The effect of methacholine, theophylline, and cyclic adenyl and guanyl nucleotides on gastric secretion from antral and proximal duodenal mucosa of the guinea pig was studied. Both 2 mM dibutyryl (db) cAMP and 5 mM theophylline produced significant increases in gastrin secretion, 4.3 +/- 0.7 (P less than 0.001) and 9.3 +/- 2.4 pg mg-1 min-1 (P less than 0.005) respectively, above basal gastrin secretion (1.5 +/- 0.4 pg mg-1 min-1). The combined effect of the two agents was additive (14.5 +/- 3.6 pg mg-1 min-1). Db cGMP (2 mM) had no effect on gastrin secretion. Methacholine produced a dose-related increase in gastrin secretion which at maximum equaled the combined effect of theophylline and db cAMP. The results suggest that gastrin secretion is mediated in part by intracellular cAMP but do not exclude a cooperative involvement of cGMP.