PRO GRESS IN GASTROENTEROLO GY

Transcription

1 Gastroenterology 72: , 1977 Vol. 72, No.3 Copyright by The Williams & Wilkins Co. Printed in U.S A. PRO GRESS IN GASTROENTEROLO GY NEURAL CONTROL OF ESOPHAGEAL PERISTALSIS A conceptual analysis NICHOLAS E. DIAMANT, M.D., AND TAHER Y. EL-SHARKAWY, PH.D. Institute of Medical Science and Department of Medicine, University of Toronto and Toronto Western Hospital, Toronto, Ontario, Canada The characteristic feature of esophageal motor activity is an orderly peristaltic contraction which passes from the upper esophageal sphincter through the striated and smooth muscle portions of the esophageal body, and terminates in closure of the lower esophageal sphincter. I. 2 The voluntary act of "swallowing" is the usual stimulus for i n i t i of ~ tesophageal i o n peristalsis, and in addition the presence of a bolus within the esophageal lumen can produce a contraction pattern in the esophageal body that closely resembles that initiated by swallowing For esophageal peristalsis initiated by swallowing, or by a bolus within at least the upper esophageal lumen, there is convincing evidence that the primary control mechanism resides in a complex swallowing center of brain stem nuclei and reticular formation. 2, 3, 5-8 From this center a programmed sequence of efferent discharges passes to progressively aboral segments of the esophageal striated and smooth muscle body. However, stimulation of the isolated whole esophagus directly or via the vagus nerves can also result in the peristaltic progression of a contraction along the smooth muscle esophagus Therefore, there is an intrinsic peripheral control mechanism in the wall of the smooth muscle portion of the esophagus which can function independently of the central control mechanism. Activation of either the central or of the peripheral control mechanism results in a wave of excitation that proceeds aborally. The presence of two control mechanisms for peristalsis in the smooth muscle esophagus has raised a number of intriguing questions. (1) Is the peripheral control mechanism neurogenic, or myogenic, or a combination of both? (2) Is the peripheral control mechanism isolated to the smooth muscle esophagus, or can the striated muscle esophagus also be influenced by or participate in Received November 10, Accepted July 1, Address requests for reprints to: Dr. N. E. Diamant, Suite 234, Nurses' Residence, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. This research was supported by Medical Research Council of Canada Grant MA3353, by Toronto Western Hospital Department of Medicine Research Foundation, and by the Elsie Watt Research Fund. The authors express their gratitude to H. Mui and N. Lackey for technical assistance, to Mrs. C. Sproule for secretarial help, and to Dr. W. J. Dodds for his constructive criticism. 546 the peripheral control mechanism? (3) How is the central control mechanism and its programmed sequence of efferent discharges imprinted on the local control mechanism? That is, does the central program regulate and/ or excite the peripheral control mechanism to activity, or does it operate independently of the peripheral control mechanism? (4) What and where are the neural pathways connecting the central and peripheral control mechanisms? (5) Is the regulation of longitudinal smooth muscle activity and its coordination with the circular layer of muscle controlled by the central or peripheral mechanisms, or by both? (6) What role do the central and peripheral control mechanisms play in distal inhibition in both the striated and smooth muscle esophageal body, and in the lower esophageal sphincter? (7) What role do the central and peripheral control mechanisms play in regulation of upper and lower esophageal sphincter function? (8) What influence do afferent sensory discharges from the esophagus have on the central and local control mechanisms for esophageal peristalsis? (9) Are disorders of esophageal motor function attributable to abnormality of the central control system, the peripheral system, or both? One of the most exciting prospects raised by these questions centers on understanding the nature of the peripheral control mechanism in the smooth muscle of the esophageal body. This becomes particularly important as it may provide insight into the neural mechanisms responsible for excitation and inhibition, and the various contraction patterns seen more distally in the gastrointestinal tract. In contrast to the stomach, small bowel, and colon, esophageal smooth muscle does not have at rest, phasic oscillations of the membrane potential (electrical slow wave, pacesetter potential, basic electrical rhythm), 12 although the lower esophageal sphincter may be an exception and exhibit some form of slow wave activity.13 On the surface at least, the wave of excitation spreading along the esophageal smooth muscle body does not seem to be mediated primarily by the presence of an electrical slow wave, and in fact the wave of excitation in the esophagus resembles in some respects the migrating bursts of spiking activity seen lower in the gastrointestinal tract, in stomach, small bowel, and colon. I 4-J6 In these organs, an intense burst of spiking activity is seen to pass aborally, its timing independent of slow wave activity.

