Investigations are reported pertinent to the physiologic relevance of the antagonism between cAMP and cGMP. SV40 transformed SV3T3 fibroblasts are characterized by cAMP and cGMP levels, respectively about half and twice those found in growing untransformed 3T3 cells. Intracellular cGMP concentrations in 3T3 fibroblasts are sensitive to environmental factors which regulate their proliferation. Serum restriction causes increased cAMP and greatly decreased cGMP levels. Reinitiation of growth by serum addition to quiescent fibroblast cultures in medium + 0.5% serum is correlated with early transient increases in cGMP and decreases in cAMP levels. Density dependent inhibition of growth does not significantly affect cAMP whereas cGMP decreases continuously, reaching finally, in confluent monolayers, concentrations about one fifth those found at a density of 106 cells/75 cm2 plate. These responses of cyclic nucleotide concentrations to culture conditions are significantly altered in SV3T3 cells. Their reduced sensitivity to serum deprivation is reflected by a less markedly decreased cGMP and increased cAMP than in untransformed 3T3. The cGMP content of SV3T3 decreases only slightly over the range of cell densities, where the 3T3 line enters a state of density inhibition. The transformed cells grow exponentially up to densities of 30 x 106 cells, when the cultures begin to peel off. Only then did they show a drop in cGMP, with a concomitant decrease in cAMP levels, as reported previously. The data presented are consistent with the hypothesis that cAMP and cGMP act respectively as negative and positive intracellular signals for controlling the growth of cultured cells. Other observations relating transient increases in cGMP, but with little change in cAMP, with stimulation of cell proliferation include the response of fibroblasts to phorbol myristate acetate, a purified fibroblast growth factor, prostaglandin F(2α) and the activation of human lymphocytes hy phytohemagglutinin. ; SCOPUS: ar.j ...