To study the potential of inflammatory mediators to alter colonic motility, we characterized the response of distal colonic smooth muscle to antigen challenge. Addition of ovalbumin to isolated segments of circular smooth muscle obtained from sensitized guinea pigs produced a biphasic contraction. The initial response consisted of a rapid contraction followed by a late response, which was a more sustained but smaller increase in tone and phasic activity. Interestingly, these two responses could be antagonized differentially. Pretreatment with mepyramine (10 microM) inhibited the initial response, whereas the leukotriene antagonist WY 48252 (10 microM) inhibited the late response. The mast cell stabilizer doxantrazole (0.1 microM) reduced only the late response. Inhibition of cyclooxygenase with meclofenamic acid (1 microM) potentiated both responses, whereas blocking neuronal activity with tetrodotoxin (1 microM) only enhanced the initial response. These data indicate clear differences between the inflammatory mediators important in the initial vs. the late response. The initial response is probably mediated by the release of histamine, with enteric neuronal interactions important in attenuating the magnitude of this response. In contrast, the late response appears to be mediated by the release of peptidyl leukotrienes. In this system, cyclooxygenase products apparently function to decrease the response of the smooth muscle to these mediators. These results suggest that release of mediators during an inflammatory response could profoundly alter colonic motility and that these alterations may be important in the pathophysiological manifestations associated with colonic inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
Studies on the Metabolic Fate of Leukotriene Antagonist ONO-1078. (3). Absorption, Distribution and Excretion after Single Administration to Beagle Dogs.
