Dysphagia Institute and Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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We investigated the mechanisms of esophageal distension-induced reflexes in decerebrate cats. Slow air esophageal distension activated esophago-upper esophageal sphincter (UES) contractile reflex (EUCR) and secondary peristalsis (2P). Rapid air distension activated esophago-UES relaxation reflex (EURR), esophago-glottal closure reflex (EGCR), esophago-hyoid distraction reflex (EHDR), and esophago-esophagus contraction reflex (EECR). Longitudinal esophageal stretch did not activate these reflexes. Magnitude and timing of EUCR were related to 2P but not injected air volume. Cervical esophagus transection did not affect the threshold of any reflex. Bolus diversion prevented swallow-related esophageal peristalsis. Lidocaine or capsaicin esophageal perfusion, esophageal mucosal layer removal, or intravenous baclofen blocked or inhibited EURR, EGCR, EHDR, and EECR but not EUCR or 2P. Thoracic vagotomy blocked all reflexes. These six reflexes can be activated by esophageal distension, and they occur in two sets depending on inflation rate rather than volume. EUCR was independent of 2P, but 2P activated EUCR; therefore, EUCR may help prevent reflux during peristalsis. All esophageal peristalsis may be secondary to esophageal stimulation in the cat. EURR, EHDR, EGCR, and EECR may contribute to belching and are probably mediated by capsaicin-sensitive, rapidly adapting mucosal mechanoreceptors. GABA-B receptors also inhibit these reflexes. EUCR and 2P are probably mediated by slowly adapting muscular mechanoreceptors. All six reflexes are mediated by vagal afferent fibers.
secondary peristalsis; belching; swallowing; capsaicin; baclofen
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INTRODUCTION |
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A NUMBER OF
DISTENSION-INDUCED reflexes of the esophagus have been
identified, but the mechanisms of these reflexes are largely unknown.
Five distension-induced esophageal reflexes have been identified and
characterized (Table 1), and they include
1) secondary peristalsis (30); 2)
esophago-upper esophageal sphincter (UES) contractile reflex (EUCR)
(9); 3) esophago-UES relaxation reflex (EURR)
(40, 42, 43); 4) esophago-glottal closure
reflex (EGCR) (40, 42); and 5) the esophageal
belch (EB) (19, 41). Some of these reflexes have been
characterized primarily in humans, which precluded full
characterization of all muscular elements of the motor responses,
identification of the neural pathways, or full quantification of
sensory mechanisms. Most of these reflexes were investigated
independent of the other esophageal reflexes, which precluded a full
understanding of the role or function of these reflexes. Therefore,
although five separate esophageal reflexes have been identified, the
relationship of these reflexes to each other is unclear.
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The neural pathways for some but not all of these reflexes have been investigated. The motor nerves to all of the muscles of these reflexes are known (13, 16), but the afferent pathways of the some of these reflexes have not been investigated (Table 1). The esophagus has receptors that project to the central nervous system via the vagus or splanchnic nerves (14), but the specific afferent pathways of EURR, EGCR, and EB are unknown.
The distension-induced esophageal reflexes can be categorized according to the general type of stimulus that produces the response. Slow esophageal distension with fluid, air, or balloon activates EUCR and secondary peristalsis (9, 17, 33), whereas more rapid esophageal distension using air or balloon triggers EGCR (40, 42), EURR (40, 42), or EB (19, 41). The specific responses depend on the type and magnitude of the esophageal stimulus. These reflexes have not been investigated in the same species under the same experimental conditions; therefore, it is difficult to quantitatively compare activation characteristics among these reflexes. However, this qualitative difference among reflexes suggests that there may be at least two different types of mechanosensory mechanisms of the esophagus, a set of responses activated by slow distension and a set of responses activated by rapid distension. The mechanisms that account for this difference are unknown.
A number of mechanoreceptors of the esophagus that project centrally through the vagus nerves have been identified physiologically, but the function of these individual receptors has not been investigated. Esophageal mechanoreceptors have been classified according to their 1) location in the gut wall: mucosal (29, 31) or muscular (6, 31, 37, 39); 2) response characteristics: rapidly adapting (29) or slowly adapting (6, 31, 37, 39); 3) activating force: tension (6, 31, 37, 39) or touch (29, 31); 4) activating stimulus direction (39): circular or longitudinal tension; and 5) effects of chemical stimulation (15, 31): responsive or not responsive. However, the role of any of these receptors in mediating specific esophageal functions or reflexes is unknown.
The neurochemical pathways mediating the esophageal reflexes have not been investigated. Transient lower esophageal sphincter (LES) relaxation activated by gastric distension may be controlled by GABA-B receptors, as this response is blocked by the GABA-B agonist baclofen (5, 25), but the effects of baclofen on distension-induced esophageal reflexes are unknown.
The aims of this study were to 1) characterize and quantify the previously identified distension-induced reflexes of the esophagus, 2) determine the types of receptors that mediate these reflexes, 3) determine the afferent pathways of these reflexes, and 4) determine the effects of GABA-B receptor activation on these reflexes.
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METHODS |
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Animal Preparation
We studied 45 decerebrate cats of either sex weighing 2.4-4.3 kg. The cats were decerebrated so that the invasive preparation could be performed with minimal anesthesia and analgesia. In prior studies (23), we found that all esophageal reflexes were preserved and highly responsive with our technique, whereas anesthesia with Telazol (42) orBipolar electrodes were sutured onto the geniohyoideus (GH), cricopharyngeus (CP), cricothyroideus (CT), thyrohyoideus (TH), thryoarytenoideus (TA), cricoarytenoideus dorsalis (CD), and intraarytenoids (IA) to record electromyography (EMG) activity, and a five-channel solid state manometric catheter was inserted into the esophagus through a stomach fistula and the LES to record esophageal pressure. A small-diameter polyethylene tube (PE 90) was placed at midesophagus to be used for injection of air or fluid. This injection tubing was attached to the manometric catheter so that the tip was situated between the third and fourth strain gauges (~8-9 cm from the LES) with Parafilm strips.
