Nonneural regulation of motility

1
Non-neural regulation of motility

• Kenton M. Sanders, Ph.D.
• University of Nevada School of Medicine
• Department of Physiology and Cell Biology
• Reno, NV 89557
• kent_at_unr.edu

2
http//www.gastrosource.com/

• After registering,
• Look at Site Map under
• Scientific Resources for
• Varenna Group

GI physiology and pathophysiology slide package
3
The Varenna Group Ashley Blackshaw (Royal
Adelaide Hospital, Australia) Simon Brookes
(Flinders University, Australia) Ian Cook
(University of New South Wales,
Australia) Marcello Costa (Flinders University,
Australia) John Dent (Royal Adelaide Hospital,
Australia) Roberto De Giorgio (University of
Bologna, Italy) David Grundy (University of
Sheffield, UK) Kenton Sanders (University of
Nevada, Reno, USA) Michael Schemann (Technical
University, Munich, Germany) Terez Shea-Donahue
(University of Maryland, USA) Terry Smith
(University of Nevada, Reno, USA) Marcello Tonini
(University of Pavia, Italy)
4
Gastric motility the roles of the proximal and
distal stomach
The Moving GUT movie By Hans Jörg Ehrlein and
Michael Schemann 12 Antral pump
http//www.wzw.tum.de/humanbiology/data/motility
?altenglish
5
Website for GI motility movies

• http//www.wzw.tum.de/humanbiology/data/motility/3
  4/?altenglish

Professor Michael Schemann Technical University
Münich
6
Regions of the stomach have different roles in
gastric motility
Pyloric Spincter (sieving of particles)
Proximal stomach (reservoir function)
Distal stomach (grinding of solids)
7
Proximal stomach actively relaxes to accommodate
meals
Ingestion of food
Gastric accommodation (NO dependent inhibition
of muscle)
8
Proximal stomach actively relaxes to accommodate
meals
Restoration of fundic tone and volume (ACh-depende
nt tonic contraction)
Gastric emptying
9
Effects of TTX and truncal vagotomy on gastric
pressure in vivo
(Rat stomach)
TTX
Figure 1 from Takahashi T, Owyang C.
Characterization of vagal pathways mediating
gastric accommodation reflex in rats. J Physiol.
1997 504479-488. Freely accessible at
http//jp.physoc.org/cgi/reprint/504/Pt_2/479
Instilled 6 ml into rat stomach. This caused a 9
cmH2O increase in gastric pressure.
Pretreatment with TTX (A) or truncal vagotomy
(B) in vivo caused a much larger increase in
gastric pressure with the same volume (to 17
cmH2O)
10
Effects of hexamethonium and L-NAME on gastric
accommodation
(Rat stomach)
Vagal efferents
Hex
ACh (nicotinic receptor)
Figure 2 from Takahashi T, Owyang C.
Characterization of vagal pathways mediating
gastric accommodation reflex in rats. J Physiol.
1997 504479-488. Freely accessible at
http//jp.physoc.org/cgi/reprint/504/Pt_2/479
Myenteric motor neurons
Post-ganglionic Inhibitory myenteric motor
neurons
(purine, peptides)
NO
Relaxation of fundus
11
Classical concept of en passant neurotransmissio
n
12
Structural relationship between enteric nerve
terminals, ICC and smooth muscle cells
Imaizumi and Hama(1969) described gap junctions
between ICC and smooth muscle cells and ICC lying
in close proximity with nerves (Z. Zellforsch.
97 351357, 1969). Roman (1975) observed
close relationship between enteric nerves and ICC
in the cat esophagus (INSERM 50 415422,
1975). Daniel and Posey-Daniel (1984) quantified
the close apposition between enteric nerves and
ICC to be as little as 20 nm (Am J Physiol. 246
G305-G315, 1984).
Fig. 2B. From Daniel Posey-Daniel Am J
Physiol. 1984 246 G305-G315. Available at
http//ajpgi.physiology.org/cgi/reprint/246/3/G305
(under access control)
13
(No Transcript)
14
Synaptotagmin-positive nerve varicosities are
closely apposed to ICC-IM (Murine Gastric Fundus)
Figure showing micrograph of Synaptotagmin-Li
Kit-Li with enlargement of region from Beckett et
al., J Comp Neurol. 493193-206, 2005. Under
access control at http//www3.interscience.wiley.c
om/cgi-bin/jissue/112137360
15
Gastric intramuscular ICC (ICC-IM) are lost in
W/WV mutants
Figure 1 A C from Burns et al. PNAS 1996
9312008-12013 Freely accessible at
http//www.pnas.org/cgi/reprint/93/21/12008
16
Neurotransmission is greatly reduced in gastric
muscles of W/WV mice
Figure 4 from Ward et al. J. Neuroscience 2000
201393-1403 Freely accessible at
http//www.jneurosci.org/cgi/content/full/20/4/13
93
17
Intramuscular interstitial cells of Cajal
(ICC-IM) are interposed between nerve terminals
and smooth muscle cells
Interstitial cell (ICC-IM)
18

19
Blocking breakdown of ACh reveals a smooth muscle
response component (Murine fundus)
Figure 8 from Ward et al. J. Neuroscience 2000
201393-1403. Freely accessible at
http//www.jneurosci.org/cgi/content/full/20/4/13
93
20
Non-cholinergic excitatory responses persist in
muscles lacking ICC-IM(Murine gastric fundus)
Figure 7 from Beckett, et al. J. Physiol. 543
871-887, 2002 Freely accessible at
http//jp.physoc.org/cgi/content/full/543/3/871
21
Summary of important points

• Vagal inputs regulate tone and volume of the
  proximal stomach via activation of enteric motor
  neurons.
• Vagal efferent nerves synapse on myenteric motor
  neurons and activate inhibitory neurons (NO) or
  excitatory neurons (Ach neurokinins).
• Enteric motor neurons synapse on interstitial
  cells of Cajal (ICC-IM) within muscle bundles.
• ICC-IM transduce neural inputs and convey
  depolarization or hyperpolarization responses via
  gap junctions to smooth muscle cells.
• ICC appear to be damaged or lost in a variety of
  GI motility disorders.

