Cyclic nucleotide content of lung tissue is altered by anesthesia, ventilatory pattern, and pharmacologic manipulation (e.g., isoproterenol). In addition the lung releases cyclic nucleotides into its circulation, but little is known about factors that might alter this release. We isolated and perfused rat lungs (IPL) to determine: 1) if cyclic nucleotides are released into the perfusate in the control state; and 2) if their release changes after alteration of the ventilatory pattern or the addition of isoproterenol. We demonstrated that the rat IPL releases both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into the perfusate. Isoproterenol has no effect on cGMP release but increases cAMP release dramatically. Perfusate cAMP is not affected by ventilatory pattern, but perfusate cGMP is higher during high-pressure ventilation than it is in nonventilated or normally ventilated lungs.