The animal was placed supine on a surgical board; esophageal manometry, EMG activities, and femoral arterial blood pressure were recorded on polygraph and computer; and the experiments were begun. The entire preparation time from the point of decerebration was at least 2 h, which allowed for metabolism and excretion of halothane and residual adrenergic agents (10).
Manometric Recording of Esophageal Peristalsis
The intraluminal pressures of the esophagus were recorded using a five-channel solid-state manometric catheter (Gaeltec, Medical Measurements). The individual recording sites were situated 3 cm apart, allowing for recording sites throughout most of the length of the cat esophagus (15-20 cm long). The most distal recording site was situated ~4 cm orad to the LES. The pressures were recorded using DC preamplifiers (P122) of a Grass polygraph (model 7) and stored on a computer.EMG of Pharyngeal and Laryngeal Muscles
Bipolar Teflon-coated stainless steel wires (AS 632; Cooner Wire, Chatsworth, CA) bared for 2-3 mm were placed in each muscle, and the wires were fed into differential amplifiers (Grass P15 or A-M Systems 1800). The electrical activity was filtered (bandpass of 0.1-3.0 KHz) and amplified 1,000-10,000 times before feeding into the computer.Characterization and Quantification of Esophageal Reflexes
In prior studies (14), it was found that esophageal mechanoreceptors can be differentiated on the basis of their response characteristics. We investigated the response characteristics of the five previously identified esophageal reflexes to determine which reflexes behaved similarly to the different types of esophageal receptors.The five previously identified distension-induced esophageal reflexes were activated by the injection of air into the esophagus but at different rates. Secondary peristalsis and EUCR were stimulated by slow air injection (0.1-10 ml) at 1-50 ml/min with a Harvard infusion pump attached to the esophageal injection catheter. EURR, EGCR, and belching were stimulated by rapid air injection. The plunger of a 10-ml syringe was struck as rapidly as possible by the same individual in all experiments. The time for injection of tested volumes (2-15 ml) was determined, and the rate (ml/s) of injection was found to be a linear relationship (R2 = 0.992) of rate [= 48.9 + (30.2 × volume)]. The rates ranged from 100 to 470 ml/s, and time of injection ranged from 0.020 to 0.032 s for volumes of 2-15 ml.
The reflexes were identified as follows. Secondary peristalsis was identified as esophageal peristalsis that was not preceded by a swallow (11). EUCR was identified as activation of the CP without prior inhibition and without activation of the GH or the laryngeal muscles (33). EURR was identified as inhibition of the CP without concomitant activation of swallowing (19, 40, 42). EGCR was identified as activation of glottal closure muscles (IA, TA, or CT) without concomitant activation of swallowing (23, 40, 42). EB was identified as long-term (>0.5 s) inhibition of the CP with concomitant activation of the laryngeal muscles and hyoid muscles [TH (primarily) or GH] (19, 21, 41). Secondary peristalsis often occurred after the belch (19, 21, 41). Swallowing was identified as sequential activation of GH, TH, and CP, and preceding CP activation as inhibition of CP (<0.35 s) simultaneous with activation of laryngeal closure muscles (11).
Relationship Between Secondary Peristalsis and CP EMG Activity
Prior studies (43) found that secondary peristalsis is associated with an increase in UES pressure, but it is unknown whether this UES response is part of the peristaltic wave or due to EUCR. We correlated the timing and magnitude of secondary peristalsis with the injected volume and CP EMG activity to determine the mechanism of this association.In 18 cats, we injected air into the midesophagus at 50 ml/min as described in Characterization and Quantification of Esophageal Reflexes to activate secondary peristalsis and associated increase in CP EMG. The magnitude of the peristaltic wave at the five esophageal recording sites was quantified and correlated with the magnitude of the associated increase in CP EMG. In addition, we quantified the delay from peak of the CP EMG response to the peak of the peristaltic wave at five esophageal recording sites.
Effect of Transection and Bolus Diversion
Many of the protocols required transection of the esophagus just below the UES; therefore, we tested whether this transection affected the distension-induced esophageal reflexes. In addition, prior studies in other species with a striated muscle esophagus (27) indicated that a bolus was necessary for initiating primary as well as secondary peristalsis, and we wanted to test this in a species with an esophagus with smooth muscle.In 28 cats, we determined the threshold for activation of the distension-induced esophageal reflexes before and after transection of the esophagus just caudal to the UES. In four cats, we placed a three-way stopcock between the UES and proximal esophagus through a longitudinal stab wound to minimally disturb esophageal innervation. We then tested the effects of diverting a swallowed bolus. Swallowing was stimulated by injection of water (1 ml) into the pharynx through small-diameter polyethylene tubing (PE 50). In one cat, swallowing was stimulated by centripetal electrical stimulation (1 V, 0.2 ms, 30 Hz for 10 s) of the superior laryngeal nerve (SLN) without injection of air or water in the pharynx or esophagus.
Role of Longitudinal Tension Receptors in Distension-Induced Esophageal Reflexes
Prior studies by Sengupta et al. (39) found that some tension-sensitive esophageal mechanoreceptors responded to longitudinal rather than circular stretch. We investigated whether longitudinal stretch of the esophagus could elicit any of the reflexes activated by air injection.In three cats, the esophagus was transected just below the UES to prevent stimulation of supraesophageal structures. The cut ends were ligated, and the distal cut end was fixed in its anatomically correct position by a clamp. A ligature was placed around the gastroesophageal junction similar to the studies of Sengupta at al. (39), which was used to apply caudal longitudinal tension on the esophagus. The gastroesophageal junction was rapidly pulled caudally for a distance of 1-2 cm.
