Changes in neuromuscular transmission in the W/W^v mouse internal anal sphincter

Abstract

Background Intramuscular interstitial cells of Cajal (ICC-IM) have been shown to participate in nitrergic neuromuscular transmission (NMT) in various regions of the gastrointestinal (GI) tract but their role in the internal anal sphincter (IAS) is still uncertain. Contractile studies of the IAS in the W/Wv mouse (a model in which ICC-IM numbers are markedly reduced) have reported that nitrergic NMT persists and that ICC-IM are not required. However, neither the changes in electrical events underlying NMT nor the contributions of other non-nitrergic neural pathways have been examined in this model. Methods The role of ICC-IM in NMT was examined by recording the contractile and electrical events associated with electrical field stimulation (EFS) of motor neurons in the IAS of wildtype and W/Wv mice. Nitrergic, purinergic and cholinergic components were identified using inhibitors of these pathways. Key Results Under NANC conditions, purinergic, and nitrergic pathways both contribute to EFS induced inhibitory junction potentials (IJPs) and relaxation. Purinergic IJPs and relaxation were intact in the W/Wv mouse IAS whereas nitrergic IJPs were reduced by 50–60% while relaxation persisted. In the presence of L-NNA (NOS inhibitor) and MRS2500 (P2Y1 receptor antagonist), EFS gave rise to cholinergic depolarization and contractions that were abolished by atropine. Cholinergic depolarization was absent in the W/Wv mouse IAS while contraction persisted. Conclusions and Inferences ICC-IM significantly contribute to the electrical events underlying nitrergic and cholinergic NMT whereas contractile events persist in the absence of ICC-IM. The purinergic inhibitory neural pathway appears to be independent of ICC-IM.

Purinergic neuromuscular transmission is absent in the colon of P2Y1 knocked out mice

“…The fast component of the IJP is inhibited after incubating the tissue with P2Y 1 antagonists such as MRS2179, MRS2279 or MRS2500, suggesting that P2Y 1 receptors are responsible for this mechanism. This pharmacological effect has been demonstrated in several areas of the gastrointestinal tract such as the small intestine (Gallego et al 2008 b ), colon (Gallego et al 2006, 2011; Grasa et al 2009; Zhang et al 2010 b ) and internal anal sphincter (Opazo et al 2011; Duffy et al 2012). All these results suggest that P2Y 1 receptors are responsible for purinergic neurotransmission in the gastrointestinal tract.…”

Interstitial cells of Cajal mediate nitrergic inhibitory neurotransmission in the murine gastrointestinal tract

“…The second component is blocked by inhibitors of nitric oxide synthase (NOS) and is therefore regarded as nitrergic (5,23,31). This characteristic biphasic IJP has been shown for several other regions of the GI tract of different species as well, such as antrum (15), small intestine (12), and internal anal sphincter (6,30).…”

Interstitial Cells of Cajal Modulate the Tone of the Human Internal Anal Sphincter In Vitro

“…however, there is still controversy regarding the role of iCCs in nitrergic transmission in the ias, and some authors have suggested that these cells are part of the nitrergic pathway in murine ias. 16 it is important to consider that the inhibitory neuromuscular transmission in the murine ias involves nitrergic and purinergic components, and, therefore, differences between species could be responsible for conflicting data. 15 the role of the iCC in the rectoanal inhibitory reflex (RaiR) is also unclear.…”

“…11,12 so far, the function of iCCs in the ias has only been investigated in 2 using transgenic mice. [13][14][15][16] hypotensive ias has been described in transgenic W/W v mice lacking muscular iCCs, and no clear relationship has been described between iCCs and nitrergic transmission. the role of iCCs in human ias is, therefore, still unclear.…”