1 Departments of Medicine and Physiology, University of Western Ontario, London, Ontario, N6A 5B8 Canada; and 2 University of Toronto, Toronto, Ontario, M5S 1A1 Canada
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ABSTRACT |
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A myogenic control system (MCS) is a fundamental determinant of peristalsis in the stomach, small bowel, and colon. In the esophagus, attention has focused on neuronal control, the potential for a MCS receiving less attention. The myogenic properties of the cat esophagus were studied in vitro with and without nerves blocked by 1 µM TTX. Muscle contraction was recorded, while electrical activity was monitored by suction electrodes. Spontaneous, nonperistaltic, electrical, and mechanical activity was seen in the longitudinal muscle and persisted after TTX. Spontaneous circular muscle activity was minimal, and peristalsis was not observed without pharmacological activation. Direct electrical stimulation (ES) in the presence of bethanechol or tetraethylammonium chloride (TEA) produced slow-wave oscillations and spike potentials accompanying smooth muscle contraction that progressed along the esophagus. Increased concentrations of either drug in the presence of TTX produced slow waves and spike discharges, accompanied by peristalsis in 5 of 8 TEA- and 2 of 11 bethanechol-stimulated preparations without ES. Depolarization of the muscle by increasing K+ concentration also produced slow waves but no peristalsis. We conclude that the MCS in the esophagus requires specific activation and is manifest by slow-wave oscillations of the membrane potential, which appear to be necessary, but are not sufficient for myogenic peristalsis. In vivo, additional control mechanisms are likely supplied by nerves.
smooth muscle; slow waves; tetraethylammonium chloride; propagation; coupling
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INTRODUCTION |
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THE HUMAN ESOPHAGUS as well as that of a number of other species, including nonhuman primates, the cat, and the opossum, is composed of smooth muscle in its distal portion. Most studies exploring the control mechanisms responsible for peristalsis in this smooth muscle portion of the esophagus have focused on neural mechanisms and have led to the conclusion that the innervation, extrinsic and particularly intrinsic, is the only important controller of peristalsis in the smooth muscle portion (17, 20). However, operation of a myogenic control system (MCS) is a fundamental property of gastrointestinal smooth muscle (9), and its contribution in mediating esophageal peristalsis may be underestimated.
Elsewhere in the gastrointestinal tract, the MCS is of major importance in the control of peristalsis. The MCS displays two fundamental characteristics: 1) electrical control activity or slow waves, which cyclically depolarize the smooth muscle cells, and 2) the ability of the smooth muscle cells to communicate with each other (coupling) so that the whole tissue can operate as a functional unit (9). Consequently, the MCS of the stomach, small bowel, and colon smooth muscle can be modeled as populations of coupled relaxation oscillators (9). This model allows for the omnipresent myogenic electrical slow wave to dictate the timing and location of contractions, whereas intrinsic and extrinsic nerves modulate the slow wave and thus influence characteristics of the accompanying contractions such as velocity, duration, and amplitude.
Many characteristics of esophageal smooth muscle support the presence of a MCS in this organ as well. These include the morphology of esophageal smooth muscle, including the presence of interstitial cells of Cajal (ICC) (15), and the observation that esophageal circular muscle oscillates electrically and mechanically when adequately stimulated (4, 6, 19, 21, 23, 30). The esophageal body in vivo is normally electrically quiescent until a primary or secondary peristaltic contraction occurs. However, with the nerves blocked, a single or repetitive contraction can also traverse the smooth muscle esophagus at velocities similar to swallow-induced peristalsis (18, 27), suggesting that a MCS is present and can operate in the absence of functional innervation. The accompanying electrical events that might support a MCS, such as slow-wave activity, have not been adequately studied.
The present investigation using the cat was undertaken to further explore the nature of a myogenic mechanism that might contribute to the control of peristalsis in the smooth muscle esophagus and to examine whether an esophageal electrical slow wave participates in such a mechanism.
