Ischemic preconditioning or phosphodiesterase inhibition improves lung protection during prolonged hypothermic storage. In ischemic preconditioning of cat lungs, adenosine A1 receptor antagonism was suggested as a possible mechanism. Some phosphodiesterase inhibitors (such as theophylline) are also adenosine antagonists; we showed theophylline to be particularly effective in protecting lungs. In isolated, perfused and ventilated rat lungs, we examined (1) whether synergy exists between phosphodiesterase inhibition and ischemic preconditioning and (2) whether theophylline acts both to inhibit phosphodiesterase and block adenosine receptors, by comparing its effects with enprofylline (selective phosphodiesterase inhibition) or xanthine amine congener (selective adenosine A1 receptor antagonism). In Study 1, rolipram (added to St Thomas' cardioplegia) or ischemic preconditioning before hypothermic storage (8 h) did not improve lung function during reperfusion (40 min); a combination of these treatments was also ineffective. In Study 2, lungs stored in St Thomas' cardioplegia containing enprofylline or theophylline had improved recovery of function compared to control lungs; however, xanthine amine congener was without effect. Thus, no interaction exists between phosphodiesterase inhibition and ischemic preconditioning. Adenosine A1 receptor antagonism plays no role in protecting rat lungs from the effects of prolonged hypothermic storage by either preconditioning or addition of theophylline to the storage solution.