Cellular swelling is controlled by an active mechanism of cell volume regulation driven by a Na+/K+-dependent ATPase and by
aquaporins which translocate water along the osmotic gradient. Na+/K+-pump may be blocked by ouabain, a digitalic derivative,
by inhibition of ATP, or by drastic ion alterations of extracellular fluid. However, it has been observed that some tissues are still able
to control their volume despite the presence of ouabain, suggesting the existence of other mechanisms of cell volume control. In
1977, by correlating electron microscopy observation with ion and water composition of liver slices incubated in differentmetabolic
conditions in the presence or absence of ouabain, we observed that hepatocytes were able to control their volume extruding water
and recovering ion composition in the presence of ouabain. In particular, hepatocytes were able to sequester ions and water in
intracellular vesicles and then secrete themat the bile canaliculus pole.We named this “vesicularmechanismof cell volume control.”
Afterward, thismechanism has been confirmed by us and other laboratories in several mammalian tissues.This review summarizes
evidences regarding this mechanism, problems that are still pending, and questions that need to be answered. Finally, we shortly
review the importance of cell volume control in some human pathological conditions