Anatomy and Physiology of the Upper Esophageal Sphincter

Anatomy and Physiology of the Upper Esophageal Sphincter Ivan M. Lang, DVM, PhD, Reza Shaker, MD, Milwaukee, Wisconsin

The upper esophageal sphincter (UES) is composed of the cricopharyngeus (CP), thyropharyngeus (TP; inferior pharyngeal constrictor [IPC] in humans), and cranial cervical esophagus. All 3 muscles may at times function to maintain tone in the UES, but only the CP contracts and relaxes in all physiologic states consistent with the UES. The CP is a striated muscle composed of variable-sized small (25– 35 mm) muscle fibers that are primarily type I (slow twitch), highly oxidative, and contain abundant (40%) endomysial elastic connective tissue. The fibers may attach to the connective tissue framework, forming a muscular net. In humans and rats, but not other animals, the CP has no median raphe. The optimum length of the CP for development of active tension is about 1.7 times resting length; therefore, in some respects the CP acts more like cardiac than striated muscle. A passive tone in the CP is present and increases through all degrees of stretch. The high compliance of the CP allows it to be opened by distraction of other muscles (e.g., geniohyoideus) or increased intraluminal pressure. The CP is innervated by branches of the vagus nerves: pharyngoesophageal (PE), superior laryngeal (SLN), and recurrent laryngeal (RLN); glossopharyngeal (GPN); and cervical sympathetics. Only the PE and SLN provide motor fibers to the CP. The GLN may be sensory; the sympathetics may innervate the mucosa, blood vessels, and glands; but no functional innervation by the RLN has been identified. Parasympathetic ganglia and various peptides (galanin, cGRP, VIP, neuropeptide Y, substance P, tyrosine hydroxylase) have been found in the CP, but their role in control of the CP is unknown. The motoneurons of the CP are found in the nucleus ambiguus, and the innervation is ipsilateral for animal species in which the CP has a median raphe. These motoneurons are topographically organized with

From the Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Requests for reprints should be addressed to Ivan M. Lang, DVM, PhD, Dysphagia Research Laboratory, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226.

50S

other pharyngeal and laryngeal muscles and the striated muscle esophagus. Pharyngeal motoneurons often have a respiratory rhythm, but not a spontaneous background discharge. Therefore, the CP motoneurons may not generate CP tone. Various reflexes control the tone of the CP. Distension of the esophagus causes contraction of the CP and UES, which is mediated by a vago-vagal reflex. Pressure on the pharyngeal mucosa contracts the CP and UES and is mediated by a glossopharyngo-vagal reflex. Inflation of the lungs causes contraction of the CP and UES, which is mediated by a vagovagal reflex. The pharyngo-UES and pulmonaryUES reflexes may generate the respiratory rhythm often observed on UES pressure or electromyographic activity. The UES or CP also contracts with arousal or with changes in posture. All of these reflexes and responses and the passive elastic properties of the CP may contribute to the generation of tone in the CP and UES. Am J Med. 1997;103(5A):50S–55S. Q 1997 by Excerpta Medica, Inc.

T

he upper esophagus presents an organ that must be defined both anatomically and physiologically.

DEFINITION OF THE UPPER ESOPHAGEAL SPHINCTER The upper esophageal sphincter (UES) is defined as the pharyngo-esophageal segment that maintains a closed pharyngo-esophageal junction and that phasically opens during various physiologic states. When one compares the UES intraluminal high-pressure zone to the anatomic components of the pharyngo-esophageal segment,1 – 6 one finds an elevated pressure encompassing the proximal cervical esophagus, cricopharyngeus (CP), and inferior pharyngeal constrictor (IPC; thyropharyngeus [TP] in animals). Experimental evidence has been found to implicate each muscular element as the UES. The proximal cervical esophagus was found to have an innervation pattern histologically similar to that of other gastrointestinal sphincters.7 Careful comparison8 of the location of the UES high-pressure zone with the radiographic anatomy of the laryngo-pharynx revealed in most studies that the peak UES pressure was observed at the IPC in humans3,5,9 and animals.1,2 In addition, some investigators found that the elec-

Q1997 by Excerpta Medica, Inc. All rights reserved.

