Division of Basic Biomedical Sciences, School of Medicine, The University of South Dakota, Vermillion, South Dakota 57069-2390
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ABSTRACT |
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This in vitro study tested
the hypothesis that muscularis mucosae contractile activity contributes
to rabbit colonic mucosal function by mechanisms other than simple
mechanical deformation of the epithelium. Experiments were performed by
using a technique that allows simultaneous recording of muscle activity
and transmucosal potential difference, a measure of epithelial ion
transport. ATP, bradykinin, histamine, PGE2,
PGF1, and PGF2
elicited muscularis
mucosae contractions that were resistant to atropine and TTX. Only
ATP-induced contractions were indomethacin sensitive, and only those to
dimethylphenylpiperazinium iodide (DMPP) were reduced by atropine. All
agonist-evoked increases in transmucosal potential difference were
atropine resistant, and, with the exception of those to
PGE2, PGF2
, and VIP, they were also TTX
sensitive. Mucosal responses to ATP, bradykinin, and histamine were
indomethacin sensitive, whereas those to DMPP, the prostaglandins, and
VIP were not. When cyclooxygenase activity or the mucosal innervation was compromised, even maximal muscularis mucosae contractions did not
produce large secretory responses. It is concluded that contraction-related prostaglandin synthesis and noncholinergic secretomotor neuron stimulation represent the physiological
transduction mechanism through which muscularis mucosae motor activity
is translated into mucosal secretion.
motility; mucosa; submucosal plexus; transduction pathway; integrated function; rabbit
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INTRODUCTION |
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THE RELATIONSHIP BETWEEN INTESTINAL motility and mucosal absorption and secretion has been given only scant attention over the last three decades, and almost without exception the focus has been on the effects of muscularis propria motor activity on mucosal function (15-19, 37). More recently, attention has shifted to the influence of muscularis mucosae contractions on mucosal activity. This was based on the observations that this muscle layer is physically attached to the mucosa, both are innervated via the submucosal plexus (30), and the muscularis mucosae can respond to specific changes in the luminal environment via a neurally mediated afferent-efferent link (27, 30). In the rabbit colon, the latter pathway appears to be associated with mucosal protection, as evidenced by the potentially harmful stimuli required to elicit this type of response (30).
In an early Ussing chamber study, morphological analysis of rat colonic mucosa immediately following stimulation with bradykinin revealed significant changes in mucosal architecture associated with anion secretion (3). The authors felt that this was unrelated to muscularis mucosae contraction because bradykinin caused relaxation of the colonic muscularis propria (13); therefore, they assumed it would have the same effect on the third muscle layer. Subsequent work on the muscularis mucosae has shown this belief to be incorrect in any region of the rat colon (29), and thus a significant contribution by this muscle layer to mucosal events cannot be excluded based solely on those experiments.
The mechanisms by which mechanical events occurring in the muscularis mucosae are translated into secretion by the mucosa remain unknown. In the stomach, for example, it was long believed that, on the basis of its anatomic relationship to the mucosa, this muscle layer would promote gastric acid secretion by "squeezing" the gastric glands (39). Recent studies (35) in the rabbit stomach have shown that this assumption may not be correct, because the muscularis mucosae in this region receives a predominantly inhibitory intrinsic innervation, is not contracted by secretagogues, and may thus actually facilitate acid secretion by relaxing and opening the gastric glands.
The importance of the muscularis mucosae to mucosal activity is further emphasized by a recent in vitro investigation of their integrated function in rabbit distal colon, where it was noted that, in the presence of TTX, large agonist-induced muscle contractions persisted but the corresponding mucosal responses were attenuated (30). This led to the suggestion that the functional relationship between these structures might be more complex than epithelial secretion simply being augmented via muscularis mucosae contraction-induced squeezing of the mucosa. On the basis of this proposition, the aim of the present in vitro study was to test the hypothesis that in rabbit distal colon mucosal compression is not the primary mechanism through which muscularis mucosae motor activity is linked to epithelial secretion.
The pharmacological agents used to test this hypothesis were selected on the basis of their respective abilities to 1) directly stimulate either the muscularis mucosae (30) or the mucosa (1, 14), 2) initiate prostaglandin production (1, 2, 8, 20, 23, 25), 3) reproduce the actions of endogenous eicosanoid mediators, 4) stimulate ganglionic nicotinic receptors on submucosal neurons, and 5) block the synthesis or the effects of agents with actions on the muscle or the mucosa and/or their respective innervation.