22
Segmental contractions of the small intestine
(Canine ileum)
The Moving GUT movie 71. Segmenting
contractions of ileum By Hans Jörg Ehrlein and
Michael SchemannFreely accessible
at http//www.wzw.tum.de/humanbiology/motvid01/mo
vie_63_1mot01.wmv
23
Major functions of the small intestine (and
motility requirements)

• Digest macromolecular nutrients (requires
  significant agitation)
• Absorb digestion products (requires stirring to
  maximize contact between nutrient molecules and
  epithelial cell membranes)
• Retain nutrients in the small bowel until maximal
  digestion and absorption can be accomplished
  (requires slow distal movement of chyme)
• Move chyme from duodenum to point of emptying at
  the ileo-colonic sphincter.

24
Electrical rhythmicity in GI muscles
Murine
Human
Canine
A. Gastric antrum
B. Small intestine
C. Colon
Figure from Sanders et al., Ann Rev Physiol.
200668307-43. Under access control at
http//arjournals.annualreviews.org/toc/physiol/68
/1
25
Excitation-contraction coupling in GI smooth
muscles
Intact muscle Ca2
Single cell Ca2
Panels A-C from Fig. 1 in Ozaki et al., Am J
Physiol. 1991260C917-C925 Under access control
at http//ajpcell.physiology.org/cgi/reprint/260/
5/C917 Panels D-F from Fig. 8 in Vogalis et al.,
Am J Physiol. 1991260C1012-C1018 Under access
control at http//ajpcell.physiology.org/cgi/repr
int/260/5/C1012
26
Slow waves are generated in specific pacemaker
regions in GI muscles
Data from Fig. 4 in Smith et al., Am. J. Physiol.
1987 252C215-C224Under access control
at http//ajpcell.physiology.org/cgi/reprint/252/
2/C215
27
Interstitial cells of Cajal form an electrical
syncytium and couple to smooth muscle cells
Contributed by Sean M. Ward
28
Structure of ICC networks in pacemaker regions
ICC form a mesh-like network in all pacemaker
regions of GI tract
Contributed by Sean M. Ward
29
Human ICC-MY network
Contributed by Hyun Tai Lee Grant Hennig
30
Electrical rhythmicity is lost in Kit mutant
animals
Figure 3 from Ward et al. J. Physiol 1994
48091-97. Freely accessible at http//jp.physoc.
org/cgi/reprint/480/Pt_1/91
31
Simultaneous recordings of slow waves from from
ICC-MY and circular smooth muscle cell
Recording from ICC
Recording from circular smooth muscle cell
Longitudinal layer
ICC-MY
SMCs
Circular layer
Adapted from drawing by David Hirst
32
Simultaneous recording of slow waves in ICC and
adjacent smooth muscle
(Guinea pig antrum)
Figure 3 from Hirst Edwards J. Physiol.
535165-180, 2001 Freely accessible at
http//jp.physoc.org/cgi/content/full/535/1/165
Slow wave initiated slightly ahead in ICC
33
Slow waves fail to propagate through regions
devoid of ICC
Slow waves actively propagate along
the submucosal surface of the circular muscle
layer in the colon.
When submucosal surface is removed, slow waves
decay with distance away from the intact region.
ICC provide a pathway for active propagation
in gastrointestinal muscles
Data from Figs. 2 3 in Sanders et al., Am J
Physiol. 1990 259G258-G263. Under access
control at http//ajpgi.physiology.org/cgi/reprin
t/259/2/G258
34
Slow waves propagate without decrement in
regions with ICC, but decay in regions without
ICC
35
The dominant pacemaker in the stomach resides in
the orad corpus
1. Fundus Quiescent 2. Corpus 3.7 CPM 3.
Orad antrum 1.4 CPM 4. Terminal antrum 0.66
CPM
The dominant pacemaker runs at the highest
frequency
36
Slow waves propagate rapidly around the stomach
and more slowly down the stomach
1. Fundus 2. Corpus 3. Orad antrum 4.
Terminal antrum
Corpus pacemaker to pylorus is 15-20 cm, so 13-18
sec are required for slow wave propagation from
the corpus to the pylorus.
37
Slow waves propagate as a band toward the
pylorus, activating contractions as smooth muscle
cells depolarize
1. Fundus 2. Corpus 3. Orad antrum 4.
Terminal antrum
38
Intrinsic frequencies of the proximal and distal
stomach
INTRINSIC FREQUENCIES OF THE PROXIMALAND DISTAL
STOMACH
Activity in dominant pacemaker (3 CPM)
Antral spontaneous activity (1 CPM)
Intrinsic frequency of antral pacemaker is a
fraction of the dominant corpus pacemaker
frequency. Thus in the intact Stomach there is
time for slow waves to propagate to the antrum
and entrain activity of antral pacemaker.
39
Frequency of proximal and distal stomach follow
rate of dominant pacemaker
Corpus pacemaker
Antrum follower
Frequency of the entire stomach runs at the
frequency of the dominant (corpus) pacemaker!