/ 2312 5513 Mp

50

Friday Dec 05 06:18 PM

0002-9343/97/$17.00 PII S0002-9343(97)00323-9

EL–AJM (v. 1500)

5513

SYMPOSIUM ON GASTROESOPHAGEAL REFLUX DISEASE/LANG AND SHAKER

tromyographic activity of the TP (IPC) and the CP fluctuated with UES pressure and relaxed during swallows.2 The fact that the TP may function like the CP or UES at times or that the TP may be capable of generating more force than the CP (possibly due to the abundance of elastic connective tissue in the CP as described below) does not mean it is the primary muscle of the UES. The CP has been considered the primary muscular component of the UES by most investigators. Some investigators have found that the peak UES pressure does correspond with the CP6 and that the infracricoid esophagus does not have histologic characteristics consistent with a sphincter.10 Most importantly, however, in most studies using humans or animals, investigators found that the CP but not the IPC (TP) (1) had a continual basal tone1,11 – 16; (2) relaxed during swallowing1,12 – 17; and (3) experienced fluctuations in electromyographic activity associated with changes in UES pressure.1,16,18 Perhaps the UES is more complex than comprising one muscle. When all studies are considered, it appears that the muscle(s) comprising the UES depends on the physiologic state. Basal tension is produced by the CP and IPC (TP) and possibly the infracricoid esophagus1,2,11,13 – 18; active relaxation during swallowing1,11,13 – 17 and belching19,20 occurs primarily on the CP; changes in activity with respiration2,17,18,21,22 occur in both the CP and IPC; UES contraction and relaxation during retching and vomiting occur by the simultaneous action of the CP, IPC, and proximal cervical esophagus13,20; UES contraction in response to esophageal or pharyngeal distension (i.e., the esophago-UES and pharyngo-UES reflexes11) occurs with the CP rather than the IPC; and contraction of the UES during coughing and sneezing occurs in both the CP and IPC.23 Therefore, the UES may comprise the CP, IPC, and proximal cervical esophagus, depending on the physiologic state, but the one muscle that functions as the UES in all physiologic states is the CP.

ANATOMY AND CELLULAR PHYSIOLOGY OF THE CP In most species the CP attaches to the cricoid cartilage and forms a c-shaped muscular band that produces maximum tension in anteroposterior rather than lateral directions.1,2,4 In humans, two sets of muscle fibers have been identified: the horizontally oriented fibers (pars fundiformis) and an oblique band of fibers (pars obliqua), which extends from the lateral aspect of the cricoid cartilage to the posterior midline raphe, where they blend superiorly with the TP.24 Unlike the TP, the pars fundiformis of the CP has no median raphe. In most animal species the CP forms a muscular band distinct from the TP but con-

tains a median raphe.25,26 The CP is a striated muscle composed of variable-sized fibers of small average diameter (25–35 mm), which are not oriented in strict parallel fashion as most other striated muscles.24,27,28 The CP contains a large amount of endomysial connective tissue (about 40%), much of which is elastic but has no muscle spindles.27 – 30 It has been suggested that, unlike most other striated muscles, which insert on the skeletal framework, the muscle fibers of the CP insert onto the connective tissue framework, thereby forming a muscular network.29 In most species the predominant muscle fiber type is type I (slow twitch) and highly oxidative,24,28,29 and in all species examined, the predominant fiber type or oxidative state of the CP is different (i.e., slower and/or more oxidative) from surrounding pharyngeal or laryngeal muscles.24,27 – 33 The structure and biochemical properties of the CP serve its function well, allowing the CP to stretch and accommodate large boluses but maintaining a constant tone to form a barrier between the esophagus and pharynx. The CP, in all species examined, also contains type II (fast twitch) muscle fibers, and these fast twitch fibers are predominantly highly oxidative.24,27 – 29,31 The presence of both slow and fast twitch fibers provides an anatomic basis for the various functions of the CP or UES: (1) maintaining constant basal tone and (2) rapid relaxation and contraction during swallowing, belching, vomiting, and other reflexes.

BIOPHYSICS OF THE CP The CP is not only structurally and biochemically different from surrounding pharyngeal and laryngeal muscles, but its mechanical properties are different as well. The length at which the CP reaches maximum active tension is about 1.7 times its basal (or in situ) length,34 whereas this tension in most striated muscles occurs at resting length.35,36 The source of elasticity in muscle is unclear, but many investigators have proposed a model that contains both parallel and series elastic elements, where the parallel elastic element is assumed by most as contributing to the passive elastic properties of the muscle.35 – 37 Structural correlates of the parallel elastic element include connective tissue,35 i.e., collagen and elastin; sarcolemma; and the contractile apparatus itself,38 i.e., the contractile proteins, actin and myosin. Compared with other striated muscles, the CP24,27 – 29 has abundant (about 40%) connective tissue (especially elastic elements) and more sarcolemma (the cricopharyngeus muscle fibers are smaller, about 25–35 mm, than most striated muscle fibers, about 100 mm, which therefore have more sarcolemma). These structural characteristics as well as the network arrangement of muscle fibers and connective tissue could account for the passive elastic behavior

