Activation of cardiac mast cells has been shown to alter parasympathetic neuronal function via the activation of histamine receptors. The present study examined the ability of prostaglandins to alter the activity of guinea pig intracardiac neurons. Intracellular voltage recordings from whole mounts of the cardiac plexus showed that antigen-mediated mast cell degranulation produces an attenuation of the afterhyperpolarization (AHP), which was prevented by the phospholipase A₂ inhibitor, ETYA. Exogenous application of either prostaglandin D₂ (PGD₂) or prostaglandin E₂) (PGE₂) produced a biphasic change in the membrane potential and an inhibition of both AHP amplitude and duration. Examination of prostanoid receptors using bath perfusions (1 µM PGE₂ and PGD₂), specific agonists (BW245C, sulprostone, and butaprost) and antagonists (AH6809 and SC19220) found evidence for both the PGE₂-specific EP2 and EP3 receptors, but not for EP1 or the PGD₂-specific DP receptors. Sulprostone was able to mimic the PGE₂ responses in some cells, but not all PGE₂-sensitive cells. Butaprost was able to mimic the PG-induced hyperpolarization in some cells, but did not alter the AHP. Inhibition of specific potassium channels with either TEA, charybdotoxin or apamin showed that neither TEA nor charybdotoxin could prevent the PGE₂-induced AHP attenuation. Apamin alone inhibited AHP duration, with prostaglandins having no further effect in these cells. These results demonstrate that guinea pig intracardiac neurons can by modulated by prostaglandins, most likely through either EP2, EP3, or potentially EP4 receptors and this response is due, at least in part, to a reduction in small conductance K_Ca currents.