Mechanism of airway hyperresponsiveness to adenosine induced by allergen challenge in actively sensitized Brown Norway rats.
1. We have explored the role of allergen sensitization and challenge in defining the response of the airways of the Brown Norway (BN) rat to adenosine. 2. In naïve animals or in rats sensitized to ovalbumin (OA) adenosine induced only weak bronchoconstrictor responses. Challenge of sensitized animals with OA induced a marked airway hyperresponsiveness to adenosine which was not seen with methacholine or bradykinin. 3. The augmented bronchoconstrictor response to adenosine was not affected by acute bivagotomy or atropine nor mimicked by an i.v. injection of capsaicin. It was, however, blocked selectively by disodium cromoglycate methysergide or ketanserin and reduced in animals treated sub-chronically with compound 48/80. 4. The augmented response to adenosine was associated with increases in the plasma concentrations of both histamine and 5-hydroxytryptamine (5-HT), which were attenuated by pretreatment with disodium cromoglycate, and degranulation of mast cells in the lung. 5. Parenchymal strips from lungs removed from sensitized rats challenged with OA gave augmented bronchoconstrictor responses to adenosine relative to strips from sensitized animals challenged with saline. Responses were inhibited by methysergide and disodium cromoglycate. 6. These data demonstrate a marked augmentation of the bronchoconstrictor response to adenosine in actively sensitized BN rats challenged with OA. The augmented response is primarily a consequence of mast cell activation, leading to the release of 5-HT, which in turn induces bronchoconstriction. Our data further suggest the involvement of a discrete lung-based population of mast cells containing and releasing mainly 5-HT and brought into play by prior exposure to allergen.
Research Department, Novartis Pharma AG, CH-4002 Basel, Switzerland.
J P
JP
Hannon
B
B
Tigani
I
I
Williams
L
L
Mazzoni
J R
JR
Fozard
D000241:Adenosine / Q000494:pharmacology*; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects; D015550:Cell Degranulation; D004205:Cromolyn Sodium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000097:blood; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000502:physiology; D016210:Methacholine Chloride / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000503:physiopathology*; D012701:Serotonin / Q000097:blood / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D014628:Vagotomy; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D000485:Allergens; D016085:Bronchoconstrictor Agents; D012702:Serotonin Antagonists; D014662:Vasoconstrictor Agents; D016210:Methacholine Chloride; D012701:Serotonin; D003189:p-Methoxy-N-methylphenethylamine; D001285:Atropine; D006632:Histamine; D010047:Ovalbumin; D007650:Ketanserin; D000241:Adenosine; D004205:Cromolyn Sodium; D002211:Capsaicin; D001920:Bradykinin; D008784:Methysergide