Characteristics of cholinergic neuroeffector transmission of ganglionic and aganglionic colon in Hirschsprung's disease.

Abstract

Differences in the release and content of acetylcholine and the a2 adrenoceptor mediated interaction between noradrenergic and cholinergic neurons were investigated by neurochemical and pharmacological methods in aganglionic and ganglionic segments of isolated human colon taken from children suffering from Hirschsprung's disease. Both at rest and during transmural stimulation the release of acetylcholine was significantly higher in the spastic (aganglionic) segment than in the proximal dilated bowel. Significant differences were found in the tissue concentration of acetylcholine between ganglionic and aganglionic specimens. The pattern of response to transmural stimulation was also different in the spastic and dilated bowel. Transmural stimulation induced relaxation and contraction in ganglionic specimens but only contractions in aganglionic specimens. The sensitivity of the smooth muscle in the aganglionic portion to exogenous acetylcholine and to field stimulation was found to be higher than in the ganglionic portion. While noradrenaline added to the organ bath reduced the stimulation-evoked release of acetylcholine from spastic segments, via an a2 adrenoceptor mediated process, yohimbine did not enhance the release. It is suggested that in Hirschsprung's disease the increased acetylcholine release, the enhanced sensitivity of smooth muscle cells to acetylcholine, and the lack of a2 adrenoceptor mediated noradrenergic modulation of acetylcholine release from cholinergic interneurons might be responsible for the spasm of aganglionic segments.

Abnormalities of Interstitial Cells of Cajal in Dominant Megacolon Mice

“…The abnormalities of ICCs may cause the reduction in the nitric oxide synthesis, which in turn leads to the spasm of the bowel muscle. Spasm of the gut has also been observed in HSCR patients [41]. Therefore, it is postulated that there is a relationship between the poor development of ICC and bowel spasm that leads to megacolon.…”

Hirschsprung's disease: Clinical and experimental observations

“…In the aganglionic segment, therefore, accumulation of the enzyme acetylcholinesterase is excessive, resulting from continuous acetylcholine release from the axons of the extramural parasympathetic ganglion. Pharmacologic investigations of the colon in HD patients bave demonstrated higher acetylcholine release in the aganglionic segment at rest and after stimulation than in the proximal ganglionic bowel [49,50]. It is suggested that in HD the increased acetylcholine release, the enhanced sensitivity of smooth muscle cells to acetylcholine, and the lack of a2-adrenoreceptormediated noradrenergic modulation of acetylcholine release from cholinergic interneurons might be responsible for the spasm of aganglionic segment.…”

Hirschsprung’s Disease and Mimicking Conditions

“…The way forward to diagnosis both Hirschsprung's disease and these associated problems may be by immunocytochemical means [19], since there ap pears to be both smooth muscle and neuronal abnormalities present in some even if gan glion cells are seen [23,26,105], It would appear that minute changes in the micro-envi ronment may produce Hirschsprung's and similar diseases [106,107], 112 …”

“…A reduction in neuro peptides in the aganglionic segment [24] has also been demonstrated. Cholinergic innerva tion is absent in aganglionic bowel [25] and with the increased acetylcholine release may account for the spasm [26], Abnormalities can be demonstrated with specific markers [27] and antibodies to neurofilament polypeptides [28], These abnormalities would suggest that an abnormal environment has a role in the pathogenesis of Hirschsprung's disease [29],…”