2 March 1977 PROGRESS IN GASTROENTEROLOGY 547 In the esophagus and regardless of whether the muscle contributes a myogenic coordinating component such as an electrical slow wave, the question still remains: How does neurogenic stimulation either central or local cause excitation of the esophageal circular smooth muscle to produce a peristaltic contraction? Studies of the isolated whole esophagus have shown that stimulation of the vagus nerves, stimulation of the esophagus directly with square wave electrical pulses, or stimulation of the esophagus by balloon distention, causes a transient contraction at the onset of stimulation, the "on response," and a vigorous contraction occurring with a variable delay after cessation of stimulation, the "off response."7, 9-11 A similar series of events has been noted when strips of circular esophageal smooth muscle are stimulated by trains of square wave electrical pulses Therefore, esophageal circular smooth muscle exhibits the potential to contract at two different times in relation to stimulation, at the onset of stimulation with an on response, and after cessation of stimulation, with an off response. The proposal has been presented that regional differences in timing of the off response contraction explain the aboral peristaltic contraction in the smooth muscle esophagus.20 This hypothesis invoking the off response as the peripheral mechanism responsible for peristalsis in the smooth muscle esophageal body is an attractive one. 9, 10,20 However, the mechanisms responsible for the off response are unclear, and the possible role of the on response in mediating peristalsis has not been explored. It has been generally accepted that the mechanisms of excitation responsible for the on response and off response are different. 2, 17, 21 The off response is neurogenic in origin whereas the on response is considered to be a direct result of stimulation.2, 9, 10, 17,21 Therefore, the on response is usually denied a significant role in the initiation of contraction of esophageal muscle during the normal peristaltic sequence. Finally, there are large differences in the observed or calculated velocity at which a peristaltic wave can or would pass through the smooth muscle esophagus, depending on whether peristaltic velocity was observed after swallowing, after a variable period of balloon distention or vagalstimulation, or was calculated from the graded off response delays seen in isolated muscle strips (table 1). Because. esophageal circular smooth muscle can respond to stimulation with both an immediate or on response contraction and an off response contraction, definition of the local mechanism for peristalsis is still open to debate. Any attempt to define the local mechanism for peristalsis must reconcile the presence of the on and off responses and, in addition, explain the relationships between the peripheral control system and the central control system in the initiation and regulation of peristalsis. Furthermore, the integration between control mechanisms for esophageal body motor activity and lower esophageal sphincter function must be adequately explained. It seems appropriate therefore to outline briefly some of the known features of (1) the central control mechanism, (2) the peripheral control mechanism, (3) the relationships between them, in particular TABLE 1. Peristaltic velocity (centimeters per second) in lowest 4 to 5 cm of smooth muscle esophageal body Stimulation Opossum Cat In vivo 1. Swallow 2. Bolus injection 3. Vagal stimulation (1-4 sec) In vitro 1. Intact esophagus (off response after balloon distention, after local electrical stimulation, or after prolonged vagal stimulation) 2. Muscle strips (off response delay) a Reference 26. b Personal observations. C Dodds WJ, et al: J Clin Invest 52:1-13, d Reference 9. e Reference 10., Reference " 1.75 a 6,'15.7" 6.7' 1.5 b 1.75" b that affected by peripheral sensory input, and (4) the neural control oflower esophageal sphincter function. The Central Control Mechanism For the purposes of the present discussion the central control mechanism will be considered as a complex "black box." Recently Doty,3 Sumi,6 and Jean" have developed descriptions of the interconnecting pathways responsible for the central control of swallowing. Several features of this system are apparent. 2, 3, ", 6 (1) The swallowing center appears to be in the medulla, with complex connections to the midbrain and pontine reticular formation, to the cerebral cortex, and to brain stem motor nuclei of cranial nerves V, VU, X and XU. (2) The central control mechanism can be initiated to activity by voluntary excitation from the cerebral cortex, or by afferent sensory stimulation from the oropharynx, hypopharynx, and esophageal body. (3) If swallowing results from adequate voluntary or reflex stimulation, a programmed sequence of efferent discharges is produced and results in sequential excitation of the muscles of the mouth, pharynx, and esophagus. At times afferent sensory stimulation from the esophageal body is insufficient to excite the central motor neurones that control muscles of the mouth and pharynx, and efferent discharges from the central control mechanism result in sequential excitation of only esophageal musculature. In this case esophageal peristalsis is initiated although swallowing does not occur. (4) There are central mechanisms for excitation and inhibition of neurones within the swallowing center and there is a degree of polarity to the excitation and inhibition. For example, firing of motor neurones destined for more proximal levels of the esophagus inhibits motor neurones programmed to excite more distal areas of the esophagus. This provides one mechanism for "distal inhibition." (5) At least in the dog, there are efferent fibers from the central control mechanism to the lower esophageal sphincter which are probably responsibe for a degree of resting sphincter tone and active excitation of the sphincter,22 and perhaps other efferents mediating active inhibition of the sphincter and fundus of stomach. 23 (6) At present there

