We investigated the effects of hyperosmolar solutions on human ether-a-go-go related gene (hERG) potassium currents in chinese hamster ovary (CHO) cells. The addition of d-mannitol to the external solution caused cell shrinkage and reduced current amplitude. The effects were at least partially reversible. Exposure to 108 mM mannitol decreased current amplitude by 57+/-13%. Major effects on current-voltage relations were not observed. Exposure to 308 mM mannitol reduced the current by 89+/-5%, i.e. comparable to the block induced by 1 microM of the selective hERG channel blocker E-4031. We conclude that the investigation of hyperosmolar drug formulations requires control solutions of comparable osmolarity to separate specific drug effects from non-specific effects of hyperosmolarity.