Female Wistar rats exposed for 1–9 days to chronic hypobaric hypoxia (440 Torr or 4,250 m altitude) showed a significant increase of 3H-thymidine incorporation into the DNA of hypoxic lungs that was preceded by a lag phase (24 h of hypoxia). The maximum increase of the 3H-thymidine incorporation rate after 9 days of hypoxia was 351%, reflecting increased DNA synthesis and subsequent cell proliferation during hypoxia. Simultaneously determined cAMP demonstrated a significant rise and a plateau-like elevation during the first 3 days of hypoxic exposure, whereas cGMP lagged behind the increase in lung cAMP concentration. Additionally, a rise in the endogenous acetylcholine (Ach) of lung tissue in the course of chronic hypoxia was demonstrated. Tissue levels of Ach and cGMP were highly correlated. A significant correlation was obtained between lung DNA synthesis rate and cGMP/cAMP ratio. These data support the concept that chronic hypoxia stimulates lung DNA synthesis and that the increase in DNA synthesis, suggesting cellular proliferation, is associated with or mediated by alterations of cAMP and cGMP. In particular, the early predominance of cAMP may reflect a state of increased adrenergic activity, and the delayed rise of Ach and cGMP may be due to an increased parasympathetic stimulation.The cyclic nucleotides (cAMP and cGMP) are important components of an internal signaling system which regulates the activity of most cells [2] and mediates the cell response to a wide range of stimuli [8, 16]. Acute hypoxia stimulates the v. Euler-Liljestrand mechanism, resulting in pulmonary vascular constriction [5] and concomitant changes of the lung tissue cGMP/cAMP ratio that are closely related to the time course of the pulmonary vascular resistance [12]. Chronic hypoxia in its initial stage leads to a strong increase of the lung tissue DNA synthesis reflecting marked cell proliferation [24]. Acetylcholine (Ach) has been known to be a potent vasodilator of the pulmonary vasculature [6, 14], and recent evidence has been accumulated that parasympathetic stimulation can turn on mitosis [18]. Thus, a kinetic study with simultaneous determination of cyclic nucleotides, Ach and DNA synthesis was considered, to elucidate the effects of the stimulus of chronic hypoxia.