All together now: from pacemakers to gastric peristalsis

Physiological emptying of the stomach goes on successfully, and blissfully with little awareness by its owner. The emptying results from a grinding and pumping action consisting of rings of circular muscle contractions that propagate from the main body (corpus) to the antrum, pushing digesta into the duodenum. This process has been described as gastric peristalsis (Sanders & Publicover, 1989) and occurs also in isolated preparations of stomach (Berthoud et al. 2002).

The gastric contractions are generated by slow waves in the smooth muscle, which occur in the absence of neural activity and are thus regarded as myogenic. The source of myogenic activity in the digestive tract has been tracked down to the interstitial cells of Cajal (ICC), which act as pacemakers, generating slow waves in the smooth muscle (Sanders, 1996).

A direct proof of the role of ICC in generating myogenic activity was provided by the discovery that in the intestines of white-spotting (W) mutant mice, the development of ICC is impaired. In the heterozygote W/WV strain, the network of ICC between the longitudinal and circular muscle layers (ICC-MY) is absent while the ICC in the circular muscle (ICC-IM) are still present. While in the smooth muscle of the wild type mice, slow waves are present, in the W/WV mice they are absent (Ward et al. 1994; Huizinga et al. 1995). This strongly indicates that the ICC in the myenteric plexus layer (ICC-MY) act as a pacemaker. In a series of already classical papers Hirst and colleagues (see Hirst & Edwards, 2004) demonstrated that also in the guinea-pig antrum the ICC-MY acted as pacemakers, passively depolarizing the adjacent muscle layers to initiate the rhythmic depolarization (slow waves) in the circular muscle layer. In addition they demonstrated that the ICC-IM, tightly electrically coupled with the smooth muscle, are involved in augmenting the slow wave depolarization, so ensuring that voltage-dependent calcium channels are activated during each slow wave cycle, leading to effective muscle contraction (Hirst & Ward, 2003).

In intact stomach the circular muscle contractions propagate anally at speeds of millimetres per second, whereas the contraction appears quasi-instantaneously around the circumference, propagating at speeds of centimetres per second. The anal propagation has been explained by the well-established mechanism of coupled pacemakers entrained by the higher oral frequencies. Indeed gastric slow waves in the corpus have the highest frequency and, quite surprisingly, appear to be generated by the ICC-IM (Hashitani et al. 2005). Given that signals within the ICC-MY propagate at similar milimetre per second speeds in all directions (Hennig et al. 2004), a major question arises as to how signals from the network of pacemaker cells generate both anal propagation at low speed and circumferential propagation at a higher speed. An additional path of conduction of signals in the circumferential direction was suspected to be at play to generate the full spatio-temporal pattern of gastric peristalsis (Hirst et al. 2002).

Now compelling evidence for such an explanation has been provided in two elegant papers from Hirst and co-workers in this issue of The Journal of Physiology.

In the first paper (Edwards & Hirst, 2006) they present a remarkable series of technically difficult, but conceptually clear, experiments mostly based on refined physical interventions and the judicious use of a few critical pharmacological agents.

In summary, their conclusion is that the anal propagation of the ring contractions in the antrum occurs by propagation of signals within the MP-ICC network, with concomitant generation of slow waves in the underlying circular muscle of the antrum at the greater curvature. In turn the slow waves, generated in the circular muscle, are subsequently conducted circumferentially at a much faster speed via the circular muscle bundles and their ICC-IM, to produce ring contractions. The signals that are still propagated circumferentially within the ICC-MY appear to be redundant or ineffective.

In the second paper (Hirst et al. 2006) they address the question of modelling the complex system of numerous cell types in different regions of the stomach by using previously developed models of ICC and attached smooth muscle (Edwards & Hirst, 2005). The model is based on classic electrical equivalent circuits with a choice of cellular and intercellular processes selected by best fit with physiological data. This second paper represents a significant attempt to integrate separate robust models of small chunks of the complex organ, into a single multilayered model to explain some emergent properties of the entire organ. The model explains well the different slow speed of propagation of the oro-anal wave of peristaltic contractions and the rapid circumferential propagation of the slow waves responsible for the ring contractions.

These papers point to a remarkable complexity in the way in which the different types of pacemaker, conducting and contracting cells are interconnected to generate the spatial and temporal pattern of gastric contractions. Increasingly the stomach begins to looks more like the heart with its specific pacemaker and conducting systems.