3 548 PROGRESS IN GASTROENTEROLOGY Vol. 72, No.3 is no firm evidence that efferent fibers from the central control mechanism are destined primarily for an inhibitory function in the esophageal body. That is, except for the lower esophageal sphincter, the central control mechanism does not appear to play a primary role in active distal inhibition within the esophageal body (see later). (7) The central control mechanism is sensitive to afferent sensory input from the periphery which may result in excitation, inhibition, and/or alterations in timing of the sequential motor discharges from the central mechanism (see later). In summary, whatever the interconnections of the central control mechanism, the end result of its activation is production peripherally of a peristaltic contraction wave in at least the body of the esophagus. The timing and intensity of the central sequence of excitatory discharges affect the timing and amplitude of the peripheral motor responses. Therefore, ordinarily the central control mechanism appears to exert an overriding influence on the peripheral control mechanism for esophageal peristalsis. Nevertheless, afferent sensory input from the esophagus can modulate activity of the central control mechanism. The Peripheral Control Mechanism As pointed out above, circular smooth muscle from the esophageal body can be excited to contract at two different times in relation to stimulation. Prolonged (1 to 10 sec) stimulation of the local control mechanism by balloon distention, by vagal stimulation, or by electrodes applied directly to the esophageal wall results in immediate "on response" excitation at and/or above the point of stimulation and inhibition below. 24 The on response may be repetitive Termination of the stimulation is followed by an off response contraction Still undetermined are the neurogenic and/ or myogenic mechanisms that govern the production of the on response and off response, and how one or both of these contractile responses are regulated and coordinated peripherally to produce a peristaltic sequence. The on response can at times be peristaltic However, under experimental conditions with stimulation of the vagus nerve or the esophageal wall, the local peristaltic sequence is usually attributed to an off response. That is, peristalsis occurs after termination of the stimulus It seemed logical therefore to assume that peristalsis is mediated by an off response mechanism. The off response is preceded by noncholinergic, nonadrenergic nerve-mediated inhibition of the muscle There is therefore a mechanism associated with the off response that might account for distal inhibition preceding the contraction In addition, the off response contraction is associated with a slow membrane depolarization or "electrical off response" which has superimposed spike potentials. Thus, a membrane depolarization occurs that could through myogenic intercellular connections allow some local coordination of the contraction. 27 However, propagation velocity of the peristaltic contraction occurring after a short period of stimulation (1 to 4 sec) of the distal cut end of the vagus nerves, approximates that of the peristaltic wave initiated by swallowing,26 and this velocity is much slower than that usually attributed to the off response or that occurs after longer periods of vagal stimulation. 25 (see table 1). Furthermore, elsewhere in the gastrointestinal tract, muscle contraction occurs during stimulation and as a result of direct excitation of the muscle, usually via cholinergic excitatory neurones. 12 A priori, it seems reasonable to postulate a direct neurogenic excitation mechanism for the contraction sequence in the esophageal body. On the surface at least, this is difficult to do when one considers the present understanding of the off response characteristics. The off response occurs after the stimulus is terminated. Furthermore, the off response peristaltic sequence occurs as a result of simultaneous stimulation of all the nerve fibers in the vagus nerves or in the esophageal wall On the other hand, at least in cats and baboons, the peristaltic contraction wave initiated by swallowing or by a bolus within the esophageal lumen is apparently associated with a programmed sequence of excitatory discharges from the central nervous system to both striated and smooth muscle Roman, Tieffenbach, and Miolan innervated peripheral striated muscle with the central cut end of one vagus nerve, in sheep, dogs, cats and baboons. Presumably the efferent vagal fibers were preganglionic. On swallowing the firing pattern of different motor units excited by the vagal re-innervation was correlated with the esophageal contractions mediated by the other intact vagus There is a close temporal relationship between the central discharges to different motor units in the reinnervated muscle, and the sequential appearance of contraction waves along the striated and smooth muscle of the esophageal body in these species. This suggests a role for a direct neurogenic excitatory mechanism in the normal peristaltic sequence of contraction. It is therefore necessary to reconcile the mechanism responsible for the experimental production of an off response with evidence supporting a mechanism for direct neurogenic excitation of the muscle. It is not known whether the off response is a passive rebound phenomenon associated with rebound membrane depolarization after active membrane hyperpolarization,27 or whether it is an active response to excitatory stimuli that becomes apparent when the preceding inhibition is terminated. Experimentally it appears to be a combination of both. The off response is variably sensitive to atropine, and therefore in part cholinergic The off response in cat esophageal muscle 29 appears more sensitive to atropine than that in the opossum.17 It has been suggested that prostaglandins also playa role in the genesis of the offresponse 3o. 31 (N. E. Diamant and T. Y. EI-Sharkawy, unpublished observations). Cholinergic agents and perhaps prostaglandins could function in a permissive role to allow passive rebound, or could function in an active excitatory role. The difference in sensitivity of the off response to atropine in the cat and the opossum suggests that there are species differences in off response mechanisms, if these differences are not caused by differences in experimental technique.

4 March 1977 PROGRESS IN GASTROENTEROLOGY 549 The mechanisms responsible for the production of the on response in esophageal circular smooth muscle are similarly uncertain. In the opossum, initial studies suggested that the on response occurred owing to direct stimulation of the muscle rather than by a n e u r o ~ e n i c mechanism However, at least one report indicates that a transient on response was produced in strips of opossum esophageal muscle by stimulus parameters more likely to activate nerves than the muscle directlyy In the cat and the baboon, there is ample evidence that neurogenic excitatory impulses can be transmitted to the circular esophageal smooth muscle The excitatory neurones are cholinergic, and in the cat muscle, electrical recording demonstrates excitatory junction potentials that are augmented by physostigmine and blocked by atropine and hemicholinium. When of sufficient magnitude, these excitatory junction potentials are associated with spike bursts and contraction of the muscle. 19 Vagal stimulation can also produce cholinergic on contractions in the opossum. 