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MATERIALS AND METHODS |
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The experimental protocol was approved by the Animal Care Committee of
the Toronto Hospital. Twenty-four adult cats of either sex weighing
between 3.0 and 6.0 kg were anesthetized with xylazine (10 mg/kg im)
and urethan (0.8 g/kg iv). While respiration was maintained with an
endotracheal tube and ventilator (model 606; Harvard Apparatus, Doner,
MA), the left chest was opened and a marking silk suture was placed at
the angle of His and again on the esophagus, 5 cm proximally. The
esophagus was carefully excised from the arch of the aorta distally to
include a small cuff of stomach and was immediately transferred to a
tissue bath containing Krebs solution continuously aerated with 95%
O2-5%
CO2 at 37°C. Krebs solution
had the following composition (in mM) 143 sodium, 5.9 potassium, 2.5 calcium, 1.29 magnesium, 128 chloride, 2.2 phosphate, 24.9 bicarbonate,
1.2 sulfate, and 10.0 glucose. The sodium-chloride content of the Krebs
solution was adjusted to maintain normal osmolality in experiments with
tetraethylammonium chloride (TEA) and high potassium. Two types of in
vitro preparations were studied and they are shown schematically in
Fig. 1. The preparations were allowed to
equilibrate for 1 h before beginning the experiment.
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Preparation A. After the esophagus was dissected free of surrounding fascia, it was inverted onto itself, and the entire mucosa was removed by sharp dissection. After the esophagus was returned to its in situ length, circular side out, it was fixed with pins at both ends to the bottom of the bath (Fig. 1A). Circular muscle contractions were monitored by a manometric tube placed intraluminally with three ports situated 1, 2, and 3 cm proximal to the junction of the gastric and esophageal mucosa. The lumens were perfused (0.3 ml/min per lumen) with Krebs solution by low-compliance pressurized infusion pump (Mui Scientific, Mississauga, ON). Longitudinal muscle contractions were recorded by a single isometric force transducer (model FT.03c; Grass Instruments, Quincy, MA), fastened via a lever to a silk suture tied at the gastroesophageal junction.
Preparation B. The esophagus was dissected free of surrounding fascia and opened lengthwise, and the entire mucosa was removed by sharp dissection (Fig 1B). After the esophagus was returned to its in situ length, circular muscle up, it was secured by pinning half of it along its length to the bottom of the bath (Sylgard, Dow Corning, Midlands, MI). Circular contractions were recorded isometrically by three force transducers (FT.03c, Grass Instruments) and fastened by silk sutures tied to the free edge of the esophagus at a distance 1, 2, and 3 cm proximal to the junction of the esophageal and gastric mucosa. Longitudinal contractions were recorded as previously described for the intact esophagus.
Electrical stimulation. Proximal or distal electrical stimulation (ES) was achieved by a single square-wave pulse (0.5-500 ms and 10-100 V) delivered from a Grass S88 stimulator via a Grass SIU5B Stimulus Isolation Unit (Grass Instruments). Stimulating electrodes consisted of two pairs of Teflon-coated stainless steel wires from which a 0.25-cm portion of Teflon was stripped and implanted intramuscularly 0.25-0.5 cm proximal and distal to the cranial and caudal recording sites, respectively.
Electrical recording. For both preparation A and B, electrical activity was monitored by three suction electrodes spaced 1 cm apart and applied directly to the circular muscle, as close to the manometric recording sites as possible (preparation A) or 0.2-0.3 mm from the point of attachment of the isometric transducers (preparation B). Electrical signals were initially DC amplified (Intronix model 2015-1-DC; Intronix Technologies, Toronto, ON) and filtered with a low cutoff of 100 Hz by subsequently passing the signal through a bioelectric amplifier (8811A; Hewlett Packard, Waltham, MA). Contractions and electrical events were recorded on a direct-writing ink-pen polygraph (Gould 2800S).
Materials. Atropine sulfate, TEA, and TTX were obtained from Sigma Chemical (St. Louis, MO). Bethanechol chloride was obtained from Merck Frost (Kirkland, PQ).
Statistics. Values are reported as means ± SE. Statistical comparisons were made with Student's t-test. P < 0.05 was considered significant.
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RESULTS |
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Spontaneous activity.
A total of 20 experiments were performed with
preparation A. Sixteen of the 20 preparations (80%) initially showed spontaneous brief bursts of spike
potentials (0.5-2 s) superimposed on a small depolarization and
occurring at the onset of longitudinal muscle contraction. These phasic
events of longitudinal muscle occurred with a frequency of 0.9-7.8
min1 (Fig.
