We studied the role of cGMP in nitric oxide (NO)-induced changes in lung liquid production (J_v) in chronically instrumented fetal sheep. Forty-five studies were done in which J_v was measured by a tracer dilution technique. Left pulmonary arterial flow (Q_lpa) was measured by a Doppler flow probe. There were two series of experiments. In the first, we gave 8-bromo-cGMP, a cGMP analog, by either the pulmonary vascular or intraluminal route; in the second, we used agents to inhibit or enhance endogenous cGMP activity. When infused directly into the pulmonary circulation, 8-bromo-cGMP significantly increased Q_lpa but had no effect on J_v. Conversely, when instilled into the lung liquid, 8-bromo-cGMP had no effect on Q_lpa but significantly reduced J_v. Inhibition of guanylate cyclase activity with methylene blue totally blocked, whereas phosphodiesterase inhibition with Zaprinast significantly enhanced, the effect of instilled NO on J_v. Thus the reduction in lung liquid caused by NO appears to be mediated by cGMP, perhaps through a direct effect on the pulmonary epithelium.