Studies of mononuclear leukocytes from patients with atopic dermatitis showed depressed cyclic AMP (cAMP) responses after exposure to isoproterenol, histamine, and prostaglandin E1. Because plasma and tissue histamine levels are elevated in atopic dermatitis, we questioned whether histamine or other mediators might be responsible for cAMP abnormalities. We found that exposure of normal cells to low (10(-6)M) concentrations of histamine, isoproterenol, or prostaglandin E desensitized the cells to subsequent stimulatory concentrations of any of the agonists. This heterologous desensitization occurred within 15 min and persisted for days, with gradual recovery of cAMP responses roughly paralleling those of cells from patients with atopic dermatitis. These findings provide a possible explanation for Szentivanyi's beta adrenergic blockade theory and the depressed leukocyte cAMP response to multiple agonists in atopy.