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Induction and organization of Ca2+ waves by enteric neural reflexes

Nature volume 399, pages 62–66 (1999)Cite this article

Abstract

The motility of the gastrointestinal tract consists of local, non-propulsive mixing (pendular or segmental) and propulsive (peristaltic) movements1,2,3,4,5. It is generally considered that mixing movements are produced by intrinsic pacemakers which generate rhythmic contractions4,5,6, and peristalsis by intrinsic excitatory and inhibitory neural reflex pathways1,2,3,4,5,7,8, but the relationship between mixing and peristalsis is poorly understood4,5,6. Peristalsis is compromised in mice lacking interstitial cells of Cajal9, suggesting that these pacemaker cells10,11,12,13,14 may also be involved in neural reflexes. Here we show that mixing movements within longitudinal muscle result from spontaneously generated waves of elevated internal calcium concentration which originate from discrete locations (pacing sites), spread with anisotropic conduction velocities in all directions, and terminate by colliding with each other or with adjacent neurally suppressed regions. Excitatory neural reflexes control the spread of excitability by inducing new pacing sites and enhancing the overall frequency of pacing, whereas inhibitory reflexes suppress the ability of calcium waves to propagate. We provide evidence that the enteric nervous system organizes mixing movements to generate peristalsis, linking the neural regulation of pacemakers to both types of gut motility.

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Figure 1: Visualization of spontaneous Ca2+-waves.
Figure 2: Neural reflex responses.
Figure 3: Neurally organized mixing patterns lead to peristalsis.

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References

  1. Bayliss, W. & Starling, E. H. Movements and innervation of the small intestine. J. Physiol. (Lond.) 24, 99–143 (1899).

    Article  CAS  Google Scholar 

  2. Bayliss, W. & Starling, E. H. The movements and innervation of the large intestine. J. Physiol. (Lond.) 26, 107–118 (1900).

    Article  CAS  Google Scholar 

  3. Kosterlitz, H. W. & Robinson, J. A. Reflex contraction of the longitudinal muscle coat of the isolated guinea-pig ileum. J. Physiol. (Lond.) 146, 369–379 (1959).

    Article  CAS  Google Scholar 

  4. Smith, T. & Sanders, K. in Textbook of Gastroenterology(eds Yamada, T., Alpers, D., Owyang, C. & Powel, D.) 234–260 (Lippincott, Silverstein, Philadelphia, (1995).

    Google Scholar 

  5. Holman, M. in Smooth Muscle and Assessment of Current Knowledge(ed. Bulbring, E.) 311–338 (University of Texas Press, Austin, (1981).

    Google Scholar 

  6. Christensen, J. in Physiology of the Gastrointestinal Tract Vol. 1 (ed. Johnson, L. R.) 991–976 (Raven, New York, (1994).

    Google Scholar 

  7. Hirst, G. D. S., Holman, M. E. & McKirdy, H. C. Two descending nerve pathways activated by distension of guinea-pig small intestine. J. Physiol. (Lond.) 244, 113–127 (1975).

    Article  CAS  Google Scholar 

  8. Mackenna, B. R. & McKirdy, H. C. Peristalsis in the rabbit distal colon. J. Physiol. (Lond.) 220, 33–54 (1972).

    Article  CAS  Google Scholar 

  9. Huizinga, J. D., Ambrous, K. & Der-Silaphet, T. Co-operation between neural and myogenic mechanisms in the control of distension-induced peristalsis in the mouse small intestine. J. Physiol. (Lond.) 506, 843–856 (1998).

    Article  CAS  Google Scholar 

  10. Thomsen, L. et al . Interstitial cells of Cajal generate a rhythmic pacemaker current. Nature Med. 4, 848–851 (1998).

    Article  CAS  Google Scholar 

  11. Ward, S. M., Harney, S. C., Bayguinov, J. R., McLaren, G. J. & Sanders, K. M. Development of electrical rhythmicity in the murine gastrointestinal tract is specifically encoded in the tunica muscularis. J.Physiol. (Lond.) 505, 241–258 (1997).

    Article  CAS  Google Scholar 

  12. Huizinga, J. D. et al . W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373, 347–349 (1995).

    Article  ADS  CAS  Google Scholar 

  13. Koh, S., Sanders, K. & Ward, S. Spontaneous electrical rhythmicity in cultured interstitial cells of Cajal from the murine small intestine. J. Physiol. (Lond.) 513.1, 203–213 (1998).

