This in vitro study tested the hypothesis that muscularis mucosae contractile activity contributes to rabbit colonic mucosal function by mechanisms other than simple mechanical deformation of the epithelium. Experiments were performed using a technique that allows simultaneous recording of muscle activity and transmucosal potential difference, a measure of epithelial ion transport. ATP, bradykinin, histamine, PGs E2, F1 and F2 elicited muscularis mucosae contractions that were atropine-and TTX-resistant. Only ATP-induced contractions were indomethacin-sensitive and only those to DMPP were reduced by atropine. All agonist-evoked increases in transmucosal potential difference were atropine-resistant and, with the exception of those to PGE2, PGF2 and VIP, they were also TTX-sensitive. Mucosal responses to ATP, bradykinin and histamine were indomethacin-sensitive while those to DMPP, the prostaglandins and VIP were not. When cyclooxygenase activity or the mucosal innervation was compromised even maximal muscularis mucosae contractions did not produce large secretory responses. It is concluded that contraction-related prostaglandin synthesis and non-cholinergic secretomotor neuron stimulation represent the physiological transduction mechanism through which muscularis mucosae motor activity is translated into mucosal secretion.