Isolated rat and guinea pig hearts show, during perfusion with aequeous salt solutions, myocardial edema formation of different degree. The extent of tissue fluid accumulation is dependent on the species, the osmolality, and the oxygen partial pressure of the perfusion medium. With increasing edema formation there is, in both species, an increasing energy requirement for the same hemodynamic state. Addition of 50 mM mannitol to the perfusion medium can diminish edema of the hypoxic perfused rat heart and improves the myocardial function during hypoxia. The beneficial effect of hyperosmolality in the isolated hypoxic rat heart is discussed in terms of an improvement of myocardial energy balance and coronary microcirculation.