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METHODS |
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Preparation of the muscularis mucosae/mucosa cylinder. The technique used in this study was that recently described by Percy et al. (30) for the simultaneous measurement of rabbit distal colonic transmucosal potential difference and muscularis mucosae motor activity in vitro.
Male New Zealand White rabbits (2-3 kg) were euthanized by pentobarbital overdose. After laparotomy, a segment of distal colon ~4 cm in length situated immediately proximal to the pelvic brim was removed and transferred to a dish coated with Sylgard (Dow Corning, Midland, MI) and filled with oxygenated Krebs' solution. Under a low-power dissecting microscope, the longitudinal and circular muscle layers were removed en bloc by sharp dissection, leaving a cylinder composed of submucosa, submucosal plexus, muscularis mucosae, and mucosa. Throughout this procedure, the lumen was regularly perfused with fresh oxygenated Krebs' solution to ensure epithelial viability. The ability to maintain colonic mucosal integrity during extended periods of luminal perfusion with an oxygenated physiological solution has previously been noted (17, 30). A polyethylene catheter with a flared end connected to a peristaltic pump was then tied securely into the proximal end of the cylinder. The whole muscularis mucosae/mucosa cylinder was next transferred to a 50-ml organ bath where the distal end was attached to one arm of a "T" connector fixed in the base of the bath. The second arm of this connector was used as a luminal outflow. An agar salt bridge electrode was inserted into the third arm of the T piece, bringing it into electrical contact with the luminal perfusion solution of oxygenated Krebs' solution at 37 ± 0.5°C at a flow rate of 12 ml/min, delivered via a Masterflex peristaltic pump (model 7520-35; Cole-Parmer, Chicago, IL). A second agar salt bridge was then placed in contact with the bathing medium. Great care was taken to ensure that no air bubbles entered the luminal perfusion line, because these could cause regions of electrical discontinuity, preventing accurate reading of the voltage difference between the two electrodes. Potential difference between the cylinder lumen and the bathing medium was measured after amplification of the signal via a Grass polygraph preamplifier and amplifier. Increases in transmucosal potential difference recorded in this fashion represent an increase in luminal negativity resulting from chloride ion secretion (30). Finally, the oral end of the preparation was connected to a force-displacement transducer (model FTO3C; Grass Instruments, Quincy, MA). The entire preparation was maintained under a tension equivalent to a 2.0-g load (19.6 mN). The tissue was then allowed to warm up to a maintained temperature of 37 ± 0.5°C and to equilibrate for at least 30 min before the start of each experiment. All responses were recorded on a Grass model 7D polygraph. Under these recording conditions, movement artifacts were excluded from the potential difference recordings because neither electrode was in contact with the preparation itself.Effects of pharmacological agents on the cylinder preparation.
All drugs were added to the serosal bathing medium in amounts that did
not exceed 10% of the total chamber volume, and they were removed by
draining and refilling the bath. Acetylcholine (109-10
3 M) was added to the serosal
bathing solution to quantitate excitatory changes and to confirm tissue
viability. Concentration-response curves for each agonist were
constructed by using noncumulative addition protocols, and the ensuing
muscle and mucosal responses were expressed as a percentage of their
respective maximum responses to acetylcholine. To avoid tissue fatigue
and to eliminate errors associated with tissue deterioration over time,
responses to pharmacological agents in the presence of atropine,
indomethacin, and TTX were each obtained from separate preparations and
compared with untreated controls. TTX was added 5 min before beginning
pharmacological manipulation. Atropine and indomethacin exposure began
30 min in advance of the addition of the agent under study. When their effects on agonist-induced responses were being studied, TTX, atropine,
and indomethacin were present continuously throughout the entire drug
addition sequence to ensure that their concentration in the serosal
bathing medium remained constant and that their effects did not
diminish over time.
Statistical analysis. Statistical differences were assessed using a nonpaired Student's t-test or, in the case of multiple group comparisons, ANOVA with Bonferroni correction for parametric data or a Kruskal-Wallis ANOVA with a Dunn's multiple comparison post hoc test for nonparametric data. Statistical analyses were performed using GraphPad Instat version 3 (GraphPad Software, San Diego, CA), and a P value of <0.05 was considered to represent a significant difference. In all cases, n values represent one preparation from one animal.