2A). In
10 preparations the spike burst was followed at each recording site by
hyperpolarization lasting 5-10 s and occurring during the
longitudinal muscle contraction. These spike potentials were
simultaneous at each recording site and were associated with low
amplitude (<2 mmHg) increases in intraluminal pressure measured by
manometry, coordinated with the longitudinal muscle contraction and the
electrical activity described previously. The spontaneous spike bursts
and accompanying longitudinal contractions persisted in the presence of
10
6 M TTX (Fig.
2B) However, the
depolarization-hyperpolarization changes accompanying these
longitudinal contractions were blocked, suggesting neuronal involvement
in their genesis.
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Effects of muscle stretch.
Spontaneous peristaltic electrical or mechanical activity was not seen
in preparation A, except in a single
preparation (Fig. 3), which became
distended by the intraluminal perfusion. This preparation exhibited
prolonged periods of electrical membrane potential oscillations with
superimposed spiking, occurring both spontaneously and after ES. The
rate of distal progression of the electrical activity was ~0.7 cm/s.
The manometric recording did not show peristaltic contractions because
of the common cavity created by fluid distension. When the esophagus
was vented to allow the egress of fluid, repetitive activity ceased.
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ES and effects of intrinsic nerves.
Representative records of the responses to ES of
preparation A are shown in Fig.
5. A short-duration stimulus (0.5 ms), used to selectively activate nerve rather than smooth muscle, applied as a
single pulse produced a predominant hyperpolarization response frequently followed by a slight depolarization (Fig.
5A). Similar inhibitory junction
potentials have been reported previously for both vagal and field
stimulation of cat and opossum esophageal tissue (4, 7, 11, 12, 22,
25). A single long-duration pulse (500 ms) not only stimulated
intrinsic nerves, but also directly activated muscle as evidenced by
the twitch contraction of the longitudinal muscle. The electrical
responses to a long-duration stimulus were qualitatively similar to the
0.5-ms pulse but of greater magnitude (Fig. 5,
A and
B). In some preparations, the after-depolarization with superimposed spiking was accompanied by a
circular muscle contraction, consistent with a typical off contraction
(Fig. 5B) (30). Neither the short-
nor long-duration stimulus when applied as a single pulse produced a
peristaltic response. The hyperpolarization and depolarization
responses to both short- and long-duration single pulses were abolished
by 106 M TTX (Fig. 5,
C and
D), as were off contractions. The
long-duration pulse still produced a twitch contraction of the
longitudinal muscle (Fig. 5, D and
E) and depolarization accompanied by
circular muscle contraction with adequate stimulation (500 ms at 100 V as shown in Fig. 5E).
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Cholinergic stimulation.
With nerves blocked by 106
M TTX, stimulation by bethanechol
(10
7-10
6
M) enhanced the circular muscle contraction to direct myogenic activation by broad-pulse ES. In 5 of 7 preparations, a brief electrical depolarization with superimposed spiking and an associated second component to the muscle contraction were observed (Table 1 and Fig. 6).
Both the spike potentials and the rapid pressure rise were peristaltic
distally when the stimulus was applied at the proximal site and
reversed with stimulation at the distal site (Fig. 6). Higher
concentrations of bethanechol
(10
6-10
5
M) often produced continuous slow-wave-like electrical oscillations and
superimposed spiking accompanied by phasic circular muscle contraction
(Fig.
7A).
These slow waves were similar to those observed with distension of the
esophagus (Fig. 3) and with bethanechol stimulation of
preparation B (Fig. 4). Slow waves had
a duration of 5.7 ± 0.3 s and a rate of 8.4 ± 1.1 min
1 at maximum bethanechol
concentration (n = 7). In some
preparations the amplitude of the slow waves, the presence of spiking,
and the amplitude of the accompanying contractions tended to wax and wane with a period of 1.3 ± 0.1 min
(n = 4), as shown in Fig. 7A. However, in contrast to
preparation B, this continuous
slow-wave activity and the repetitive contractions were not
peristaltic.
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High K+.
