Pharmacological analysis of rebound excitation in large intestine of piebald mouse model for Hirschsprung's disease

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Abstract
Pharmacological agents that might influence the poststimulus rebound contractile response (PSRR) through an action on the intrinsic inhibitory innervation of the circular muscle coat were studied in the large intestine of the piebald mouse model for Hirschsprung's disease. Tetrodotoxin (0.3–3 μM) suppressed, in a dose-dependent manner, the amplitude, duration, and area under the contractile traces of the PSRR and increased the latency for the response in ganglionated segments of the large intestine of piebald and normal mice. Sensitivity to tetrodotoxin was greater in the megacolon of piebald mice than in the colon of normal mice. Norepinephrine (6–360 μM) suppressed all parameters of the PSRR in ganglionated regions of the large intestine of abnormal mice. Sensitivity to norepinephrine was greater in the megacolon than in the colon of normal mice. Norepinephrine abolished spontaneous contractile behavior in ganglionated regions of the large intestine of normal and diseased mice and in the aganglionic segment of the piebald mice. Suppression of the PSRR by phentolamine and propranolol were interpreted as nonspecific local anesthetic effects. Atropine (20–200 μM) increased the area under the contractile traces in the midcolon of the intestine of both normal and piebald mice and had no effects on the terminal segment of the large intestine of normal mice. Spontaneous contractile activity and baseline tension were increased by atropine (350 μM) in all preparations. The nicotinic agonist, DMPP (3–157 μM), suppressed the PSRR in the ganglionated regions of the bowel from both normal and abnormal mice. DMPP relaxed resting tension in ganglionated regions, but did not affect the aganglionic terminal segment of the piebald mouse. Indomethacin (2.7–28 μM) suppressed or abolished the PSRR in ganglionated regions of the large intestine of both normal and diseased mice. Actions of the drugs are interpreted in terms of the role of excitatory and inhibitory neurons in generation of the PSRR.