    Article  Google Scholar 

  14. Publicover, N. G. in Pacemaker Activity and Intercellular Communication(ed. Huizinga, J. D.) 175–192 (CRC, Boca Raton, (1995).

    Google Scholar 

  15. Cousins, H. M., Edwards, F. R., Hirst, G. D. & Wendt, I. R. Cholinergic neuromuscular transmission in the longitudinal muscle of the guinea-pig ileum. J. Physiol. (Lond.) 471, 61–86 (1993).

    Article  CAS  Google Scholar 

  16. Horowitz, B., Ward, S. & Sanders, K. Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles. Annu. Rev. Physiol. 61, 19–43 (1999).

    Article  CAS  Google Scholar 

  17. Ozaki, H., Stevens, R. J., Blondfield, D. P., Publicover, N. G. & Sanders, K. M. Simultaneous measurements of membrane potential, cytosolic Ca2+, and tension in intact smooth muscles. Am. J. Physiol. 260, C917–925 (1991).

    Article  CAS  Google Scholar 

  18. Holman, M. E. Membrane potentials recorded with high resistance microelectrodes and the effects of changes in ionic environment on the electrical and mechanical activity of the smooth muscle of the taenia coloi of the guinea pig. J. Physiol. (Lond.) 141, 464–488 (1958).

    Article  CAS  Google Scholar 

  19. Gillespie, J. S. Spontaneous mechanical and electrical activity of stretched and unstretched intestinal smooth muscle cells and their response to sympathetic nerve stimulation. J. Physiol. (Lond.) 162, 54–75 (1962).

    Article  CAS  Google Scholar 

  20. Smith, T. K., Reed, J. B. & Sanders, K. M. Interaction of two electrical pacemakers in muscularis of canine proximal colon. Am. J. Physiol. 252, C290–299 (1987).

    Article  CAS  Google Scholar 

  21. Costa, M. & Furness, J. B. The peristaltic reflex: an analysis of the nerve pathways and their pharmacology. Naunyn Schmiedebergs Arch. Pharmacol. 294, 47–60 (1976).

    Article  CAS  Google Scholar 

  22. Smith, T. K. & Robertson, W. J. Synchronous movements of the longitudinal and circular muscle during peristalsis in the isolated guinea-pig distal colon. J. Physiol. (Lond.) 506, 563–577 (1998).

    Article  CAS  Google Scholar 

  23. Smith, T. K. & McCarron, S. L. Nitric oxide modulates cholinergic reflex pathways to the longitudinal and circular muscle in the isolated guinea-pig distal colon. J. Physiol. (Lond.) 512, 893–906 (1998).

    Article  CAS  Google Scholar 

  24. Costa, M. & Furness, J. B. in Mediators and Drugs in Gastrointestinal Motility I. Morphological Basis of Neurophysiological Control(ed. Bertacchini, A.) 279–382 (Springer, Berlin, (1982).

    Google Scholar 

  25. Smith, T. K. & Furness, J. B. Reflex changes in circular muscle activity elicited by stroking the mucosa: an electrophysiological analysis in the isolated guinea-pig ileum. J. Auton. Nerve Syst. 25, 205–218 (1988).

    Article  CAS  Google Scholar 

  26. Tomita, T. Electrical responses of smooth muscle to external stimulation in hypertonic solution. J.Physiol. (Lond.) 183, 450–468 (1966).

    Article  CAS  Google Scholar 

  27. Burnstock, G. & Prosser, C. Conduction in smooth muscle, comparative electrical properties. Am. J. Physiol. 199, 553 (1960).

    Article  CAS  Google Scholar 

  28. Smith, T. K., Bornstein, J. C. & Furness, J. B. Convergence of reflex pathways excited by distension and mechanical stimulation of the mucosa onto the same myenteric neurons of the guinea pig small intestine. J. Neurosci. 12, 1502–1510 (1992).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations

  1. Biomedical Engineering Program and Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, 89557, Nevado, USA

    Randel J. Stevens, Nelson G. Publicover & Terence K. Smith

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  1. Randel J. Stevens
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  3. Terence K. Smith
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Correspondence to Terence K. Smith.

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Stevens, R., Publicover, N. & Smith, T. Induction and organization of Ca2+ waves by enteric neural reflexes. Nature 399, 62–66 (1999). https://doi.org/10.1038/19973

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