25 Therefore, there is in some species a demonstrable neurogenic excitatory mechanism for stimulating circular esophageal smooth muscle, and this mechanism is cholinergic. As with the off response, the differences in the ease with which this mechanism can be demonstrated could represent species differences or differences in experimental technique. The experimental technique probably explains the observed characteristics of this on response mechanism. Direct stimulation of the vagus nerves or the muscle stimulates all excitatory and inhibitory nerve fibers as well as sensory neurones within the esophageal wall. As a result the on response, if present, appears immediately in muscle strips, and in the intact esophagus is usually simultaneous at more than one level, although it can be peristaltic. 25 With repetitive stimulation, either the excitation mechanism fatigues or inhibition appears to dominate and quickly obliterates any excitatory influence of the stimulation Therefore the excitatory on response is usually transient and in the intact esophagus, usually nonperistaltic. On cessation of stimulation, the off response occurs and in the intact esophagus is usually peristaltic. This series of events suggests that the on response and off response are separated temporally by a dominant inhibitory mechanism. 29 In addition, the neurogenic on response contraction is cholinergic and a significant portion of the off response is cholinergic, suggesting that a similar cholinergic excitatory mechanism is common to both contractions. However the importance of a cholinergic mechanism is still open to debate, inasmuch as the administration of atropine alters but does not abolish the peristalsis induced by swallowing At present, there is no evidence that other excitatory mechanisms are of prime importance in the genesis of the off or on response. Circular esophageal smooth muscle has excitatory IX adrenergic receptors,20 excitatory dopaminergic receptors, and excitatory histamine (HI) receptors.35 It is likely that these and perhaps other excitatory agents such as hormones, along with inhibitory influences, e.g., f3 adrenergic receptors,21 histamine (H 2 ) receptors,35 and inhibitory dopamine receptors,36 modulate the local control mechanism for peristalsis at a neural or myogenic level. There are interesting regional differences in contractile responses that could contribute to coordination of peristalsis regulated by the peripheral control mechanism. Some ofthe differences appear to be myogenic and others neurogenic. The onset of the off response contraction occurs at progressively longer times after stimulation as one proceeds distally along the esophageal body.20 Although this may represent a myogenic difference at each level, it is just as likely that this gradient in timing is the result of differences in the innervation at each level. This is supported by experiments that show that increases in stimulating frequency applied to vagus nerve or esophageal muscle delay the off response, and this delaying effect is most marked distally Perhaps differences iii density of innervation, either inhibitory or excitatory, or differences in the rates of transmitter release or uptake explain the findings. However, muscle properties are no doubt important in determining characteristics of the local contraction, once it is initiated. There is a gradient in contraction frequency along the esophagus when transverse strips of cat esophageal muscle are stimulated to repetitive contraction by carbachol (N. E. Diamant and T. Y. EI-Sharkawy, unpublished observations), or when rings of frog esophageal muscle contract spontaneously.38 Longitudinal strips of opossum esophageal muscle show a similar frequency gradient when contractions are induced by KCl. 20 Higher frequencies are present orally and the frequency decreases as one progresses distally. This corresponds to the increase in duration of the muscle contraction as one proceeds along the esophagus. In the opossum, for example, the duration of the off response contraction 2 cm above the gastroesophageal sphincter is almost twice that at 12 cm above the gastroesophageal junction. 20 Electron microscopic study of esophageal circular smooth muscle demonstrates intercellular connections resembling gap junctions There is therefore an anatomical structure that could allow functional electrotonic communication between cells, and potentially, some myogenic coordination of contraction. The control mechanisms responsible for coordination between circular and longitudinal esophageal muscle during peristalsis are not known. Longitudinal and circular esophageal smooth muscle layers can contract in a coordinated temporal sequence, or the longitudinal layer may contract independent of the esophageal circular smooth muscle Excitation of the longitudinal muscle appears to be through a cholinergic mechanism When the longitudinal muscle contracts there can be distal hyperpolarization and inhibition within the circular muscle and, in particular, the sphincter areay Because these phenomena are observable in the intact whole esophagus in vitro, at least a local control mechanism for coordination between circular and longitudinal muscle is present. Finally, the myenteric plexus is easily visible in both the smooth and striated muscle of the esophageal body.

5 550 PROGRESS IN GASTROENTEROLOGY Vol. 72, No.3 In the smooth muscle portion of the esophageal body it is assumed that the myenteric plexus, along with the neural elements in other layers of the esophageal wall, provide the foundation of the local control mechanism for peristalsis. 2 Neurogenic blocking agents alter or abolish the locally produced neural responses and peristalsis. 9, 10, 17 The role of the nerve plexus in the striated muscle is unclear, and at least three functions have been proposed for the plexus in the striated muscle. The neurones may function in a sensory capacity,2 the neurones may possibly behave as interneurones in the excitatory pathway from the swallowing center to the esophageal striated musculature,41 and some of the neurones may serve to mediate distal inhibition within the esophageal wall. 42 The latter feature suggests that some of the coordination between esophageal striated and smooth muscle function is also mediated locally. In summary: the local control mechanism for peristalsis appears to be primarily n e u r o g However ~ n i c. there are myogenic properties which may contribute to it. The mechanism provides for a propagated circumferential aboral contraction, coordination of longitudinal and circular smqoth muscle, and distal inhibit jon. Experimentally, perie;talsis occurs predominantly as an off response, although on response peristalsis can also occur. The exact nature of the on r ~ s p and o n off s e response is unclear. The on response can be produced by direct cholinergic excitation of the muscle, and it is probable that cholinergic or other excitatory influences play an important active or permissive role in production of the off response. The roles of the on response and off response in the production of swallow-induced peristalsis are not yet known. Peripheral Sensory Input to the Central and Peripheral Control Mechanisms In the intact animal there are a number of relationships which become apparent when sensory afferent stimuli from the esophagus exert their influence on the centrally programmed peristaltic sequence. (1) Sensory afferent stimulation from the oropharynx and esophagus enhances voluntary excitation of the central control mechanism. 