Drugs and solutions.
Experiments were performed using a Krebs' solution of the following
composition (in mM): 118.5 NaCl, 4.75 KCl, 2.54 CaCl2, 1.19 NaH2PO4, 1.19 MgSO4, 25.0 NaHCO3, and 11.0 glucose. Acetylcholine chloride (Sigma,
St. Louis, MO) was dissolved in 5% sodium phosphate and diluted in
Krebs' solution acidified to pH 4.0 with 0.1 N HCl. Atropine
sulfate, dimethylphenylpiperazinium iodide (DMPP), famotidine,
histamine diphosphate, pyrilamine maleate, PGE2,
PGF1, and PGF2
(all Sigma) were dissolved
in, and diluted with, a modified Krebs' solution (in mM: 143 NaCl,
4.75 KCl, 2.54 CaCl2). TTX (Sigma) was dissolved in a
citrate buffer (50 mM citric acid, 48 mM
NaH2PO4). ATP, bradykinin, and VIP (all Sigma)
were dissolved in, and diluted with, distilled water. ATP, bradykinin,
PGE2, PGF1
, PGF2
, and VIP
stock solutions were frozen at
5°C when not in use, and fresh
dilutions were made daily. Indomethacin (Sigma) was initially dissolved
in 10 ml of a 54-mM Na2CO3 solution and
subsequently diluted with distilled water.
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RESULTS |
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Histamine.
The muscularis mucosae and the mucosa responded to histamine
(109-10
3 M) with increases in tone and
in transmucosal potential difference that reached, respectively,
105.7 ± 3.7 and 75.6 ± 10.0% of the acetylcholine maximum
(Fig. 1). These responses were
significantly reduced by a 30-min pretreatment with the histamine
H1 receptor antagonist pyrilamine (10
6 M) to
65.4 ± 4.1 and 21.2 ± 3.8% (both P < 0.001; n = 6 each) but not by the H2
receptor antagonist famotidine (10
6 M; not shown). This
concentration of pyrilamine did not alter the responses of the
muscularis mucosae or the mucosa to acetylcholine (not shown).
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Bradykinin.
As with histamine, bradykinin (4 × 1013-4 × 10
6 M) elicited contractions and increases in
transmucosal potential difference whose respective largest responses
(96.5 ± 4.4 and 137.5 ± 9.8%; n = 12) were
unaffected by atropine (10
6 M), although the linear
portion of the mucosal bradykinin concentration-response curve was
shifted to the left under these conditions (Fig.
2). TTX (10
6 M)
significantly attenuated the mucosal responses to bradykinin, whereas
the contractile responses of the muscularis mucosae were unchanged by
this procedure (Fig. 2). Indomethacin (10
6 M) caused a
rightward shift in the bradykinin concentration-response curves for
both the muscularis mucosae and the mucosa, but the largest responses
of each tissue were not significantly reduced in either case (Fig. 2).
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ATP.
Muscularis mucosae and mucosal responses to ATP
(109-10
3 M) were concentration
related. Paradoxically, although the largest ATP-induced responses of
the muscularis mucosae were small (63.0 ± 4.4%;
n = 7), the corresponding mucosal responses were large (120.5 ± 15.3%; n = 7; Fig.
3). In contrast to all other agents studied, muscularis mucosae responses to ATP were significantly reduced
by indomethacin (10
6 M) but were resistant to both
atropine (10
6 M) and TTX (10
6 M). Mucosal
responses to ATP were atropine resistant, but they were significantly
attenuated by both indomethacin (10
6 M) and TTX
(10
6 M; Fig. 3).
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DMPP.
The ganglion-stimulating agent DMPP
(109-10
3 M) elicited muscularis
mucosae contractions that reached 54.6 ± 6.6% (n = 10) of the acetylcholine maximum. These responses were unaffected by indomethacin (10
6 M) but were significantly attenuated in
the presence of atropine (10
6 M; P < 0.001; Fig. 4). Mucosal responses to DMPP
reached 84.7 ± 12.9% (n = 10) of the
acetylcholine maximum and were also resistant to indomethacin
(10
6 M). In the presence of atropine (10
6
M), the mucosal concentration-response curve for DMPP was shifted to
the right, but, although the largest response to this agent was then
numerically smaller than the control (65.6 ± 11.4%;
n = 8), this was not a statistically significant
difference (Fig. 4).