Because cholinergic excitation of smooth muscles occurs in part by
membrane depolarization, we examined the effects of increasing bath
K+ concentration in this
preparation. In the presence of
106 M TTX, increasing bath
K+ (10-40 mM) enhanced the
amplitude of the circular muscle contraction to broad-pulse ES (not
shown), similar to the effect seen with bethanechol (Fig. 6). High
K+ also induced low-amplitude,
repetitive circular muscle contractions (4.5-9
min
1) associated with
slow-wave-like electrical oscillations with spiking (Fig.
7D). Neither the spontaneous
repetitive contractions nor ES contractions were peristaltic. The high
K+-induced slow waves were
transient, and the effect of cholinergic blockade could not be assessed.
TEA.
TEA has certain similarities in its action to cholinergic activation in
cat esophageal muscle (28), and others have shown that TEA can
facilitate myogenic peristalsis in the presence of neural blockade in
the opossum esophagus (18, 27). Hence, the effects of TEA were examined
in the present model. As observed in the presence of bethanechol (Fig.
6) and high K+, circular muscle
contraction to broad-pulse ES was markedly enhanced by TEA (not shown).
In addition, slow-wave-like oscillations of the membrane potential were
observed (Figs. 7C and
8). These occurred at a frequency of 5.4 ± 0.9 min1 and had an
average duration of 7.5 ± 0.7 s with 20 mM TEA. The associated
spike potentials were usually seen on the upstroke phase of the slow
wave and coincided with the onset of circular muscle contraction. These
spontaneous electrical oscillations gave rise to circular muscle
contractions that were peristaltic either proximally or distally (Table
1 and Fig. 8). Broad-pulse ES produced a slow wave accompanied by a
contraction, both of which were peristaltic distally or proximally,
depending on the site of stimulation (Fig. 8). The rate of propagation
of these events was the same both proximally and distally and was not
significantly different from the rate of peristalsis of the spontaneous
activity seen in the presence of bethanechol (Table 1). Unlike
bethanechol, peristaltic contraction could be initiated by broad-pulse
ES in the presence of TEA-induced repetitive spontaneous peristaltic contractions. At TEA concentrations >30 mM, oscillations became rapid
and appeared to initiate at several sites along the esophagus, obscuring peristaltic activity. Neither spontaneous nor electrically stimulated peristalsis nor TEA-induced slow waves were blocked by
10
6 M atropine (not shown).
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DISCUSSION |
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When adequately stimulated and with nerves blocked by TTX, a single or repetitive electrical oscillation with superimposed spiking and associated contraction can proceed along the cat esophagus in peristaltic fashion. Therefore, in the smooth muscle esophagus of the cat as in the opossum (18, 27), there exists the capability for peristalsis through operation of a myogenic mechanism. The present study demonstrates that this myogenic peristaltic contraction is associated with electrical control activity, similar to the myogenic slow waves that have been recorded from muscles of the stomach, small bowel, and colon. The esophageal slow wave could be produced by depolarization with high K+, cholinergic stimulation, muscle stretch, or blockade of K+ channels by TEA.
The validity of our demonstration of a myogenic mechanism is based
primarily on the premise that TTX completely blocks all nerves in the
esophagus. Although some nerves are TTX-insensitive (3), this is
exceptional and has never been demonstrated in the esophagus. We used
106 M TTX, a concentration
several times greater than usually needed to adequately block nerves.
Furthermore, in each experiment, we confirmed that the nerve-mediated
responses to ES with a short-duration pulse (0.5 ms) were blocked and
could not be overcome with larger pulses (50-500 ms) required for
direct muscle activation. We cannot rule out the possibility that a
500-ms pulse might stimulate the release of neurotransmitter directly
from nerve varicosities. Even if this were so, the peristaltic
responses we observed would nonetheless not involve axonal signaling
nor represent a physiological contribution of the intrinsic nerve pathways.
Sarna et al. (27) and Helm et al. (18) have shown myogenic peristaltic contraction in the opossum in vivo and in vitro, respectively, but did not record the associated electrical events in their studies. However, a number of investigators have shown, usually in isolated strips, that esophageal circular (4, 6, 21-23, 27) and longitudinal (5, 23) smooth muscle can be stimulated to produce repetitive electrical slow-wave-type activity with superimposed spike bursts and associated repetitive contractile activity. Progression of such combined electrical and mechanical activity along the esophagus was not assessed. We studied the progression of this combined activity. In the present study, electrical recordings were made from the circular muscle side of the esophagus and therefore reflect primarily the electrical activity of this layer. Even recordings from the outer longitudinal muscle layer in the intact esophagus faithfully pick up the circular muscle activity with little interference from the longitudinal layer (29).