2, 3, 28 (2) In the dog 43,44 and perhaps baboon,8 sensory reinforcement from at least the cervical esophagus appears to be necessary for progression of the central peristaltic program into the lower esophagus, although this may not be necessary in the monkey.45 (3) Progression of secondary peristalsis via the central control mechanism has similar sensory requirements. 2, 8, 45,46 It is probable that with adequ/lte sensory stimulation, the central control mechanism can be triggered from any level of the esophagus.45 (4) Afferent sensory impulses from the esophagus may cause inhibition of the central program. 28 Usually however, sensory input is mainly excitatory and increases the frequency and duration of the central firing pattern and as a result produces higher amplitude and longer contractions. 8, 24,47 (5) Afferent sensory input has an effect on the timing of the central sequence of discharges. The sequence of central discharges initiated by swallowing is slowed when a bolus is provided. Peristalsis induced by a bolus within the esophageal lumen is associated with an even slower central program. 8,46-48 Generally, as sensory input from the esophagus increases, the frequency and duration of the efferent discharges increase and the sequential program slows. A parallel is seen in the effect of raised intraabdominal pressure on peristalsis, which slows the velocity of peristalsis and increases the duration and amplitude of the contraction. 49 (6) Balloon distention held stationary within the esophagus produces repetitive local contractions which may be peristaltic above the point of distention. 4, 7, 8, 50 In the striated muscle esophagus the repetitive contractions require central connections. 28 The repetitive contractions can occur independently of central connections in the isolated smooth muscle esophagus.7-9 (7) Balloon distention produces distal inhibition within the esophagus via the intramural peripheral control mechanism,24 and also initiates within the central control mechanism inhibition of neurones responsible for excitation of the esophagus belqw the balloon. 5 (8) Upon deflating the balloon, peristalsis occurs through excitation frorri the central control mechanism, or ip the isolated smooth muscle esophagus, by action of the peripheral control mechanism. In summ!lry; afferent sensory input from the esophagus plays an important role in initial excitation of the central control mechanism, in regulation of the intensity and timing of the efferent discharges from the central mechanism, and in the central component of "distal inhibition." Local sensory stimulation can also initiate excitation and inhibition within the peripheral control mechanism. Neural Control of the Lower Esophageal Sphincter The control of lower esophageal sphincter function is still not completely elucidated. From the functional point of view three characteristics of the sphincter are of importance: (1) resting sphincter tone; (2) active inhibition or relaxation of the sphincter; (3) contraction of the sphincter, which follows sphincter relaxation. There are reasons to speculate that myogenic specialization of the gastroesophageal junction is important in the production of resting g/lstroesophageal tone and that my{)genic properties contribute to' the increased responsivepess of this zone to other controlling influences, inch,lding intrinsic and extrinsic nerves, and circulating humoral substances such as gastrointestinal hormones. 5 1 ~ 5 5 The innervation to the gastroesophageal j1.lpction functions in a number of ways in the maintenance of resting tone. (1) The effect of circulating humoral!'i'ubstances such as hormones may be mediated through a neural mechanism, 56 although this is contrqversia1. 2l (2) In the dog at least, there lireb tonic excitatory discharges from the central control mechanism to the gastroesophageal sphincter in the resting state. 22 (3) Iniiddition, some degree of resting tone appears to result from a adrenergic receptor excitation. 57 The pathway for this excitation is not known. 58 (4) From the afferent point of view, there are mechanical receptors sensitive to tonic and phasic changes in the sphincter and these provide

6 March 1977 PROGRESS IN GASTROENTEROLOGY 551 feedback infonnation to the central control mechanism. 59 Relaxation of the gastroesophageal sphincter, or a decrease in its resting tone, can occur through a number of mechanisms. (1) The gastroesophageal area has a prominent nonadrenergic, noncholinergic neural inhibitory mechanism and this pathway has intramural cholinergic ganglia. 6 CH>3 (2) The sphincter muscle also has inhibitory {3 adrenergic receptors. 21, 64 (3) In some species, inhibitory dopaminergic and histamine (H2)65 receptors may be present. (4) Humoral substances such as gastrointestinal hormones and prostaglandins can have an inhibitory influence on the sphincter either directly or through a neural mechanism (5) Reduction of tonic excitatory influences from the central control system will reduce sphincter muscle contraction. 22 Any or all of these mechanisms may be active in modulating the level of resting sphincter tone. Similarly, all ofthese mechanisms could potentially function to produce sphincter relaxation, in concert with motor activity in the body ofthe esophagus. However, {3 adrenergic inhibition and dopaminergic receptors do not seem to be of significance in mediating this relaxation, and there is no evidence that circulating humoral substances or histamine (H2) receptors playa major role The active inhibition of the sphincter in this case appears to be mediated by the peripheral noncholinergic, nonadrenergic neural mechanism This inhibitory mechanism can be excited via local intramural pathways from as far away as the striated muscle portion. 42 The suggestion has been made that the central control mechanism can excite active relaxation of the sphincter during esophageal peristalsis induced either by swallowing or by balloon distention within the esophagus. Under these circumstances efferent discharges coinciding with sphincter relaxation and presumably destined for the inhibitory neurones in the sphincter zone would occur. At the same time, tonic excitatory discharges to the sphincter are temporarily inhibited. 22 The mechanisms responsible for contraction of the gastroesophageal sphincter in sequence with the peristaltic contraction in the body are not clear. The sphincter area is sensitive to acetylcholine and a adrenergic excitation Other substances such as hormones, prostaglandins, and histamine (HI receptor) also cause sphincter contraction This provides a number of potential excitatory mechanisms. Return of tonic efferent excitatory discharges to the sphincter area at the end of sphincter relaxation in the dog is associated with an increased intensity of firing which is transient. 22 A pathway for these excitatory discharges to the esophagus is present in the vagus nerves of the dog 22 (but not the opossum),58 and the mechanism is presumed to be cholinergic at the muscle level. There is evidence of another excitatory pathway, perhaps involving a adrenergic receptors, at the gastroesophageal junction in the opossum, which is not carried in the vagus nerves and which is yet to be elucidated. 58 In summary: there is myogenic specialization in the gastroesophageal junctional area. Resting lower esophageal sphincter tone is the net result of myogenic specialization and of many excitatory and inhibitory influences, which include central and local neural mechanisms, ~ l owith n g other modulating controls such as circulating humoral substances. Relaxation of the sphincter on swallowing involves cessation of tonic central excitation, and active stimulation of a peripheral nonadrenergic, noncholinergic inhibitory pathway via the local and perhaps the central control mechanisms. Active contraction of the sphincter occurs predominantly through vagal excitatory influences, although alternate neural pathways may also be present. Hypothesis A hypothesis for the local mechanism of peristalsis must explain a number of features: (1) the presence of the on and off responses; (2) distal inhibition; (3) proximal excitation; (4) coordination of longitudinal and circular muscle activity; (5) the manner in which the central control mechanism initiates and regulates esophageal peristalsis; (6) the function of sensory receptors within the esophagus; (7) some integration between body motor activity and lower esophageal sphincter function. Recording from neural elements within the wall of the small intestine has provided some insight into the neural control of muscle activity in that region of the gastrointestinal tract In the esophagus, recording from myenteric and submucosal neurones has not been reported. Nevertheless, physiological and pharmacological studies indicate that the esophagus contains many of the neural mechanisms that have been described lower in the gastrointestinal tract. In particular, there are intramural neurones that mediate cholinergic excitation, HI. 29 and neurones that mediate nonadrenergic, noncholinergic inhibition of esophageal muscle These neurones are excited at the ganglion level by a cholinergic mechanism Furthermore, there is evidence for mechanical receptors within the esophageal wall From the functional point of view, there is polarity to the excitation and inhibition within the esophagus which is similar to that seen lower in the gastrointestinal tract. In the small intestine the major uncertainty lies in trying to describe the pathways interconnecting the excitatory and inhibitory neurones, the mechanical receptors, and the input from the central nervous system and other sensory pathways Wood, for example, has suggested that an important mechanism for excitation of the muscle is release of the muscle from tonically present inhibition. 70 On the other hand, Hirst et ai., 73 and Hirst and Mckirdy74 have proposed that excitation of the muscle occurs predominantly through direct excitatory neurones. Both mechanisms may potentially be operative. There is general agreement for the presence of an inhibitory neurone that can be excited to activity by mechanoreceptors via a cholinergic synapse Hirst and co-workers have provided evidence that the sensory neurone of the mechanoreceptor lies in the myenteric plexus, has no synapic input, and is characterized by a prolonged after-hyperpolarization which

7 552 PROGRESS IN GASTROENTEROLOGY Vol. 72, No. 3 follows its excitation. Further, they have demonstrated in the myenteric plexus neurones which are excited by a cholinergic synapse and can respond with one of two patterns after distention of the bowel or transmural electrical stimulation. 73 (1) One group fire after a short delay and for a transient period. These neurones appear to mediate the noncholinergic, nonadrenergic inhibition of the muscle. (2) The other group fire after a longer delay and once excited maintain their firing pattern for the duration of stimulation or longer. These neurones appear to mediate the cholinergic excitation of the muscle. Finally, Hirst and McKirdy suggested that there may be a delay circuit in the excitatory pathway which relays through the submucous plexus via an inhibitory neurone. 74 In designing a simple circuit to explain esophageal motor behavior it seemed reasonable from the information presently available to make a number of assumptions. (1) In its simplest form there are four basic neural units: (a) an excitatory cholinergic neurone; (b) an inhibitory nonadrenergic, noncholinergic neurone; (c) a local excitatory mechanism probably mediated by stimulation of a mechanoreceptor; and (d) central efferent fibers carrying excitation from the central control mechanism. (2) Active distal inhibition in the esophageal body is probably a local phenomenon. That is, an active mechanism for distal inhibition is present within the local intramural neuronal mechanism and does not require central fibers connecting. directly on the intramural inhibitory neurones. This is supported by the vagal reinnervation experiments of Roman, Tieffenbach and Miolan,7,8,22,28 in which there was no evidence of an active efferent discharge from the central control mechanism that would fit temporally with direct inhibition of the esophageal body muscle and which should precede excitation. In these experiments it is unlikely that preganglionic vagal fibers destined to synapse on the intramural inhibitory neurones were present but failed to reinnervate the striated muscle. The inhibitory neurones are excited via cholinergic receptors probably located at the ganglia. 60, 61 Therefore one would expect vagal efferents innervating these neurones to be cholinergic and to reinnervate the striated muscle, as did the preganglionic vagal fibers destined for the excitatory intramural ganglia. (3) At any level of the esophagus, the excitatory input from either the local mechanoreceptors or from the central control mechanism is unitary in function and destination. That is, this input excites the local control mechanism at that level only, and distant effects within the esophagus, either oral or aboral, are mediated thereafter via the local control mechanism. (4) The on response is attributable to cholinergic excitation of the muscle. At any level of the esophagus the on response can be stimulated to activity directly without opposing inhibition by efferent discharges from the central control mechanism, or by discharges from the local sensory input. (5) The off response has at least two components: (a) a cholinergic atropine-sensitive component; and (b) a noncholinergic atropirte-resistant component. Unmasking of cholinergic influences on cessation of stimulation could result from differences in kinetics of transmitter removal from receptor sites, or if the cholinergic excitation continues to fire for a short period of time after the stimulus is terminated. The nature of the noncholinergic atropineresistant component of the off response is not clear. (6) On simultaneous firing of the excitatory and inhibitory neurones, the inhibitory effect on the muscle is dominant. (7) Propagation velocity of the excitatory wave along the esophagus has as its simplest component the sequential synaptic delays along the esophagus. It is likely that regional differences in the neuronal firing patterns and/or in postganglionic neural characteristics, e.g., density of innervation, transmitter release and uptake, etc., contribute to propagation velocity in the peripheral control mechanisms. Postganglionic influences would tend to slow propagation velocity beyond that dictated by synaptic delays alone, with the most marked effect observed distally.ib, 37 (9) The unaltered propagation velocity of the peripheral control mechanisms is equal to or faster than that which can be dictated by the unaltered central control mechanism. Slowing of the central program of sequential efferent discharges to the esophagus will slow the peripheral control mechanism for peristalsis. This assumption is supported by comparison of the propagation velocity of centrally elicited peristalsis with the velocity determined by the peripheral control mechanism in the isolated or vagally denervated esophagus (table 1). In the latter case the unaltered propagation velocity of the peripheral mechanism also includes that portion of the velocity presumably contributed by the regional differences in timing of the off response contraction. 20, 26 Figure 1 is a schematic diagram of a simple neuronal network that can lead to a caudally moving wave of contraction in the esophageal smooth muscle when excited by either the central vagal connection or by stimulation of local sensory fibers. The longitudinal muscle appears to have only postganglionic excitatory cholinergic input. Intramural excitatory postganglionic cholinergic fibers, as well as intramural noncholinergic nonadrenergic inhibitory neurones, innervate the circular ABORAL --- Vagal preganglionic efferenl fiber. - Cholinergic excitatory neurone..-.- Intramural non cholinergic, non adrenergic inhibitory neurone Sensory receptor. FIG. 1. Proposed intramural neural network mediating peristalsis in the smooth muscle esophagus. Open circles, cholinergic excitatory neurones; closed circles, noncholinergic nonadrenergic inhibitory neurones; hatched circles, sensory receptors which synapse on local cholinergic excitatory neurones, and also send afferent fibers to the central control mechanism. Vagal efferent fibers from the central control mechanism synapse on cholinergic excitatory neurones. C, circular muscle; L, longitudinal muscle. See text and figure 2 for further details.

8 March 1977 PROGRESS IN GASTROENTEROLOGY 553 smooth muscle cells. At each level, the excitatory neurones are innervated by cholinergic fibers from more proximal areas, excitatory input from local sensory receptors, and excitatory input from preganglionic cholinergic vagal fibers relaying command signals from the swallowing center in the brain. At any level, the intramural nonadrenergic noncholinergic inhibitory neurone receives only cholinergic fibers running from more proximal areas. As previously noted, we have made the assumption that when the same stimulus excites both the excitatory and inhibitory fibers to a smooth muscle cell, the inhibitory influence will dominate, and the excitatory cholinergic influence will last longer than the inhibitory influence on cessation of stimulation. The functional responses of this system are represented in figure 2. Figure 2A is a diagrammatic representation of the expected responses of the proposed neuronal network to sequential excitation of the preganglionic vagal fibers, as might occur with a swallow. A peristaltic contraction wave will pass along the esophagus preceded by active inhibition of the muscle. It can be seen that stimulation ofthe sensory fibers in response to the presence of a bolus or to a wet swallow cannot increase the propagation velocity ofthe peristaltic wave because of the presence of distal inhibition. The sensory stimulation would indeed have the effect of decreasing the propagation velocity and of increasing the amplitude and duration of contraction, as experimentally observed. This could be mediated centrally or locally, and ORAL... j... ; ~ ~. ~ ~ F Ig..._._._._._ _...-.._._._._ _ ~..-.-._ s L ~ + ~ w ~ ~ ABORAL the magnitude of these effects would depend on the temporal relationship between the firing of the preganglionic vagal fibers and the sensory ones, and on regional differences in innervation. Figures 2, Band Care schematic representations of the expected responses to simultaneous excitation of vagal preganglionic fibers (as occurs when the vagus nerve is electrically stimulated), and to stimulation of the sensory input at one level in the esophagus (as occurs with distention of a stationary balloon in the esophagus), respectively. With simultaneous stimulation of all nerve fibers by transmural stimulation, or by stimulation of the vagus nerves, a transient on response contraction can frequently be seen before the dominating effect of the nonadrenergic, noncholinergic inhibitory innervation is apparent. This might occur if there were differences in the kinetics of transmitter release or diffusion from the nerve to its receptor on the muscle cells, or ifthere were differences in the characteristics of activation of excitatory versus inhibitory neurones on stimulation. The present network provides for the transient "on response" on the basis of extra synaptic delay to excitation of the inhibitory neurone. This circuit proposes that the on response and the off response can be mediated by the same mechanism, that is, by stimulation of intramural excitatory cholinergic nerves common to both responses. The two responses are separated temporally by a dominant inhibitory mechanism. This does not exclude direct muscle stimulation as a factor contributing to the on response, or A B c rebound excitation as a contributing factor in the production of the off response. The occurrence of rebound..