis, but the underlying mechanisms have yet to be elucidated. The effects of repeated antigen inhalation on the characteristics of histamine H(1) receptors and expression levels of heterotrimeric guanosine 5'-triphosphate-binding proteins in nasal mucosa were investigated to understand the mechanisms of the pathogenesis of nasal hyperresponsiveness in allergic rhinitis.


METHODS
Male Hartley guinea pigs were sensitized by the inhalation of dinitrophenylated ovalbumin antigen (10 mg of protein/ml) and repeatedly challenged by inhaling aerosolized dinitrophenylated ovalbumin antigen for 3 weeks. Twenty-four hours after the last antigen inhalation, in vivo nasal responsiveness to histamine was measured. [(3)H]Mepyramine binding assays and immunoblotting for alpha subunits of the G(q) protein were also performed using membrane preparations of isolated nasal mucosae.


RESULTS
The histamine-induced increase in intranasal pressure was significantly augmented after repeated antigen challenge, indicating that nasal hyperresponsiveness was achieved. In saturation binding studies, no significant change was observed in the density and antagonist affinity of H(1) receptors in the hyperresponsive animals. On the other hand, the affinity of histamine for high-affinity agonist binding sites in the hyperresponsive group, measured by histamine competition binding studies, was much greater than that in control animals, and these results were affected by guanosine 5'-O-(3-thiotriphosphate) in both groups. Moreover, Galpha(q) levels in nasal mucosal homogenates were significantly increased after repeated antigen challenge.


CONCLUSIONS
Elevated G protein levels in nasal mucosa might induce an increased binding affinity of histamine to its receptors, resulting in an augmented nasal response to histamine, that is, nasal hyperresponsiveness, in guinea pigs.
Chiba
Yoshihiko
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. chiba@hoshi.ac.jp
Saitoh
Nobuyuki
N
Matsuo
Kensuke
K
Misawa
Miwa
M
D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive; D015153:Blotting, Western; D004195:Disease Models, Animal; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000276:immunology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D020962:Heterotrimeric GTP-Binding Proteins / Q000032:analysis / Q000276:immunology; D006632:Histamine / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D008297:Male; D009297:Nasal Mucosa / Q000276:immunology* / Q000378:metabolism; D011738:Pyrilamine / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology*
D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006632:Histamine; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D011738:Pyrilamine