Role of Mucosal Layer Receptors in Distension-Induced Esophageal Reflexes
Intraluminal infusion of lidocaine. Lidocaine has been used successfully in the past to anesthetize mucosal receptive pathways of the digestive tract to determine their role in various functions (3). We investigated the effect of intraluminal administration of lidocaine on the distension-induced esophageal reflexes.
In three cats, the esophagus was isolated by cannulation at the UES and LES (through the gastric fistula) for infusion of lidocaine to the esophagus only. After obtaining control responses to air injection into the esophagus, we slowly infused 15 ml of lidocaine (2%) into the esophagus through the air injection catheter. Lidocaine was infused slowly to prevent stimulation of secondary peristalsis. After 10 min, we flushed the esophagus with 50 ml of 0.9% NaCl over a period of 5 min and retested the responses to air injection.Intraluminal perfusion of capsaicin. It was found previously that intraluminal administration of capsaicin stimulates (at low doses or initially) and then desensitizes (at high doses or after prolonged administration) primary vagal afferents of the esophagus (32). We investigated the effects of capsaicin given intraluminally on the sensitivity of the distension-induced esophageal reflexes.
In six cats the esophagus was isolated by cannulation at the UES and LES as described in Intraluminal infusion of lidocaine. This preparation allowed us to stimulate the esophagus only. The esophagus was then perfused through the air injection catheter for 12-min periods at 2 ml/min with a Harvard infusion pump and the following solutions at room temperature and in the following order: 1) H2O, 2) vehicle, and 3) two to three perfusion periods of capsaicin (1 mg/ml of vehicle). The vehicle was 0.2% HCl in a 50%-50% solution of H2O and propylene glycol. Capsaicin was first dissolved in HCl and then in the 50% propylene glycol solution. The H2O perfusion was used as a control for the effects of esophageal perfusion of fluid. The distension-induced reflexes were tested after each capsaicin infusion period, and the capsaicin perfusion periods were terminated when one or more of the reflexes were significantly altered.Removal of esophageal mucosal layer. In prior studies it was found that vagally innervated esophageal mechanoreceptors were found either in the mucosa or muscularis (6, 14, 34, 35) and that excision of the mucosal layer could help identify the location of these mucosal receptors (6). We investigated the effects of removal of the mucosal layer (mucosa and submucosa) on the distension-induced esophageal reflexes to determine the role of mucosal mechanoreceptors in these reflexes.
In 15 cats, the esophagus just caudal to the UES was transected and the proximal end was ligated before the experiments were conducted. After control recordings of all reflexes were obtained, the mucosal layer of the esophagus was removed. A ligature was fed up through the stomach and LES to the transected esophagus. The mucosal layer was bluntly dissected from the overlying muscularis layer for 1-2 cm. The ligature was tied around the mucosal layer and was pulled caudad through the LES in a slow but steady motion. The mucosal layer was pulled out of the stomach until most of the mucosal layer was removed from the esophagus. The proximal end of the esophagus was then ligated, and the reflexes were tested again. At the end of the experiment, the esophagus was opened to confirm removal of the mucosal layer from the entire esophagus. If the total extent of the esophageal mucosal layer was not removed, the results were discarded.Determination of Afferent Pathway of Esophageal Reflexes
In prior studies it was found that some of the esophageal receptors project to the spinal cord via the splanchnic nerves (7) and some project to the brain stem via the vagus nerve (3, 6, 15) and nodose ganglion (6). We investigated the effects of vagotomy on the distension-induced esophageal reflexes.Thoracic vagotomy. The effects of thoracic vagotomy on the distension-induced esophageal reflexes were tested in three cats to determine whether any of the esophageal reflexes were mediated by vagal afferents. Because the vagus nerve contains efferents to the esophagus and branches of the vagus nerve supply efferent innervation to many of the muscles we investigated, the vagus nerve was transected in a location that would have minimal effects on efferent pathways but maximal effects on afferent pathways. Therefore, we transected the vagus nerve at the level of the heart, which was caudal to the branch points of the superior laryngeal (motor nerve of CT), recurrent laryngeal (motor nerve of IA, TA, and CD), and pharyngoesophageal (motor nerve for the CP) nerves. This preserved motor innervation to the pharynx, larynx, and proximal cervical esophagus but severed afferents and efferents to most of the esophagus.
After control responses to the distension-induced esophageal reflexes were obtained, the chest was opened between T3 and T4 on both sides and the vagus nerves coursing near the heart were identified. The effectiveness of these reflexes were confirmed, and the vagus nerves were transected. After a 30-min wait, the distension-induced esophageal reflexes were tested again to determine which of these reflexes was mediated by vagal afferents.Effects of Baclofen
Baclofen, the GABA-B agonist, has been found to inhibit the reflex transient relaxation of the LES (TLESR) activated by distension of the proximal stomach (5, 25), and its effects may be centrally mediated (4). We investigated whether baclofen may also inhibit distension-induced reflexes of the esophagus. In nine cats, we tested the distension-induced esophageal reflexes before and after the intravenous administration of baclofen (1 mg/kg or 4.7 µM/kg).Data Acquisition, Reduction, and Analysis
The data were acquired on a computer using CODAS hardware and software. The threshold volumes for activation of each muscular response was determined two ways: 1) determining the ES50 for activation of a response at 50 ml/min using probit analysis or 2) determining the volume at which a response was first observed at a given rate of injection. The first method was used to characterize and quantify the specific motor responses to different volumes of injection. The ES50 was defined as the stimulus that activated the response 50% of the time, and it is analogous to and calculated the same way as ED50. The second method was used to determine the effects of various experimental procedures. The EMG response of the CP during secondary peristalsis was correlated with the magnitude of the esophageal peristaltic contractions using Pearson's product moment correlation coefficient (R value). The R value (+1.0 to
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RESULTS |
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Responses to Slow Air Distension of Esophagus
Effects of volume of injection.