We observed spontaneous repetitive activity in the cat esophagus with nerves intact. However, peristalsis of this activity or that induced by ES was seen only when a generalized stimulus of some type was present: bethanechol (both preparations) or distension (preparation A). Similarly, after the addition of TTX (preparation A), we were able to demonstrate electrical or mechanical peristalsis only in the presence of bethanechol or TEA. In the intact opossum esophagus in vitro, spontaneous contractile activity was not seen and both repetitive activity and its peristaltic progression required stimulation with TEA, bethanechol, or high K+, with or without TTX nerve blockade (18). Sarna et al. (27) found that in vivo, myogenic peristaltic responses in the opossum esophagus were more easily elicited with multiple electrical stimuli, with local infusion of TEA, or shortly after the animal was killed by asphyxiation (27). They hypothesized that membrane depolarization facilitated the myogenic response, as did Helm et al. (18).
Although we occasionally recorded slow-wave-like activity after the addition of high K+, the activity was never peristaltic, both electrical activity and contractions were of low amplitude, and neither were well maintained. Similarly in the opossum esophagus, K+ stimulation of peristaltic activity in vivo (27) or in vitro (18) is less effective even with nerves blocked. Therefore, depolarization of the smooth muscle alone may not be sufficient for the myogenic oscillatory and peristaltic mechanism to become established. Mechanisms other than tissue depolarization are likely to be important in producing conditions suitable for myogenic peristalsis to occur. For example, TEA and bethanechol similarly suppress K+ channel activity (28), an effect that would not be mimicked by depolarization of the tissue by high K+. In contrast to findings in the opossum (18), myogenic peristalsis in the cat esophagus with bethanechol stimulation was observed infrequently. This could be the result of simultaneous stimulation of the entire cat esophagus by bethanechol, resulting in multifocal excitation that obscured peristalsis, reflecting the species difference in the cholinergic sensitivity of peristalsis, with the cat being more sensitive (2, 16).
The present findings in the cat and those reported in the opossum (18, 27) indicate that that there is communication (coupling) within a myogenic mechanism for peristalsis that can operate independent of the extrinsic and intrinsic neural control mechanisms. Our experiments do not determine whether the oscillatory activity and its peristaltic progression are manifestations of a coupled oscillator system (9) or to what extent an active cable-core conductor system is involved (24). Intracellular microelectrode studies using the Abe-Tomita technique have shown high electrical connectivity of the circular muscle layers of the opossum esophagus when measured in the direction of the muscle fibers but poor conduction when measured perpendicular to the circular muscle fibers, that is, in the long axis of the esophagus (8). Morphologically, the smooth muscle cells in the circular layer are arranged in bundles or lamellae that are separated by fibrous tissue septae containing nerves, blood vessels, and other types of cells (15). Therefore, it is not known how communication would occur in the long axis and across the septae that separate the lamellae. Progression of a myogenic contraction would require that the circular muscle electrical oscillation be successively activated by communication through one or more potential mechanisms. These might include 1) circular smooth muscle cells extending through the lamellae and connecting to adjacent muscle bundles, 2) a smooth muscle-ICC network; if the ICC can be considered part of the myogenic system as proposed for elsewhere in the gut, they hold the potential to serve as a muscle-muscle communication pathway (10, 26), and 3) communication with the longitudinal muscle layer such that myogenic activity propagating in the longitudinal layer is transmitted to the circular muscle. Our experiments were not designed to explore or differentiate these possibilities.
