Changes in intracellular and extracellular rat mast cell c[cyclic]AMP concentrations during stimulation of histamine release by compound 48/80 [p-methoxyphenethyl methylamine formaldehyde product] were studied. There was a rapid and progressive fall in intracellular cAMP beginning within 10 sec after the addition of compound 48/80. The lowest cAMP values were obtained at 10 min, with return to control levels by 30 min. The fall in cAMP was dose-related with progressive decreases in 10 min cAMP measurements as the compound 48/80 concentration was increased from 0.25-1.00 .mu.g/ml. There was a graded increase in histamine release over the same concentration range. Attempts to demonstrate significant amounts of cAMP in the medium during compound 48/80 stimulation were unsuccessful, indicating that the changes in cAMP intracellularly are not due to altered cellular permeability. There was a general correlation between the ability of pharmacologic agents to sustain high intracellular levels of cAMP in the presence of compound 48/80, and inhibition of histamine release. Theophylline (20 mM) which increased cAMP levels 2-3-fold prevented a detectable decrease in cAMP after 1 .mu.g/ml compound 48/80 (measured at 10 min) and almost completely inhibited histamine release. Prostaglandin E1 (27 .mu.M) also raised cAMP levels, decreased the compound 48/80-induced fall in cAMP (by 31%), and partially inhibited histamine release (by 42%). Epinephrine increased mast cell cAMP levels, but did not prevent the subsequent compound 48/80-induced decrease in cAMP and did not inhibit histamine release. Carbamyl-choline (1 nM), adenine (1 .mu.M), and diazoxide (10 .mu.M) lowered mast cell cAMP and potentiated compound 48/80 induced release. In view of previous studies indicating that compound 48/80 stimulates mast cell phosphodiesterase, it seems likely that the compound 48/80-induced fall in cAMP is due, at least in part, to increased cAMP destruction. Since agents which prevent the fall in cAMP inhibit histamine release, it is apparent that cAMP is an important part of the control mechanism of histamine secretion. It cannot be concluded that a decrease in cAMP alone is sufficient to produce a response since carbamylcholine, diazoxide and adenine, which lower cAMP, do not alter histamine release unless compound 48/80 is also present.