INHIBITORY NEUROTRANSMISSION IN LETHAL SPOTTED MUTANT MICE - A MODEL FOR HIRSCHSPRUNGS-DISEASE

Background & Aims: The pathogenesis of Hirschsprung's disease is not w ell understood. The suitability of the animal model for the unknown pa thogenesis of inhibitory neurotransmission in Hirschsprung's disease w as investigated. Methods: Circular smooth muscle strips from the inter nal anal sphincter (IAS) and distal colon (2, 6, 8, 16, and 24 mm from the anal verge) from normal and Ls/Ls mice (mice homozygous for the l ethal spotting mutation that develop fetal megacolon after aganglionos is of the terminal colon) were prepared to record changes in isometric tensions in response to different agents and nonadrenergic, noncholin ergic nerve stimulation by electrical field stimulation. Results: Beth anechol was used to produce contraction of the smooth muscle strips of distal colon to record a decrease in the tension. Conversely, the IAS smooth muscle strips developed spontaneous tone. In the normal homozy gous mice, electrical field stimulation caused a biphasic response, an initial decrease followed by an after-contraction, whereas in Ls/Ls m ice, the predominant response was contraction. Ail smooth muscle strip s from normal and Ls/Ls mice produced relaxation in response to sodium nitroprusside and vasoactive intestinal polypeptide. Conclusions: Ls/ Ls mice may serve as an appropriate animal model to investigate the pa thogenesis of the inhibitory neurotransmission in Hirschsprung's disea se in the distal colon and IAS.