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Controversies remain whether atrial natriuretic factor (ANF) may play a role in modulating the release of POMC derived peptides from pituitary corticotrophs. Employing AtT-20 mouse pituitary tumour cells, we report here the effects of rat ANF(1–28) and sodium nitroprusside (SNP), both of which augment cellular levels of cGMP through activating particulate and soluble guanylyl cyclases respectively, on the expression of POMC mRNA abundance. Furthermore, the cellular contents and secretion of (beta endorphin-like immunoreactivity) βEP-LI from these cultures were also examined. Whereas the abundance of POMC mRNA was found to be markedly suppressed following 4h of incubation with rANP(1–28) (0.01 to 1 µM), SNP (0.1 to 10 µM) and dibutyryl-cGMP (1 to 100 µM) in a dose related manner, only a modest reduction in the release and cell contents of βEP-LI was found in some of these cultures. It is also of interest to note that in all the cases examined, the inhibitory effect was associated with a significant suppression of cAMP levels in the cultures. Taken together, our present findings suggest that ANF may play a more important role in suppressing the production than the release of POMC related peptides from AtT-20 cells. Thus, it raises the possibility that hypothalamic ANF may likewise modulate the function of the pituitary-adrenal axis through exerting a greater effect on inhibiting the production than the secretion of pituitary ACTH.