Increased levels of cyclic adenosine monophosphate contribute to the hyporesponsiveness of mast cells in alloxan diabetes.

In this study, we investigated the influence of intracellular cyclic adenosine monophosphate (cAMP) changes on the rat mast cell hyporesponsiveness following immunological and non-immunological stimuli. Compared with mast cells from normal rats, those recovered from 21-day diabetic animals showed a significant augmentation in the intracellular levels of cAMP, in directly correlated with secretion of lower amounts of histamine after stimulation with antigen, bradykinin and compound 48/80 in vitro. Incubation of normal mast cells with selective inhibitors of phosphodiesterase type 4 (PDE 4) rolipram, NCS 613 and RP 73401, or the cell permeable analogue N6-2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (db cAMP), led to a decrease of histamine secretion in vitro. However, the effectiveness of either NCS 613 or db cAMP in inhibiting antigen-induced degranulation is comparable in both normal and diabetic mast cells. We suggest that (a) there is a close correlation between higher levels of intracellular cAMP and hyporesponsiveness of diabetic mast cells, phenomena probably associated with a reduction in the expression and/or activity of PDE 4 and that (b) the mechanism of cAMP-mediated down-regulation of mast cell function is saturated in diabetic rats. Copyright 2004 Elsevier B.V.