In vivo with the nerves intact, swallow-induced peristalsis and the activity following intraluminal balloon distension or vagal stimulation are characterized in the circular muscle esophagus by a preceding hyperpolarization, followed by a depolarization with superimposed spiking and the contraction (12, 22, 25). With nerves intact, we observed similar electrical events in association with the single peristaltic contraction produced by the ES. These events are usually considered the local muscle responses to neural signals directing sequential inhibition and excitation along the esophagus, and consequently neural control has been considered sufficient for regulation of peristalsis. However, the concept fails to consider muscle properties and their potential contribution and involvement. In our experiments, when peristaltic progression of activity occurred in the presence of nerve blockade, only an electrical depolarization or slow wave was seen and the preceding hyperpolarization was absent. Therefore, the slow wave appeared as an actively generated event independent of rebound depolarization, and the wave progressed with a delay along the esophagus without the influence of inhibitory innervation or timed neural excitation. That is, when adequately excited, there is within the muscle itself the capacity to generate a peristaltic electrical slow wave and associated contraction, the characteristics of a MCS.
The relationship between a MCS, including the inducible slow-wave activity we have demonstrated, and normal peristalsis is not known. The esophagus is normally quiescent in vivo except for the single swallow-induced or secondary peristaltic contraction. Sarna et al. (27) proposed that the MCS in the esophagus is consistent with a mechanism involving a chain of bidirectionally coupled oscillators, and in the context of a coupled oscillator system its behavior could be considered a "one-shot" oscillation. It is of interest that the velocity of spontaneous and electrically stimulated myogenic peristaltic activity is similar to that of primary and secondary peristalsis in the opossum (18, 27), although slightly slower in the cat (0.8-1.0 vs. 1.5-2.0 cm/s, respectively). Therefore the myogenic system is intrinsically set to operate in a time frame similar to normal swallow-induced activity, a characteristic feature of linked control systems serving a common function (14). Of particular importance is the integration of the MCS with the neural control involved in normal swallow-induced peristalsis. We speculate that this could include 1) the myogenic system playing no significant role, the peristaltic contraction being controlled entirely by the timing and balance of the excitatory and inhibitory innervation; 2) the MCS serving as the primary mediator of the peristaltic contraction, with nerves regulating the coupling, the excitability, and the oscillatory characteristics, thus modulating the direction, velocity, and amplitude of the contraction, and ensuring the occurrence of a single contraction; and 3) regional differences in muscle properties along the length of the esophagus permitting different muscle responses (e.g., timing, duration of muscle contraction) to the innervation.
Nonetheless, the MCS may have particular relevance to esophageal motor disorders. In this context, simultaneous contractions, reversed peristalsis, and repetitive contractions may be best characterized and understood as alterations of the myogenic system, whether directly or indirectly, by physiological events or disease processes. Neural derangement would be seen as impacting on operation of a MCS. For example, most spastic motor disorders such as achalasia and diffuse esophageal spasm are associated with repetitive contractions. One view of these disorders sees the MCS as overtly expressing its oscillatory self when normal neural control mechanisms (especially inhibition) fail and the muscle is subject to an excitatory-inhibitory imbalance (1, 13). This imbalance could also explain simultaneous contractions. Furthermore, the potential is present to utilize the MCS in those conditions where central or peripheral neural mechanisms are damaged or ineffective. Therapy such as electrical pacing of the muscle and pharmacological tools could be more specifically directed.
In conclusion, the smooth muscle portion of the cat esophagus is capable of peristalsis by a purely myogenic mechanism in vitro when specifically activated. Under these conditions, a myogenic electrical slow wave is observed. If this mechanism also functions in vivo, it likely requires neuronal input to activate and maintain conditions required for its expression. As such, the myogenic mechanism working in concert with neuronal mechanisms would represent an additional level of motor control in the esophagus. The extent to which this MCS normally contributes to esophageal peristalsis remains for further study.
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ACKNOWLEDGEMENTS |
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We are grateful to T. T. Hynna-Leipert and L. Tremblay for technical assistance and T. Chrones and D. Valdez for help in preparing the manuscript.
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FOOTNOTES |
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This work was funded by the Medical Research Council of Canada. H. G. Preiksaitis is an Ontario Ministry of Health Career Scientist and was supported by an ICI Pharma/Medical Research Council of Canada Research Fellowship while conducting some of the studies reported.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: H. G. Preiksaitis, Dept. of Medicine, St. Joseph's Health Centre, 268 Grosvenor St., London, ON, Canada, N5X 1C6.
Received 19 November 1998; accepted in final form 3 May 1999.
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