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Prostaglandins.
Muscularis mucosae responses to PGE2, PGF1,
and PGF2
(2.8 × 10
11-2.8 × 10
6 M) were resistant to atropine (10
6
M), indomethacin (10
6 M), and TTX (10
6 M).
The largest muscularis mucosae responses were elicited by PGE2 (68.5 ± 4.6%; n = 6; not shown)
and PGF2
(64.4 ± 6.1; n = 10; not
shown); the smallest were elicited by PGF1
(27.4 ± 5.6; n = 6; Fig. 5).
Similarly, mucosal responses to these prostaglandins occurred in the
following order: PGE2 (119.4 ± 9.0%;
n = 10), PGF2
(83.1 ± 13.4%;
n = 10), and PGF1
(61.7 ± 12.8%; n = 6). The potential difference changes elicited by
PGE2 and PGF2
were resistant to atropine
(10
6 M), indomethacin (10
6 M), and TTX
(10
6 M; not shown). In contrast, the largest mucosal
response to PGF1
was significantly reduced by TTX
(10
6 M), but, as with the other eicosanoids, it was
unaffected by either atropine (10
6 M) or indomethacin
(10
6 M; Fig. 5).
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VIP.
The responses of the muscularis mucosae to VIP (3 × 1012-3 × 10
6 M) were small,
reaching only 6.8 ± 2.0% (n = 5) of the
acetylcholine maximum. In contrast, the largest VIP-induced increase in
potential difference was 126.0 ± 16.8% (n = 5)
of the acetylcholine maximum. Atropine (10
6 M),
indomethacin (10
6 M), and TTX (10
6 M) had
no significant effects on the mucosal responses to this peptide (Fig.
6). Muscularis mucosae responses to VIP
were too small for a meaningful determination of the effects of these
agents to be made.
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DISCUSSION |
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The data obtained in this study add to our understanding of the physiological role of the muscularis mucosae and demonstrate that in rabbit distal colon there is a complex relationship between the motor activity of this muscle and the corresponding mucosal function. It has previously been shown that the muscularis mucosae may be linked to epithelial protection via a neural pathway that causes muscular contraction in response to noxious agents in the lumen, thus reducing the mucosal surface area (27, 30). The present data now suggest that this muscle plays a second important role in integrated gut function, namely promotion of epithelial secretion. However, this is not simply the fortuitous result of mechanical deformation of the mucosa as a consequence of muscularis mucosae shortening.
The nature of the relationship between the muscularis mucosae and the mucosa in this colonic region is clearly illustrated by the effects of histamine. In earlier Ussing chamber studies it was found that responses of rabbit distal colonic mucosa to histamine were H1 receptor mediated, small, transient, TTX resistant (28), and sometimes absent altogether (28, 30). With the use of the cylinder preparation, mucosal responses to histamine were again found to be H1 receptor mediated, but under these conditions they were large, persistent, and sensitive both to indomethacin and to TTX. The only significant functional difference between these two recording methods is the ability of the muscularis mucosae to contract. This strongly suggests, therefore, that the motor activity of this muscle is the first step in a complex series of events that can ultimately lead to mucosal secretion.
In addition, because histamine is essentially without a direct effect
on this epithelium, the 80% maximal increase in transmucosal potential difference elicited by this agent in the cylinder preparation represents a measure of the total amount by which muscularis mucosae contraction can influence secretion at this site. Agents such as ATP or
bradykinin that can promote additional prostaglandin production or
directly stimulate secretomotor neurons can exceed
80% maximal
transmucosal potential difference increases by augmenting these
components of the intrinsic response to contraction.
The relationship between muscularis mucosae contraction and epithelial secretion characterized in the present investigation may also provide an explanation for the variable responses of this mucosa to histamine seen in a variety of Ussing chamber studies. If, in the Ussing chamber, the mucosa was pinned tightly and the muscularis mucosae was truly held immobile, the mucosa would appear to be unresponsive to histamine (28, 30); in instances in which the preparation was stretched to a lesser extent and the muscularis mucosae was able to contract in response to histamine, the mucosal responses would be attenuated by indomethacin, pyrilamine, and TTX (e.g., Ref. 38). Thus, although appearing to be mucosal in origin, the latter responses would represent muscularis mucosae-initiated secretion via the pathways identified here.
