title: Increased levels of cyclic adenosine monophosphate contribute to the hyporesponsiveness of mast cells in alloxan diabetes.
abstract: 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.
authors.affiliation: Laboratory of Inflammation, Physiology and Pharmacodynamics Department, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, no 4365, Manguinhos, Rio de Janeiro, CEP 21045-900, Brazil.
authors.forename: Emiliano O
authors.initials: EO
authors.lastname: Barreto
authors.forename: Vinicius F
authors.initials: VF
authors.lastname: Carvalho
authors.forename: Vincent
authors.initials: V
authors.lastname: Lagente
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
authors.forename: Renato S B
authors.initials: RS
authors.lastname: Cordeiro
authors.forename: Marco A
authors.initials: MA
authors.lastname: Martins
authors.forename: Patrícia M R
authors.initials: PM
authors.lastname: E Silva
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D000941:Antigens / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004140:Dinitrophenols / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007073:Immunoglobulin E / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010994:Pleura / Q000166:cytology / Q000187:drug effects; D051381:Rats; D020889:Rolipram / Q000494:pharmacology; D013268:Stimulation, Chemical; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: D000941:Antigens; D004140:Dinitrophenols; D010726:Phosphodiesterase Inhibitors; D007073:Immunoglobulin E; D003189:p-Methoxy-N-methylphenethylamine; D003994:Bucladesine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D001920:Bradykinin