A model has been developed which allows an isolated lung to be perfused by a blood-PSS solution continuously processed by an intact animal. This model combines the advantage of control of the isolated perfused lung with a recirculated perfusate that is physiologically maintained. Substances that are generated by the isolated lung are, therefore, removed by metabolism in the intact animal and essential consumables in the perfusate are restored. Studies were performed in rabbits utilizing isolated perfused lung both with and without the intact animal processing the perfusate. The greatest pressor responses to hypoxic ventilation are obtained with a non-processed recirculated perfusate circuit, but the pressor responses decrease with time (12.5 +/- 1.7 cmH2O to 8.2 +/- 1.3 cmH3O) and the baseline pressure is higher initially (18.5 +/- 0.7 mmH2O). With the whole animal in the circuit, the baseline pressure and the initial hypoxic pressor responses are not as large, but are maintained constant (6.8 +/- 0.5 cmH2O to 8.1 +/- 1.0 cmH2O) over the same time period. When the isolated lungs are perfused with either blood-PSS or PSS in a non-processed, non-recirculated system, the hypoxic responses are 8.7 +/- 1.7 cmH2O and 5.7 +/- 1.0 cmH2O at the beginning of the study and decrease with time to 6.5 +/- 1.3 cmH2O and 4.2 +/- 1.0 cmH2O, respectively. The response of the isolated lung is, therefore, more stable with time and shows less individual variability when the whole animal perfusion circuit is employed.