Ruthenium red (RR) is an inorganic dye that has shown to block the actions of capsaicin on primary sensory neurons in different animal models. The aim of this study was to assess whether RR is able to antagonize the release of vasoactive intestinal polypeptide (VIP) evoked by capsaicin in the human colon. Samples of descending colon were collected from patients undergoing colectomy for carcinoma of the colon. Tissue slices from the muscle of human colon were exposed to either 10 microM capsaicin or an isotonic high K+ medium (KCl 80 mM), in the absence or presence of 10 microM RR. Either capsaicin or high K+ produced a prompt release of VIP. RR (10 microM) completely antagonized the capsaicin-induced release of VIP from muscle of human colon. This effect was elective, since VIP release evoked by high K+ was unaffected by the presence of RR. These findings indicate that RR acts as a selective antagonist of capsaicin in human tissue and that the mechanism underlying peptide release by capsaicin is preserved across species. Multiple mechanisms leading to VIP release exist in the human colon.