November 24, 1997 The American Journal of MedicineT Volume 103 (5A)

/ 2312 5513 Mp

51

Friday Dec 05 06:18 PM

EL–AJM (v. 1500)

5513

51S

SYMPOSIUM ON GASTROESOPHAGEAL REFLUX DISEASE/LANG AND SHAKER

of the CP. The functional implications of the passive tension characteristics of the CP are that (1) a basal passive pressure is generated intraluminally at all levels of distension (there will always be tension recorded intraluminally from the UES that is not due to active contraction); (2) the tension of the sphincter increases throughout its range of distension34 similar to the Frank-Starling characteristics of cardiac muscle (the diameter of the UES during a swallow of maximal volume does not exceed the optimal length of the UES34); and (3) the UES may be opened by increased intraluminal pressure or active distraction without active relaxation of the UES.2

NEUROPHYSIOLOGY OF THE CP The CP receives innervation from the pharyngeal plexus, which is supplied by 3 major nerves: vagus nerve through the pharyngoesophageal, superior laryngeal, and recurrent laryngeal branches; glossopharyngeal nerve; and sympathetics through the cranial cervical ganglion.34,39 – 48 Dissection techniques are incapable of determining the particular pharyngeal muscles innervated by these nerves, because all of these nerves form communicating branches with each other. In addition, dissection techniques do not identify the nerve terminals and, therefore, cannot distinguish sensory from motor nerves or identify the effector organs involved (e.g., muscle or blood vessel). Although the anatomical architecture of the pharyngeal plexus differs among species,34,39 – 48 the pattern of functional innervation is quite uniform and consistent. Functional studies have determined that in most species the primary motor innervation of the CP is the pharyngoesophageal nerve.2,22,39,45 – 50 Electrical stimulation of the pharyngoesophageal nerve depleted 60% of the CP muscle fibers of glycogen,39 resulted in an integrated electromyographic response much greater than that activated by the superior laryngeal nerve34 or glossopharyngeal nerve,48 and strongly contracted the CP, whereas recurrent laryngeal nerve stimulation did not.22,46 Furthermore, transection of the pharyngoesophageal nerve rather than glossopharyngeal49 or superior laryngeal46,47 nerves had profound long-term deficits on swallowing and resting pharyngeal pressure and produced denervation potentials in the CP muscle.48 Although the superior laryngeal nerve may contribute to the motor innervation of the CP, there is no functional evidence for a role of the glossopharyngeal nerve or recurrent laryngeal nerve in the motor control of the CP.

Sensory Information The glossopharyngeal nerve and sympathetics may provide important sensory information from the CP, underlying pharyngeal mucosa, or blood vessels, 52S

but the role of these nerves is unclear. Some early investigators found that peripheral electrical stimulation of the cervical sympathetics caused changes in CP motor activity,51 but these results have not been corroborated.46,50 Considering the large amount of branching among the nervous inputs to the CP, it is possible that some of these effects may have been due to stimulation of vagal pathways. The glossopharyngeal nerve may mediate the afferent limb of pharyngeal mucosal reflexes, because transection of the glossopharyngeal nerve blocked the pharyngoUES contractile reflex without affecting the esophago-UES contractile reflex.11 This sensory role for the glossopharyngeal nerve may explain some of the deficits in swallowing observed after transection of the glossopharyngeal nerve.48

Neurotransmitters The neurotransmitters involved in the control of the CP include acetylcholine as well as various neuropeptides. The following peptides have been found52 within the CP using immunohistochemistry: calcitonin gene related peptide, neuropeptide Y, tyrosine hydroxylase, substance P, vasoactive intestinal polypeptide, and galanin. The calcitonin gene related peptide is also found in other pharyngeal and laryngeal muscles and the striated muscle esophagus.53,54 The CP has significantly less calcitonin gene related peptide than the TP, but the functional significance of this difference is unknown. These neuropeptides may simply represent the autonomic innervation of the muscle, because calcitonin gene related peptide, neuropeptide Y, and tyrosine hydroxylase are found in sympathetic nerves and substance P, vasoactive intestinal polypeptide, and galanin are found in parasympathetic nerves. Interestingly, the sympathetic peptides were more abundant than the parasympathetic peptides. Clusters of neurons, i.e., ganglia, were found in the CP rather than the TP, and these contained mostly parasympathetic peptides, suggesting that these were parasympathetic ganglia.52 The role of either the sympathetic or parasympathetic innervation and peptides are unknown, but control of blood vessels, glands, and pharyngeal mucosa are the most likely functions. Motor Neurons The motor neurons controlling the CP are found primarily within the semi-compact and rostral compact portions of the nucleus ambiguus (NA)55 – 62 and the innervation is mostly (ú95%) ipsilateral58,61 in those species with a median raphe. The CP motor neurons are topographically organized with the other muscles of the pharynx and esophagus, although there is considerable overlap.56,60,61 The ipsi-