The slow injection of air into the esophagus activated both
secondary peristalsis and EUCR as evidenced by the activation of CP EMG
activity but not activation of glottal or hyoid muscles (Fig.
2, top; Table
2). The minimal volume needed to
activate CP EMG and secondary peristalsis at 50 ml/min was 0.5 ml. The ES50 volumes for activation of secondary peristalsis and
EUCR at a constant rate of 50 ml/min were not significantly different (Table 2); however, in a number of cases it was possible to activate EUCR independent of secondary peristalsis (Fig.
3, top).
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Effects of rate of injection. The threshold volumes for activation of EUCR (1.9 ± 0.2; N = 36, P = 0.871) or secondary peristalsis (1.9 ± 0.2; N = 34, ANOVA, P = 0.886) were not related to the rate of injection at 50, 10, 5, and 1 ml/min. The minimal volume at any rate of injection needed to activate CP EMG and secondary peristalsis was 0.3 ml at 10 ml/min.
Relationship between Secondary Peristalsis and CP EMG Activity
The magnitudes of CP EMG and the injection volume were correlated significantly (P < 0.05) with the magnitudes of the esophageal peristalsis at the orad four and three recording sites, respectively. However, the R values for the relationships between CP EMG and esophageal peristalsis were about twice as large as the R values for the relationships between injection volume and esophageal peristalsis (Fig. 4; Table 3).
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We also found a temporal relationship between secondary peristalsis and
activation of CP EMG. Secondary peristalsis did not always begin at the
most orad recording site at 16 cm (58 times in 14 animals) from the LES
but sometimes occurred at 13 cm (36 times in 9 animals) or 10 cm (6 times in 4 animals) from the LES (Fig. 4; Table
4). The activation of CP EMG did not
occur at a fixed time relative to esophageal peristalsis but occurred
at the same time as the first occurrence of peristalsis (Fig. 4; Table
4). The time delays between activation of CP EMG and the first
occurrence of peristalsis were close to 0 s, and this delay did
not differ (P > 0.05) whether peristalsis began at 16, 13, or 10 cm from the LES (Table 4). A similar relationship was found for the second and third occurrences of the peristaltic wave (Fig. 4;
Table 4).
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Responses to Rapid Air Distension of Esophagus
We found that rapid air injection into the esophagus caused changes in EMG activity that occurred concurrently in the CP, TH, GH, CT, IA, TA, and esophagus. TH, GH, CT, IA, and TA EMG activities were activated and the esophagus contracted, but the CP EMG was inhibited (Figs. 2 and 5). The thresholds for activation of the TH, CT , IA, or esophagus or inhibition of the CP were not significantly different (P > 0.05; Table 2). The time delays to the occurrence of responses among the laryngeal (IA and CT) and hyoid (TH and GH) muscles were not significantly different (ANOVA, P > 0.05) and ranged from 0.17 ± 0.02 to 0.22 ± 0.02 s. The time delay to inhibition of the CP (0.27 ± 0.02 s) was significantly longer than the delays for activation of the CT (0.20 ± 0.02 s) and TH (0.17 ± 0.02 s). The time delays between rapid esophageal distension and the responses of these muscles were not related (ANOVA, P > 0.31) to the volume of air injected. These responses were often followed by secondary peristalsis and activation of CP EMG similar to the responses to slow air injection (Figs. 2 and 5). Although we found no statistically significant (all were P > 0.05) correlation (at most R < 0.182) between EMG response of any muscle and volume of injected air, we did find that sometimes (10 of 94 trials in 6 of 23 animals) the responses of the CP and laryngeal muscles were not accompanied by a response of the hyoid muscles (Fig. 3, bottom). The time delays to activation of the laryngeal muscles (IA and CT) and inhibition of the CP were not significantly different (ANOVA, P > 0.05) whether or not the hyoid muscles were activated. The mean duration of EMG responses to rapid air injection (4.7 ± 0.3 ml; N = 23) when all responses were activated simultaneously are listed in Table 5.
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The rapid injection of air into the esophagus caused contractions of
the esophagus that occurred with delays from 1.1 to 1.6 s (Fig. 5;
Table 6). Although in some cases these
contractions seemed to propagate orad and caudad from the site of
injection (Fig. 5), no statistically significant (P > 0.05) differences in delays were found, except between 10 cm and 4 cm
from the LES (Table 6). These esophageal contractions were smaller than
secondary peristaltic contractions, occurred before secondary
peristalsis, and could be activated independent of secondary
peristalsis (Fig. 5).
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In prior studies the above muscular responses to rapid distension of the esophagus were characterized separately as EURR (inhibition of CP or relaxation of UES) and EGCR (contraction of the intra-arytenoid muscles or glottal closure). The responses of the TH and esophago-hyoid distraction reflex (EHDR), along with activation of the EURR and EGCR, have previously been recognized as the EB. The esophago-esophagus contraction reflex (EECR) has not previously been reported.
Effects of Longitudinal Esophageal Stretch
We found that longitudinal stretch of the esophagus for 1-2 cm in three cats did not activate any of the examined reflexes, although this stimulus was strong enough to cause an increase in intraluminal pressure at the most distal recording site of 13 ± 6 mmHg (N = 3; Fig. 2, bottom).Effects of Transection and Bolus Diversion
Transection of the esophagus just caudal to the UES had no effect on the thresholds for activation of any of the distension-induced esophageal reflexes (Table 2). In addition, we found after placement of a three-way stopcock between the transected esophagus and the UES (N = 4) that injection of water into the pharynx stimulated swallowing accompanied by esophageal peristalsis (i.e., activated primary peristalsis) (4 of 4 cats, 6 of 6 trials; Fig. 6, top). When the stopcock was turned to divert the bolus outside of the esophagus, swallowing activated by pharyngeal stimulation with water was not (4 of 4 cats, 6 of 6 trials) followed by esophageal peristalsis (Fig. 6, top).
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We also found (1 cat, 3 trials; Fig. 6, bottom) that electrical stimulation of the SLN activated swallowing that was accompanied by esophageal peristalsis even though no bolus was injected into the pharynx. However, when the stopcock was turned to divert pharyngeal contents from the esophagus, SLN stimulation without pharyngeal stimulation activated swallowing but not esophageal peristalsis (3 of 3 trials).
Role of Mucosal Layer Receptors in Distension-Induced Esophageal Reflexes
Intraluminal infusion of lidocaine.
We found that infusion of lidocaine into the esophagus blocked EGCR,
EURR, EHDR, and EECR but not secondary peristalsis or EUCR
(N = 3, 3 of 3 cats; Fig.
7, top). Although secondary
peristalsis was not blocked by lidocaine perfusion, the magnitude and
propagation of secondary peristalsis was altered (Fig. 7,
top).
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Intraluminal perfusion of capsaicin.
We found that the frequencies of swallowing during esophageal perfusion
with H2O (1.0 ± 0.1/min; N = 5) or
capsaicin vehicle (1.1 ± 0.1/min; N = 5) were not
significantly different (P > 0.05). Capsaicin
administered intraluminally to the esophagus increased the frequency of
swallowing for the first of three periods of capsaicin perfusion only
(Table 7). We tested the responses to slow and rapid inflation of the esophagus after capsaicin and found
that after up to three perfusions of capsaicin, no significant changes
in threshold of the responses to slow inflation, i.e., secondary
peristalsis or EUCR, occurred (Table 7). On the other hand, after two
perfusions of capsaicin the threshold volumes for the initiation of the
rapid inflation induced reflexes, i.e., EURR, EGCR, EHDR, and EECR,
increased significantly (P < 0.05; Table 7 and Fig. 7,
bottom). The threshold volume increased significantly (P < 0.05) from 3.0 ± 0.2 ml with vehicle to a
maximum of 6.5 ± 0.5 ml with two to three (2.3 ± 0.2 perfusions; N = 5) perfusions of capsaicin.
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Role of mucosal layer in distension-induced esophageal reflexes.
We found that after removal of the mucosal layer of the esophagus EURR
(CPinh), EGCR (CT, IA, TA), EHDR (TH), and EECR (ESO) were
blocked, whereas the thresholds for activation of secondary peristalsis
and EUCR (CPact) were not significantly
(P < 0.05) altered (see Table 2 for definition of
terms; Fig. 8, top). In addition, mucosal layer removal had no significant (P > 0.05) effect on the velocity of propagation (1.5 ± 0.2 cm/s; N = 13), magnitude, or duration of secondary
peristalsis (Table 8).
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Determination of Afferent Pathways for Distension-Induced Esophageal Reflexes
Effects of thoracic vagotomy. We found that bilateral vagotomy at the level of the heart blocked all distension-induced esophageal reflexes: EUCR and EURR, EGCR, EHDR, EECR, and secondary peristalsis in three of three cats. Although most of the efferents to the esophagus were blocked by this vagotomy, innervation of the proximal cervical esophagus was intact, as this area of the esophagus still exhibited primary peristalsis (Fig. 8, bottom). This vagotomy did not block the pharyngeal or laryngeal responses to swallowing (Fig. 8, bottom).
Effects of Baclofen
We found that baclofen administration blocked the responses to rapid inflation of the esophagus, EURR, EGCR, EHDR, and EECR, but had no significant (P > 0.05) effect on the responses to slow inflation of the esophagus, secondary peristalsis and EUCR (Table 9; Fig. 9, top). In addition, baclofen significantly (P < 0.05) reduced the swallowing frequency induced by pharyngeal stimulation (Table 9; Fig. 9, bottom).
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DISCUSSION |
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Mechanical stimulation of the esophagus activated numerous reflexes, which included EUCR, EURR, EGCR, EECR, EHDR, and secondary peristalsis. All of these reflexes had been identified previously except EHDR and EECR. Our goal in this study was to understand the functions and mechanisms of these reflexes.
Functions of Distension-Induced Esophageal Reflexes
We found that the reflexes activated by esophageal distension occurred in two sets depending on the rate rather than magnitude (i.e., volume) of distension. Reflexes activated by slow distension activated EUCR and secondary peristalsis, whereas EURR, EGCR, EHDR, and EECR were activated by rapid distension only. We investigated the function of these reflexes by examining the relationships of these reflexes with the type of stimulus and with each other.Function of Esophago-UES Contraction Reflex
We found that secondary peristalsis was always accompanied by activation of the CP; however, the mechanism of this association has not previously been investigated. The CP response during secondary peristalsis may either be part of the central neural program that controls secondary peristalsis or it may be due to activation of EUCR by the progressing esophageal peristalsis. EUCR was not dependent on secondary peristalsis, as esophageal distension at a slow rate activated the CP without causing secondary peristalsis, but a relationship between secondary peristalsis and CP EMG was apparent. We found that the magnitude of the CP EMG response during esophageal peristalsis was related to the magnitude of the peristaltic wave and the position of the peristaltic wave in the esophagus. The more caudal the peristaltic wave, the less significant the relationship between peristaltic magnitude and CP EMG magnitude. Moreover, we found that the CP EMG response did not occur at a fixed time relative to esophageal peristalsis but occurred at the same time as the first occurrence of peristalsis in the esophagus. The more caudal the first occurrence of peristalsis, the more delayed the activation of the CP. These findings strongly suggested that the CP response during esophageal peristalsis was not controlled by the central pattern generator for peristalsis but was activated by stimulation of EUCR. Therefore, the function of EUCR may be to prevent esophago-pharyngeal reflux during propagation of peristalsis through the proximal esophagus.Function of Rapid Distension-Induced Esophageal Reflexes
We found that at high rates of distension of the midesophagus a number of reflexes were activated that were not activated by slow distension. Rapid esophageal distension caused inhibition of the primary closure muscle of the upper esophageal sphincter (CP), activation of the laryngeal closure (IA, TA, CT) and hyoid distraction muscles (GH, TH), and a rapid contraction of the esophagus. The laryngeal and hyoid muscle responses to rapid esophageal distension occurred simultaneously, but the CP response was slightly (0.05 s) delayed. The thresholds for activation of these responses were not significantly different. Similar reflexes were observed previously in humans (40, 42). Rapid air distension of the midesophagus in humans closed the glottis (40, 42), i.e., EGCR, relaxed the UES (40, 41, 43), i.e., EURR, and moved the hyoid and glottis anteriorly (41), i.e., EHDR. At low injected air volumes (median of 30 ml) that caused glottal closure, EURR was activated in 45% of trials but the hyoid or glottis did not move (40). At high injected air volumes (median of 40 ml), all of the above reflexes occurred and a belch was heard (41). Similarly in dogs (21), it was found that belching was accompanied by simultaneous activation of the superior hyoid muscles, inhibition of the cricopharyngeus muscle, and activation of rapidly propagating esophageal peristalsis. Therefore, we concluded that rapid distension of the esophagus activates EGCR and EURR, as well as the previously unidentified EHDR and EECR; all of these reflexes may contribute to the belch response.Function of Secondary Peristalsis of Striated Muscle Portion of Esophagus
It has been proposed that the function of secondary peristalsis of the striated muscle portion of the esophagus is to evacuate esophageal contents missed by primary peristalsis (16), but the relationship between primary and secondary peristalsis of the striated muscle portion of the esophagus is unclear. Some studies suggested that a bolus is necessary for both types of peristalsis, whereas others suggested that only secondary peristalsis requires a bolus. In animals with striated muscle esophagus (i.e., dogs), it was found that bolus diversion at the cervical esophagus during swallowing prevented peristalsis from progressing beyond the point of diversion, which suggested that the bolus was necessary for activation of primary peristalsis (18, 27). On the other hand, in animals with a partial smooth muscle esophagus (primates), diversion of the bolus at the cervical level during swallowing did not prevent primary peristalsis from progressing into the distal segment (17). These authors (17) suggested that this difference in results was due to species differences related to the smooth muscle content of the esophagus. However, we found in another species (i.e., the cat) with a partial smooth muscle esophagus that the presence of a bolus in the cervical esophagus was necessary for peristalsis to occur after swallowing. Furthermore, we found that the stimulus required to activate peristalsis during swallowing need not be a liquid bolus but may simply be as small as the air bolus of a dry swallow. Air boluses as small as 0.3 ml injected into the esophagus at very slow rates (10 ml/min) were capable of activating secondary peristalsis. We concluded that in the cat, and perhaps in other species with or without smooth muscle in the esophagus, an esophageal bolus is essential for the expression of primary peristalsis. That is, all peristalsis may be secondary to an esophageal bolus. This conclusion may partly explain the observation that not all swallows are accompanied by esophageal peristalsis.Function of Esophago-Esophageal Contraction Reflex
EECR may be the segmental rapid reflex (elementary reflex; Ref. 11) of the esophagus previously found to occur after electrical stimulation of afferent nerves (36). However, no physiological stimulus was previously identified that activates this reflex, and some authors (36) concluded that this reflex was the basis for secondary peristalsis. It is clear from this study that EECR is different from secondary peristalsis, as these responses occur independent of each other and are controlled differently. On the other hand, rapid, orad-propagating, bolus-related activation of the striated muscle esophagus was previously found to occur during rumination (44), belching (21), and vomiting (24). We suggest that EECR (perhaps the elementary reflex) does not form the basis of secondary peristalsis but may form the basis for the rapid retrograde esophageal contractions during rumination, belching, and vomiting.Mechanisms of Distension-Induced Reflexes of Esophagus
Mechanical stimulation of the esophagus activates numerous reflexes. Many of these reflexes have motor responses mediated by striated muscles with well-known motor nerves and effector functions, but the sensory mechanisms of these reflexes have not been investigated previously. Our goal was to identify the afferent pathways of these reflexes, to associate specific reflex responses with specific receptor types, and to understand the manner in which these reflexes are organized.Neural pathways. We found that all investigated esophageal reflexes were mediated by the vagus nerves. Transection of the esophagus between the CP and the esophagus did not affect the threshold for activation of any of the esophageal distension-induced reflexes, indicating that intramural pathways did not mediate these reflexes. On the other hand, transection of the thoracic vagus nerves blocked the responses to slow and rapid distension of the esophagus but not to swallowing, indicating that the afferent limb of all of these reflexes is the vagus nerve. Others have found that some esophageal receptors project through the splanchnic nerves to the spinal cord (7, 8), but it is unlikely that any of these receptors played any role in the esophageal reflexes we investigated. Therefore, we concluded that all of the reflexes we investigated were mediated by vagal esophageal mechanoreceptors.
Type of receptor. location in esophageal wall. Mechanoreceptors that project to the central nervous system through vagal afferent fibers have been found in two different layers of the esophagus (14), the mucosal and muscular layers. We attempted to determine which set of receptors was responsible for the observed responses to esophageal distension by examining the effects of anesthetizing the mucosa or removal of the mucosal layer. We found that mucosal anesthesia (i.e., lidocaine applied intraluminally) or mucosal layer removal blocked the responses to rapid air distension, EURR, EGCR, EHDR, and EECR, but not the responses to slow air distension, secondary peristalsis and EUCR. Therefore, we concluded that the responses to rapid distension of the esophagus were mediated by mechanoreceptors of the mucosa, whereas the responses to slow esophageal distension were mediated by receptors of the muscularis.
CIRCULARLY VS. LONGITUDINALLY ORIENTED RECEPTORS. Prior studies found esophageal mechanoreceptors sensitive to circularly or longitudinally directed tension (39). Pulling caudad on the gastroesophageal junction at low tension (<5 g) activated vagal afferent fibers that were not sensitive to esophageal distension (39). We found that strong (1-2 cm) caudad longitudinal stretch of the gastroesophageal junction did not activate any of the reflexes stimulated by esophageal distension. Therefore, we concluded that none of the esophageal distension-induced reflexes was probably mediated by longitudinally oriented tension receptors. SLOWLY VS. RAPIDLY ADAPTING RECEPTORS. We found that some reflexes, i.e., secondary peristalsis and EUCR, were activated by any rate of esophageal distension whereas the other reflexes, i.e., EGCR, EURR, EHDR, and EECR, were activated by rapid stimuli only. This observation of two sets of esophageal reflexes is mirrored in the dichotomy of previously identified esophageal mechanoreceptors. Two basic types of esophageal mechanoreceptors have been identified, the slowly and rapidly adapting mechanoreceptors (14). The slowly adapting mechanoreptors respond to distension throughout the stimulus and at any rate of distension (14), but the rapidly adapting mechanoreceptors respond only at the beginning or end of the stimulus and respond more strongly with rapid stimuli (14). We also found that the reflexes that responded only to rapid distension of the esophagus depended on the integrity of the mucosal layer. This is consistent with the findings regarding the location of specific esophageal mechanoreceptors. The rapidly adapting esophageal mechanoreceptors have been identified in the mucosal layer (6, 29, 31), whereas the slowly adapting esophageal mechanoreceptors are located in the muscularis (6, 31, 37, 39) [probably in the myenteric plexus (34)]. Our findings, therefore, are consistent with the hypothesis that the reflexes activated by slow distension of the esophagus are mediated by slowly adapting mechanoreceptors of the muscularis whereas the reflexes activated by rapid distension of the esophagus are meditated by rapidly adapting receptors of the mucosal layer. CHEMICALLY SENSITIVE VS. INSENSITIVE RECEPTORS. We found that repeated applications of capsaicin selectively attenuated the reflexes activated by rapid distension rather than slow distension of the esophagus. It is unknown whether the necessity for repeated application of capsaicin was due to the relatively low dose, the long delay in response to capsaicin, or some other factor. Capsaicin is a primary afferent excitant and neurotoxin that at first activates and then desensitizes afferent pathways (1). Previous studies showed that capsaicin effects mucosal mechanoreceptors (32, 38) but not muscular mechanoreceptors (2). We concluded, on the basis of these findings and our results, that the reflexes activated by rapid distension of the esophagus were mediated by chemically sensitive esophageal mechanoreceptors whereas those reflexes activated by slow distension were mediated by chemically insensitive mechanoreceptors. TENSION VS. TOUCH RECEPTORS. Three types of mechanoreceptors based on activating force have been identified: tension-sensitive muscular receptors (6, 31, 37, 39), touch-sensitive mucosal receptors ( 29, 31), and tension-sensitive mucosal receptors (31). It is likely that tension-sensitive muscular receptors mediated the effects of slow distension, as these receptors are slowly adapting (6, 31, 37, 39). It is likely that the touch-sensitive mucosal receptors mediate the reflexes activated by rapid distension, as these receptors are also rapidly adapting (29). The tension-sensitive mucosal receptors have been found only in an in vitro ferret model (31). Therefore, it is unknown whether these tension-sensitive receptors are specific to the ferret or caused by the in vitro preparation. Our studies were not designed to investigate the possible role of these mucosal tension-sensitive receptors, but considering that these receptors (31) are slowly adapting mucosal receptors not sensitive to chemical stimulation (i.e., capsaicin), it is unlikely that they played a role in the distension-induced reflexes of the esophagus investigated in this study. EFFECTS OF GABA-B RECEPTORS. Baclofen has been shown to inhibit the activation of TLESR due to gastric stimulation by activation of GABA-B receptors (5, 25, 26), probably located in the central nervous system (4). We found that baclofen selectively blocked the reflexes activated by rapid distension of the esophagus. Therefore, these findings suggest that GABA-B receptors mediate inhibition of reflexes activated by the rapidly adapting mucosal mechanoreceptors of the esophagus. These results also confirm our prior conclusion that all of the reflexes activated by rapid esophageal distension are controlled by a common pathway.Organization of reflexes.
The relationships among EGCR, EURR, EHDR, and EECR and belching have
not previously been addressed. Although we did not find a statistically
significant difference in the thresholds for activation of the
different muscle responses to rapid distension of the esophagus, we did
find in a number of cases that EURR and EGCR could be activated independent of EHDR. This finding that the rapid distension-induced esophageal reflexes can be activated independently of one another is
consistent with results in humans in which it was observed that EGCR
could be activated without anterior movement of the glottis
(40). However, although individual reflexes may be
activated independently, these reflexes do not occur randomly, as they
always occur in the same spatial and temporal sequence. We found that when EURR and EGCR occurred independently of EHDR, the time delays of
these reflexes were not altered. In addition, we never found that these
reflexes were activated in a different order. The EHDR activated by
rapid esophageal distension never occurred independent of EGCR.
Therefore, we concluded that belching, like vomiting (20)
and other stereotypic reflex functions, is a complex reflex involving
many different muscles in different organs and systems. Vomiting
(20) is composed of complex individual reflex components that are organized in a hierarchical fashion such that the individual components are initiated at increasing levels of stimulus intensity to
ensure that the entire event occurs in an orderly and sequential manner. Such an organization ensures proper timing of functions and
allows for subcomponents to be used in other situations that do not
necessarily require a full response. With regard to belching, low
stimulus intensities (e.g., small amounts of gastroesophageal air
reflux) may activate EGCR without activation of EHDR to allow for
airway protection during mild reflux episodes. On the other hand, high
stimulus intensities (e.g., large amount of air reflux) may activate
EGCR, EURR, EHDR, and EECR, resulting in a belch. This difference in
motor responses does not mean that these reflexes are mediated by
different receptors, afferent pathways, or central pattern generators.
Therefore, like vomiting, belching is composed of numerous reflex
responses that are organized in a hierarchical fashion such that
individual reflex components may be activated independently of others,
but at full stimulus intensity all reflexes are activated to
produce the entire response (Fig. 10).
|
Technical Considerations
Decerebration technique.
These studies were conducted using an acute model that proved to be
very useful as these data indicate and prior studies have shown.
We first tranquilized the cats using butorphenol, which also blocked
the emetic properties of the anesthetic. The cats were anesthetized
using medazoline (10), an 2-adrenergic agonist, and
then decerebrated. After decerebration the cats were given atipamazole,
an
2-adrenergic antagonist, and decerebrate rigidity occurred within
10 min. Prior studies using this anesthetic protocol found that
numerous recorded cardiovascular, respiratory, and gastrointestinal
functions returned to normal values within 1 h of administration
of the antagonist (10). We waited 2 h before beginning the experiments.
Type of stimulus. The esophageal reflexes have been activated in prior studies using different stimuli including air, fluid, and balloon. Each stimulus has its advantages and disadvantages. We chose air injection because it was a mild stimulus that could be used in a long-lasting experiment and could be readily used to activate both sets of reflexes. In preliminary studies (23), we found that the responses to balloon distension fatigue relatively quickly (~1 h). In addition, air distension is a more physiological stimulus than balloon distension. Esophageal contents are usually fluid rather than solid; therefore, generalized and nonsustained (e.g., fluid or air) esophageal stimulation is more physiological than local and sustained (e.g., balloon) esophageal stimulation. The responses to esophageal distension may depend on these differences.
The responses we found to generalized and nonsustained air distension were consistent with those observed in other studies using air injection (40-42). The rapid, sustained (10-s duration), and segmental balloon distension of the esophagus has been found to cause somewhat different responses (40, 42). Rapid, sustained, and segmental balloon distension of the esophagus consistently activated EGCR but had variable effects on the UES pressure or CP EMG and had no affect on hyoid movement (40, 42). These rapid, sustained, and segmental balloon distensions never led to a belch response regardless of the stimulus intensity (40, 42). However, rapid, nonsustained, and generalized balloon distension activated belching (19), and this finding suggests that the difference in responses may be due to the segmental or sustained character of the stimulus rather then the distending medium. These findings suggest that rapid, sustained, and segmental balloon distension either activates a different set of responses through different receptors or differentially activates the same reflexes we have identified in this study.Smooth and striated muscle esophagus. The cat esophagus is two-thirds striated (proximal end) and one-third smooth muscle; therefore, the most caudal one (4 cm from LES) or two (7 cm from LES) esophageal recording sites were situated in smooth muscle. The peristaltic waves we recorded always began in the striated muscle esophagus and almost always propagated through all recording sites. Therefore, none of our observations or conclusions concerned the mechanisms controlling secondary peristalsis of the smooth muscle esophagus. All of the distension-induced esophageal reflexes were stimulated using air injection at midesophagus; therefore, the activated receptors could have been located in either the smooth or striated muscle portions of the esophagus.
In conclusion, we found that the cat has the previously identified esophageal reflexes, EUCR, secondary peristalsis, EURR, and EGCR, and two new reflexes, EHDR and EECR. EURR, EGCR, and EHDR and EECR probably contribute to the belch response. The CP response during secondary peristalsis is probably caused by activation of EUCR by the propagating peristaltic wave. All esophageal peristalsis in the cat, and possibly in other species, is secondary to esophageal stimulation. All of the investigated distension-induced esophageal reflexes are mediated by vagal afferent fibers, but none of these reflexes is mediated by longitudinally oriented mechanoreceptors. The rapid distension-induced reflexes of the esophagus are probably mediated by capsaicin-sensitive, rapidly adapting mechanoreceptors of the mucosal layer. Secondary peristalsis and EUCR are probably mediated by slowly adapting in-series tension receptors of the muscularis. GABA-B receptors inhibit the reflexes activated by rapid esophageal distension but not secondary peristalsis or EUCR. ![]() |
ACKNOWLEDGEMENTS |
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This study was supported in part by National Institutes of Health Grants P01-DC-03191-01A1 and R01-DK-25731.
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FOOTNOTES |
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Address for reprint requests and other correspondence: I. M. Lang, Dysphagia Research Laboratory, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: imlang{at}mcw.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.
Received 14 March 2001; accepted in final form 16 July 2001.
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