This investigation was designed to elucidate the effects of hypertonic mannitol on the nonischemic myocardium. In anesthetized open-chest dogs, we collected cardiac lymph for 2 h before and for 4 h during the infusion of hypertonic mannitol or normal saline. We studied the changes in the volume of lymph flow and the release of lysosomal enzyme acid phosphatase and protein into the cardiac lymph. In group 1 (n = 7) and group 3 (n = 8), the effects of 1-h and 4-h infusions of mannitol were studied, respectively. In these dogs, mannitol caused significant rises in lymph flow and release of total acid phosphatase into the cardiac lymph. In group 3, protein efflux increased significantly. In group 2 (n = 5) and group 4 (n = 4), infusion of normal saline for 1 and 4 h did not significantly change the release of total acid phosphatase and proteins into the cardiac lymph. Thus, infusion of hypertonic mannitol for 1--4 h in the nonischemic myocardium may have some deleterious effects because of its apparent ability to impair lysosomal membranes and to increase capillary permeability.