November 24, 1997 The American Journal of MedicineT Volume 103 (5A)

/ 2312 5513 Mp

52

Friday Dec 05 06:18 PM

EL–AJM (v. 1500)

5513

SYMPOSIUM ON GASTROESOPHAGEAL REFLUX DISEASE/LANG AND SHAKER

lateral innervation pattern of the CP by the NA is consistent with swallowing studies, which found that half of the brainstem controls the ipsilateral half of the CP during swallowing.63 In contrast, reflex activation of the CP requires both halves of the brainstem64; and electrical stimulation of the nucleus tractus solitarius (NTS), the primary afferent nucleus of the vagus, causes activation of the CP bilaterally.48,49 These results suggest that control of the CP differs with different functions. The neurons of the NA have extensive dendritic arborization to the adjacent reticular formation55 and ultrastructural studies indicate the synapses on these neurons are both excitatory as well as inhibitory.65 These findings provide an anatomic basis for numerous excitatory and inhibitory reflexes and responses by the CP. Pharyngeal premotor neurons of the NA have been identified in the interstitial and intermediate subnuclei of the NTS,57 and this pathway is distinct from the esophageal swallowing circuit. This circuit may mediate nonswallowing reflex responses of the UES, such as the pharyngo-UES contractile reflex.11 Many pharyngeal motoneurons of the NA exhibit a respiratory rhythm, some units were in phase, but others were out of phase with inspiration but have no spontaneous background discharge.62 These results suggest that the pharyngeal motoneurons do not generate the basal tone observed in the CP or UES.

Reflexes Involving UES Numerous reflexes control the function of the UES. Slow balloon or bolus distension of the esophagus — proximal is more sensitive than distal— causes increased UES pressure or CP electromyographic activity mediated by vagal afferent fibers.11,12,66 – 68 The receptors mediating this reflex may be slow adapting mechanoreceptors of the muscular wall.69 Some investigators have found that slow acid infusion into the esophagus causes increased UES tone,67,70,71 but these results have not been corroborated by more recent studies,72,73 and in addition, esophageal pH was found not to correlate with UES tone.73 The increased UES tone after acid infusion may have been due to nonphysiologic concentrations of acid, activation of esophageal distension reflex, or the pull-through technique of measuring UES tone. Pharyngeal stimulation was also found to cause increase in UES tone74 and CP but not TP electromyographic activity.11 The afferent limb of this reflex is the glossopharyngeal nerve, and the efferent is the pharyngoesophageal branch of the vagus. The physiologic stimulus (i.e., air or fluid) for this reflex is unknown; therefore, the function of this reflex in unclear. This reflex may close the esophagus during inspiration to prevent reflux aerophagia, or it may close the esophagus to prevent reflux aspiration. It

has been observed for a long time that UES pressure fluctuates with respiration, but it may be in or out of phase with inspiration, and it may be associated with contraction of the CP or TP.1,18,21,55,75 This rhythm may be generated centrally by brainstem respiratory centers or peripherally by reflex mechanisms. One reflex that may account for this respiratory rhythm is the pharyngo–UES contractile reflex, but a pulmonary–UES contractile reflex has also been found.21 The magnitude of tidal volume correlated positively with CP electromyographic activity, and lung distension by positive pressure ventilation or hyperventilation caused strong contraction of the CP. The pulmonary–UES reflex was mediated by vagal afferents and may be part of the Hering-Breuer reflexes. In some situations inspiration is associated with contraction of the TP rather than the CP,2,21 suggesting that other reflexes or mechanisms may control respiratory rhythm of the UES.

Generation of Tone Perhaps the most significant function of the UES as a sphincter is the generation of tone. The mechanical properties of the CP ensure that tone will develop in the muscle at any degree of stretch without active contraction. Many sphincters have a constant basal tone generated by the neural input or intrinsic properties of the muscle. However, the UES or CP do not appear to exhibit a significant constant active basal tone. The CP electromyography of chronically instrumented awake and unanesthetized dogs experiences periods of very low activity when the animal is calm, supine, and resting its head, but awake.23 Tone of the CP of animals or UES of people falls to very low states during anesthesia18 or sleep.76 On the other hand, changes in posture8 or arousal1,76 can cause very large increases in activity. