The effects of adenine nucleotides and adenosine on DNA synthesis and cell growth have been studied in bovine aortic endothelial cells (BAECs). ATP produced a small but significant (+44%) increase of the fraction of BAECs whose nuclei are labeled by [3H]thymidine. This mitogenic effect was mimicked by ADP, the phosphorothioate analogues ATPγS and ADPβS, and the nonhydrolyzable analogue adenosine 5'-(β,γ-imido)triphosphate (APPNP), whereas adenosine 5'-(α,β-methylene)triphosphate (APCPP), a selective agonist of P2x-purinoceptors, had no effect at 10 μM and a small one at 100 μM; this profile is consistent with the involvement of P2y-receptors. Adenosine induced a mitogenic response of a magnitude similar to that of ATP. This effect was not reproduced byR-phenylisopropyl adenosine, by 5'-N-ethylcarboxamide adenosine, or by 2',5'-dideoxyadenosine, selective ligands of the A1- and A2-receptors and the P site, respectively, nor was it inhibited by 8-phenyltheophylline, an antagonist of both A1- and A2-receptors. The mechanism of this adenosine action thus remains unclear. ATP and ATPγS did not enhance the proliferation of BAECs cultured in the presence of fetal calf serum concentrations ranging from 0.5% to 10%. They inhibited the growth-promoting effect of basic fibroblast growth factor; among the various nucleotides tested, APCPP was the least effective to reproduce the action of ATP, suggesting the possible involvement of P2y-receptors. In conclusion, the action of ATP on the proliferation of BAECs is complex: an increase in the fraction of cells synthesizing DNA, no effect on the cell proliferation in the presence of serum, and inhibition of the growth-promoting effect of basic fibroblast growth factor.