It could be argued that, in the cylinder preparation, indirectly mediated mucosal responses to agents such as histamine or bradykinin did not arise secondary to muscularis mucosae contraction but rather via stimulation of intestinal subepithelial myofibroblasts (4). These cells lie adjacent to the mucosa, possess a variety of pharmacological receptors, and are a likely source of prostaglandin production in this region (4, 36). This explanation is unlikely, given that histamine has minimal mucosal effects in the Ussing chamber when muscularis mucosae contractions are curtailed (28, 30) but causes large TTX- and indomethacin-sensitive potential difference changes in the cylinder preparation where contractions are unimpeded.
On the basis of the pharmacological profile of muscularis mucosae-related transmucosal potential difference increases, it appears that they are produced indirectly via mechanically induced prostaglandin synthesis and the concurrent stimulation of noncholinergic secretomotor neurons. These conclusions are drawn from the following observations.
First, even maximal muscularis mucosae contractions did not elicit large secretory responses if prostaglandin synthesis or the innervation of the mucosa was pharmacologically compromised. This demonstrates that epithelial secretion is not simply the result of mucosal compression produced via muscularis mucosae contraction.
Second, all muscularis mucosae-related, TTX-sensitive mucosal responses in the rabbit colon were atropine resistant, despite the fact that mucosal secretion in this region is governed by both cholinergic and noncholinergic enteric nerves (6, 30). This cannot be attributed to selective damage of cholinergic neurons during the tissue preparation process, because functional cholinergic innervation of the muscle and the mucosa was seen as the atropine-sensitive component of their responses to the ganglion-stimulating agent DMPP. From this it appears that cholinergic submucosal neurons are present but that they do not participate in muscularis mucosae-initiated mucosal secretion. This contrasts starkly with the rat colon, where agonist-induced submucosal prostaglandin synthesis stimulates both cholinergic and noncholinergic secretomotor neurons (10).
The lack of a cholinergic component linking muscularis mucosae
contraction to secretion may be because rabbit colonic secretomotor neurons do not possess the appropriate eicosanoid receptors or because
of the known ability of certain inhibitory prostaglandins to attenuate
acetylcholine release from submucosal nerves (11). The
latter explanation seems improbable given the large number of
arachidonic acid metabolites produced in the lamina propria in response
to agents such as bradykinin (22, 25). Furthermore, absence of a significant endogenous inhibitory prostaglandin production in this system was strongly suggested by the inability of indomethacin to alter mucosal responses to exogenous PGE2,
PGF1, and PGF2
. There is good evidence
that indomethacin pretreatment can enhance mucosal secretion to applied
prostaglandins in regions where endogenous inhibitory prostaglandins
(such as PGD2) oppose these excitatory effects (21,
24), because this negative influence is removed when
cyclooxygenase activity is inhibited (24).
Third, on the basis of the effects of histamine and the selective actions of pyrilamine, it can be deduced that muscularis mucosae contraction is not linked to mucosal secretion via mechanically induced release of this autacoid from mast cells in the lamina propria.
Fourth, in response to VIP, a directly acting secretagogue, large TTX- and indomethacin-resistant increases in transmucosal potential difference occurred in the absence of significant muscularis mucosae motor activity; in contrast, all agonist-induced contractile activity occurred in association with increases in transmucosal potential difference. This demonstrates that muscle activity and mucosal function are indirectly coupled, because the secretory apparatus can be directly activated in the absence of significant muscularis mucosae contractions, but contractions cannot occur without concurrent secretory responses.
The ability of atropine to enhance mucosal responses to lower
concentrations of histamine, and to a lesser extent of bradykinin, remains unexplained. Because there was no corresponding change in the
magnitude of muscularis mucosae contractions to either agent, the
atropine-induced augmentation of their mucosal effects was not simply a
mechanical artifact. It would have been predicted that, if bradykinin-
or histamine-induced stimulation of the mucosa involved a cholinergic
pathway, muscarinic receptor blockade should decrease the
transmucosal potential difference changes they evoke. This would
occur not only via a reduction in the magnitude of the overall stimulus
itself but also possibly by an increase in apical K+
secretion (12). The net result would thus be a decrease in the arithmetic sum of the negative and positive charges moving into
lumen. However, because cholinergic secretomotor neurons were not found
to participate in this process, atropine should have been without
effect on these mucosal responses. One possible explanation for the
augmentation of the effects of bradykinin and histamine under these
conditions is that a component of integrated muscularis mucosae/mucosal
function involves the activation of inhibitory muscarinic receptors on
noncholinergic secretomotor neurons. Muscarinic receptor blockade would
thus remove an endogenous inhibitory influence on secretion. This locus
of action is supported by the inability of atropine to alter the
mucosal responses to secretagogues such as PGE2,
PGF2, and VIP, whose effects were TTX resistant.