-...?... ~ y ~ " -.w _ EN excitation may require the presence of cholinergic or other excitatory influences functioning in either an active or a permissive role. 27, 2(t-31 The circuit further dictates that the production of peristalsis by either sequential excitation from the central control mechanism, or _._._._._._.,-,--", _0"-"._0_._._0_ ~ ~ ~ after vagal or ~ local esophageal stimulation (off re FIG. 2. Responses of the proposed intramural neural network mediating peristalsis in the smooth muscle esophagus. A, swallowing with sequential firing of vagal efferent fibers (VEF) from the central control mechanism; B, stimulation of peripheral cut end of vagus nerve with simultaneous firing of VEF; C, local excitation of sensory neurone (SN) at one level (e.g., balloon distention). Symbols as in figure 1. CMT, circular muscle tension. Synaptic delays are represented by a short time lag. Two assumptions are made: (1) once activated, the cholinergic excitatory neurones (EN) fire for a longer time than the noncholinergic, nonadrenergic inhibitory neurones (IN); (2) on simultaneous firing of the EN and IN, the inhibitory effect on the muscle is dominant. Note that a similar neuronal firing pattern is induced in each instance and results in a peristaltic muscle contraction. A transient muscle contraction may occur at the onset of stimulation in instance B. A more prolonged repetitive contraction can occur at or above the site oflocal sensory stimulation in instance C. sponse), can result in very similar neuronal firing patterns within the distal control mechanism. Even a single stimulus or a ~ short train of stimuli (e.g., <1 sec) ~ ~ ifof sufficient magnitude could initiate peristalsis in the peripheral control mechanism. In this instance peristalsis would appear to occur as an on response. Therefore, f ~ ~ ~ the terms on response and off response should only be used in their original sense, to describe a temporal relationship between stimulation and contraction of esophageal muscle under experimental conditions In this sense, they are excellent descriptive terms. However, in describing the mechanisms of excitation, inhibition and coordination of esophageal motor activity, the terms carry no meaning and may be confusing. We suggest that descriptions of esophageal muscle contraction patterns include physiological mechanisms. The Horizon The large amount of information, often confusing if not conflicting, must be integrated in some way to organize and direct subsequent investigation of the control mechanisms responsible for esophageal motor function. Therefore, the present neuronal circuit was designed in

9 554 PROGRESS IN GASTROENTEROLOGY Vol. 72, No.3 its simplest form and is presented to provide a working hypothesis for further study. It is reasonable to assume that the actual picture is much more complex and that the circuit will require revision. For instance, it is likely that there are interneurones positioned along the simple pathways outlined in the circuit. Nevertheless, by alterations or additions to the circuit it is possible to design experiments to test the hypothesis and to explain a number of other observations and suggestions. (1) a short pathway of ascending excitation;72 (2) a delay circuit, including an inhibitory interneurone in the pathway for descending excitation, similar to that suggested by Hirst and McKirdy;74 (3) additional parallel pathways for distal inhibition through interneurones connecting the inhibitory neurones; (4) tonic inhibition of esophageal smooth muscle,68, 70 (5) efferent vagal fibers synapsing directly on intramural inhibitory neurones; (6) inhibition of the gastroesophageal sphincter by extension of the inhibitory network to the sphincter region; 11, 42, 59 in this regard, there are probably more direct intramural pathways running from the proximal esophagus to the sphincter, because proximal balloon distention causes sphincter inhibition after only a short delay; (7) coordination of circular and longitudinal smooth muscle layers; (8) modulating effect of other peripheral control systems, such as the sympathetic nervous system and humoral or hormonal substances which could act at either a neural or muscular level;21, 51 (9) "on response" peristalsis (e.g., as a result of extra delay to onset of inhibition at each subsequent leved;25 (10) off response peristalsis dictated only by graded regional differences in the delay to onset of the off response, (e.g., after simultaneous release of inhibition at all levels);26 (11) excitatory vagal efferents from the central control mechanism passing directly to the striated muscle esophagus, with the smooth muscle esophagus receiving similar direct vagal fibers to its proximal portion only, or not at all; and (12) other sensory inputs (e.g., chemoreceptors). Alterations in the peripheral and in the central control mechanisms which might result in disordered esophageal motility are legion, and are open to testing. For example, it is apparent in examining the proposed circuit that the nonadrenergic, noncholinergic inhibitory neurone is given a critical role in the organization of the peripheral control mechanism. In the esophageal body, absence or decreased function of the inhibitory neurone would result in disordered peristalsis, and heightened excitability of the muscle. The latter could result in repetitive contractile activity and increased sensitivity to excitatory stimulation. In the gastroesophageal sphincter, absence of a critical inhibitory mechanism would result in increased resting tone, poor relaxation, and increased sensitivity to excitatory agents. These are familiar features of clinical disorders such as achalasia and diffuse spasm of the esophagus. In addition to collection of isolated pieces of information through new experimentation, broader perspectives should also be observed. (1) Consideration must be given to the idea that there are a number of interlocking control mechanisms for esophageal peristalsis ranging from the central nervous system to the myogenic level, each potentially capable of organizing or contributing to coordinated motor activity under the right circumstances. (2) There are major species differences in esophageal anatomy and one must anticipate species differences in the mechanisms of esophageal motor control. (3) Differences in, and artifacts of experimental technique must be scrutinized with care, previous observations rechecked, and the effect of old bias and dogma, minimized in the interpretation of old and new observations. (4) The prime goal is to explain esophageal peristalsis in the alive, intact, healthy human being. 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