We determined the effect of protein and nonprotein oncotic agents on physiological function and substructural integrity of perfluorochemical emulsion-perfused isolated working rabbit hearts. We used four media that contained Fluosol-43 (FL) emulsion and either 3.4% hydroxyethylstarch (HES), 2.9% albumin, 0.8% HES, or neither HES nor albumin (n = 5 hearts/group). All four groups of hearts had stable function for the first 5.5 h of perfusion; the FL plus albumin hearts continued to exhibit stability in most indexes of function until 9.5 h. The FL plus albumin hearts had a longer total period of ejecting function (12.5 +/- 0.5 h) compared with the other groups (mean longevities = 7.4-8.4 h). Functional stability and longevity correlated with maintenance of coronary flow and coronary vascular resistance. The rates of excess fluid accumulation and creatine kinase leakage were lower in the FL plus albumin hearts than in the other groups. We conclude that: 1) albumin maintained function, coronary flow, and myocardial cell integrity of FL-perfused hearts better than did HES; 2) albumin may exert its effect by preserving capillary permeability, thereby reducing the rate of interstitial fluid accumulation and preventing edema-induced vascular compression; and 3) HES had no effect on cardiac function or integrity and was ineffective in preventing interstitial fluid accumulation when it was used in FL-perfused isolated hearts in the absence of protein.