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Abstract: We have developed an anatomically based model to simulate slow wave activity in the small intestine. Geometric data for the human small intestine were obtained from the Visible Human project. These data were used to create a one-dimensional finite element mesh of the entire small intestine using an iterative fitting procedure. The electrically active components of the intestinal walls were modelled using a modified Fitzhugh–Nagumo cell model embedded within a longitudinal smooth muscle layer and a layer containing Interstitial Cells of Cajal. Within these layers, the monodomain equation was used to describe slow wave propagation. To solve the monodomain equation, a high-resolution finite difference grid, with an average spatial resolution of 0.95mm, was embedded within each finite element. The resulting simulations of intestinal activity agree with the experimental observation that slow wave frequency gradually declines from 12 cycles per minute (cpm) in the duodenum to 8cpm at the terminal ileum. Furthermore, the simulations demonstrated a decrease in conduction velocity with distance along the small intestine (10.7cm/s in the duodenum, 5.1cm/s in the jejunum and 1.4cm/s in the ileum), matching experimental recordings from the canine small intestine. We conclude that the framework presented here is capable of qualitatively simulating normal slow wave activity in an anatomical model of the small intestine. [Copyright &y& Elsevier]

A novel platelet-derived growth factor receptor alpha-positive cell (PDGFR α + ) has recently been identified as part of the purinergic inhibitory neural control mechanism in the gastrointestinal (GI) tract. The mechanism through which PDGFR α + cells mediate GI muscle relaxation has been found to be associated with the purine receptors P2Y 1 and apamin-sensitive SK3 channels that are highly expressed in these cells. This study aims to develop a mechanistic model elucidating a proposed mechanism through which PDGFR α + cells contribute to purinergic inhibitory neuromuscular transmission. In accordance with recent experimental findings, the model describes how the binding of neurotransmitters, released from enteric neurons, triggers the release of Ca 2+ from the endoplasmic reticulum in the PDGFR α + cells, and how this subsequently leads to large amplitude transient outward currents, which in turn hyperpolarize the cell. The model has been validated against experimental recordings and good agreement was found under normal and pharmacologically-altered conditions. This model demonstrates the feasibility of the proposed mechanism and provides a basis for understanding the mechanism underlying purinergic control of colonic motility. [ABSTRACT FROM AUTHOR]

Abstract: Nav1.5 sodium channels, encoded by SCN5A, have been identified in human gastrointestinal interstitial cells of Cajal (ICC) and smooth muscle cells (SMC). A recent study found a novel, rare missense R76C mutation of the sodium channel interacting protein telethonin in a patient with primary intestinal pseudo-obstruction. The presence of a mutation in a patient with a motility disorder, however, does not automatically imply a cause−effect relationship between the two. Patch clamp experiments on HEK-293 cells previously established that the R76C mutation altered Nav1.5 channel function. Here the process through which these data were quantified to create stationary Markov state models of wild-type and R76C channel function is described. The resulting channel descriptions were included in whole cell ICC and SMC computational models and simulations were performed to assess the cellular effects of the R76C mutation. The simulated ICC slow wave was decreased in duration and the resting membrane potential in the SMC was depolarized. Thus, the R76C mutation was sufficient to alter ICC and SMC cell electrophysiology. However, the cause−effect relationship between R76C and intestinal pseudo-obstruction remains an open question. [Copyright &y& Elsevier]