Effects of wortmannin on bronchoconstrictor responses to adenosine in actively sensitised Brown Norway rats

The bronchoconstrictor response to adenosine in the actively sensitised Bro wn 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 th e response to adenosine. Bronchoconstrictor responses to adenosine elicited 3 h following ovalbumin challenge were markedly and dose-dependently reduc ed by wortmannin given intratracheally (i.t.), 1 h prior to or 2 h post-all ergen challenge. Responses to methacholine, which activates bronchial smoot h muscle directly, and 5-HT were also reduced following wortmannin but to a lesser extent than those to adenosine. Bronchoconstrictor responses to ade nosine 3 h post-challenge with vehicle were also markedly reduced by wortma nnin given intratracheally (i.t.), 1 h prior to the "sham" challenge. Plasm a histamine and 5-HT levels increased in response to adenosine given 3 h fo llowing ovalbumin challenge. The increases were suppressed by wortmannin gi ven i.t., 2 h post-ovalbumin challenge. A reduction in the sensitivity of t he airways to 5-HT explains in part the reduced bronchoconstrictor response to adenosine induced by wortmannin. A direct action to suppress 5-HT relea se from airway mast cells induced by adenosine also contributes to the redu ction in the response. Inhibition of phosphatidylinositol-3-kinase is the p resumed mechanistic basis for the observed effects. (C) 2000 Elsevier Scien ce B.V. All rights reserved.