Idiopathic reactions occurring during the infusion of hyperosmolar solutions, such as radiocontrast dyes, cause a significant number of deaths each year. These reactions are similar to those which follow mediator release during allergen-induced anaphylaxis. In attempting to explain these nonimmunologic reactions, we examined the direct effect of hyperosmolarity on normal human basophils with emphasis on release induced by mannitol. The cells of all donors released histamine in vitro in response to hyperosmolar (0.2-0.7 M) solutions of a number of solutes including mannitol. That this was not a toxic process was supported by a number of criteria, including inhibition of release by excess stimulus at 37 degrees C and a lack of release at 4 degrees C. Furthermore, electron microscopic studies revealed that hyperosmolar stimulation did not disrupt the cell membrane or lead to any signs of cytotoxicity. In contrast to antigen-stimulated release, where granules fuse only with the cell membrane, granules in mannitol-stimulated cells, in addition to fusing with the cell membrane, may also be extruded into a common intracellular sac before exteriorization. Characteristics similar to antigen-induced histamine release included the time-course for release, inhibition by drugs that modify phospholipid metabolism, p-bromophenacyl bromide, and eicosa-5,8,11,14-tetraynoic acid, and augmentation of release by deuterium oxide (D(2)O). The release process differed from antigen-induced release by a number of criteria, including independence from immunoglobulin (Ig)E-related mechanisms, insensitivity to agonists that elevate intracellular cyclic AMP, minimal dependence on extracellular calcium, lack of inhibition by 2-deoxyglucose and theophylline, and a temperature optimum of 32 degrees C. We conclude that this noncytotoxic hyperosmolar release process is different from IgE-mediated secretory events and may well play a role in the idiopathic reactions which occur secondary to the infusion of hyperosmolar solutions in man.