Effects of wortmannin on bronchoconstrictor responses to adenosine in actively sensitised Brown Norway rats.
The bronchoconstrictor response to adenosine in the actively sensitised Brown Norway rat is markedly augmented following low level allergen (ovalbumin) challenge. The response reflects activation of the A(2B) receptor subtype and is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of wortmannin, a potent inhibitor of phosphatidylinositol-3-kinase and mast cell exocytosis, on the response to adenosine. Bronchoconstrictor responses to adenosine elicited 3 h following ovalbumin challenge were markedly and dose-dependently reduced by wortmannin given intratracheally (i. t.), 1 h prior to or 2 h post-allergen challenge. Responses to methacholine, which activates bronchial smooth muscle directly, and 5-HT were also reduced following wortmannin but to a lesser extent than those to adenosine. Bronchoconstrictor responses to adenosine 3 h post-challenge with vehicle were also markedly reduced by wortmannin given intratracheally (i.t.), 1 h prior to the "sham" challenge. Plasma histamine and 5-HT levels increased in response to adenosine given 3 h following ovalbumin challenge. The increases were suppressed by wortmannin given i.t., 2 h post-ovalbumin challenge. A reduction in the sensitivity of the airways to 5-HT explains in part the reduced bronchoconstrictor response to adenosine induced by wortmannin. A direct action to suppress 5-HT release from airway mast cells induced by adenosine also contributes to the reduction in the response. Inhibition of phosphatidylinositol-3-kinase is the presumed mechanistic basis for the observed effects.
Tigani
B
B
Research Department, Novartis Pharma AG, 4002, Basel, Switzerland.
Hannon
J P
JP
Mazzoni
L
L
Fozard
J R
JR
D000241:Adenosine / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006632:Histamine / Q000097:blood; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D011914:Rats, Inbred BN; D012701:Serotonin / Q000097:blood / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016210:Methacholine Chloride; D012701:Serotonin; D006632:Histamine; D010047:Ovalbumin; D000241:Adenosine; D000077191:Wortmannin