We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to
adenosine in actively sensitised Brown Norway (BN) rats challenged with
ovalbumin (OA). The augmented response is mediated by
5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of
budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl derivative of D-
serine-
cyclosporine,
MLD987, a close analogue of
ascomycin and
SAR943, a
rapamycin derivative, on the hyperresponsiveness to
adenosine induced in actively sensitised BN rats by exposure to
allergen. Bronchoconstrictor responses to
adenosine elicited 3 h following intratracheal (i.t.) instillation of OA, 0.3 mg kg(-1) were reduced dose-dependently by
budesonide, IMM125, and
MLD987, given i.t. 25 and 1 h prior to
allergen challenge. In contrast,
SAR943 had no effect on responses to
adenosine. Responses to
methacholine and
5-HT were minimally affected by these agents. Bronchoconstrictor responses to
bradykinin were dose-dependently reduced by
budesonide, but unaffected following IMM125,
MLD987 or
SAR943 pre-treatment. Challenge with OA at a dose of 0.3 mg kg(-1), induced increases in bronchoalveolar lavage (BAL) fluid, leukocyte numbers,
eosinophil peroxidase (EPO) and
myeloperoxidase (MPO) activities and
protein concentration measured 24 h post challenge.
Budesonide (1 mg kg(-1) given i.t. 25 and 1 h prior to OA challenge) induced reductions in the BAL fluid parameters of
inflammation; IMM125 and
MLD987, at a dose of 1 mg kg(-1) had no significant effect whereas
SAR943 reduced lymphocyte numbers. Thus,
budesonide, IMM125 and
MLD987 block the hyperresponsiveness to
adenosine induced by
allergen challenge in sensitised rats. In the case of
budesonide the effect is associated with a powerful, generalised anti-inflammatory effect although an effect directly on the mast cells is also likely. With IMM125 and
MLD987, the effect is seen at doses that are not anti-inflammatory and may reflect direct suppression of mast cell activation by these agents.