In contrast to its inhibitory actions on a variety of smooth muscles (7), ATP elicits muscularis mucosae contractions in rabbit distal colon (33). The present data show this to be because ATP elicits excitatory prostaglandin production, which in turn causes direct stimulation of the muscle. Prostaglandin generation following exposure to endogenous or exogenous purines has been demonstrated in a variety of intestinal and nonintestinal tissues (1, 2, 8, 20, 23), and its occurrence in the muscularis mucosae/mucosa of the rabbit distal colon adds to the list of sites where this pathway operates. Paradoxically, ATP exerts its largest motor effects on the muscularis mucosae in the rabbit proximal colon, where prostaglandins elicit minimal contractions (31, 33). This suggests that regional variations in ATP-mediated responses reflect the relative contributions of the direct vs. indirect effects of this purine and supports the belief that the relationship between the muscularis mucosae and mucosa may be governed by different physiological factors in successive regions of the gut.
ATP-induced muscularis mucosae contractions were both atropine and TTX
resistant, implying that the prostaglandins generated directly
stimulate the muscularis mucosae. Mucosal stimulation by ATP was
similarly mediated via prostaglandin production, but this process also
involved the activation of noncholinergic secretomotor neurons,
because, although atropine resistant, it was significantly attenuated
by TTX. Although the prostaglandin(s) produced following ATP
administration were not specifically identified in the present study,
only the mucosal responses to applied PGF1 were found to
be TTX sensitive. It is thus possible that this particular eicosanoid
is an important component of the mucosal response to ATP and to other
agents, such as histamine and bradykinin, whose indirect effects are
also prostaglandin mediated and TTX sensitive. The indirect effects of
ATP on rabbit colonic mucosa differ from those reported in the rat
colon, where ATP-induced epithelial secretion results from a direct
effect on crypt cells (26) and on secretomotor neurons, in
the absence of prostaglandin production (9). These
observations suggest that there may be significant species differences
in the interrelationship of colonic muscularis mucosae motor activity
and mucosal secretion.
Although the involvement of prostaglandins and submucosal nerves in
epithelial secretion in the colon has previously been described (e.g.,
Refs. 5 and 10), the physiological necessity for having
this complex apparatus available has not been satisfactorily explained.
Without evidence for a functional interaction, it appeared that these
were simply duplicate systems, each of which was capable of eliciting
the same biological response under different experimental conditions. However, it is now possible to suggest that, in this region
of the rabbit colon, these components are present because they
represent the transduction mechanism through which muscularis mucosae
motor activity is translated into epithelial secretion. On the basis of
the indomethacin and TTX sensitivity of this pathway, the physiological
mechanisms underlying this interaction are muscularis mucosae
contraction-related prostaglandin synthesis coupled to the concurrent
stimulation of noncholinergic secretomotor neurons (Fig.
7). Thus, although mechanical movement of
the muscularis mucosae may change mucosal surface area, additional
processes are required for this activity to influence secretion. This
leads to the conclusion that the relationship between these structures is more complex than previously thought and that muscularis mucosae contraction is actively linked to mucosal function. The
pathophysiological consequence of using muscularis mucosae-induced
prostaglandin synthesis in a pathway that stimulates the mucosa is
that, in colitis, this system may be disproportionately disrupted
(34) because the muscularis mucosae and mucosa rapidly
become desensitized to eicosanoids (14, 32) and the
colonic mucosal innervation is significantly compromised
(14).
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ACKNOWLEDGEMENTS |
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This work was supported by the South Dakota Health Research Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: W. H. Percy, Division of Basic Biomedical Sciences, School of Medicine, The Univ. of South Dakota, Vermillion, SD 57069-2390 (E-mail: wpercy{at}usd.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published October 16, 2002;10.1152/ajpgi.00179.2002
Received 14 May 2002; accepted in final form 15 October 2002.
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