The effect of selective phosphodiesterase (PDE) inhibitors was studied on neural transmission within the enteric nervous system employing a two-compartment bath (containing the oral and the anal end of a segment of guinea-pig ileum, respectively). Ascending excitatory enteric nerve pathways were activated by electrical field stimulation (10 Hz for 2 s, 45 mA, 0.5 pulse duration) in the anal compartment and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded. The partitioned bath enables PDE inhibitors and other drugs to be applied to enteric nerve pathways (in the anal compartment) without interfering with the recording of the smooth muscle contraction in the oral compartment. The PDE 4 inhibitors rolipram (0.01-10 microM) and Ro-20-1724 (0.01-10 microM) significantly (P<0.01) inhibited (10-91% and 9-83%, respectively) the nerve-mediated contractions. When both rolipram and Ro-20-1724 were tested after phentolamine (1 microM) or yohimbine (0.1 microM), they were significantly (P<0.01) less effective. By contrast prazosin (1 microM) was ineffective. Vinpocetine (50 microM), milrinone (30 microM) and zaprinast (100 microM), which inhibit PDE 1, 3 and 5, respectively, did not modify the nerve-mediated contractions. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cyclic AMP) or N6,2'-O-dibutyryladenosine 3',5' cyclic monophosphate (dibutyryl cyclic AMP), two analogues of cyclic AMP, at lower concentrations (0.1-1 microM) significantly (P<0.01) inhibited (15-73% and 5-49%, respectively) the nerve-mediated contractions, while at higher concentrations (10-100 microM) they caused a significant (P<0.01) potentiating (48-68% and 77-78%, respectively) effect. These results indicate that inhibition of PDE 4 (but not PDE 1, PDE 3 or PDE 5) produces a depression of neural transmission within the enteric nervous system, possibly by releasing noradrenaline acting at alpha2-adrenoceptors on enteric neurons.