The model of the isolated, vascularly perfused rat colon was assessed in the present study to investigate the nervous, hormonal, and local/paracrine pathways involved in colonic mucin secretion. A colonic loop was perfused via the superior mesenteric artery with a Krebs-Henseleit buffer containing 25% washed bovine erythrocytes at a rate of 2.5 ml/min. After a 10-min control period, each compound to be tested was infused intra-arterially for 30 min. Tissue samples from the proximal and midsegments of the perfused rat colon were then fixed and stained for mucus cell count. Intra-arterial administration of bethanechol evoked a concentration-dependent decrease in the number of stained mucus cells per crypt section over the range 2•10-6 to 2•10-4M: 16.6 ± 1.4 stained mucus cells per crypt in the midportion of the perfused rat colon (n = 5) with bethanechol 2•10-4 M versus 28.8 ± 1.5 for controls (n = 6). After infusion of 1.25 and 2.5 μM 16,16-dimethyl prostaglandin E2 (dmPGE2), the number of stained mucus cells per crypt section was significantly reduced: 21.6 ± 0.6 (n = 6) and 20.6 ± 1.4 (n = 7), respectively. An increase in the number of cavitated mucus cells was also observed (22.1 ± 6.7 and 38.5 ± 4.1 % of cavitated mucus cells in the midsegment of the perfused rat colon with 1.25 and 2.5 μM dmPGE2, respectively, vs. 12.3 ± 4.1 % for controls). In contrast, prostaglandin F2α did not significantly affect mucus discharge from colonic cells. Peptide YY (10-10, 10-9 and 10-8M) induced a dose-dependent increase in the percentage of cavitated mucus cells (16.7 ± 2.8, 23.1 ± 4.2, and 31.2 ± 3.4% of cavitated mucus cells in the midsegment, respectively). The proximal and midsegments of the perfused rat colon were equally sensitive to each secretagogue. Conclusion: In the isolated, vascularly perfused rat colon, mucus cells strongly respond to the well-known mucin secretagogues, bethanechol and dmPGE2. This approach has already led to the identification of a novel stimulant of mucin secretion: peptide YY. Our ex vivo model, in which goblet cells are submitted to well-defined luminal and blood-borne stimuli is, therefore, reliable to investigate the nervous, hormonal, and local/paracrine pathways involved in the colonic mucin secretion.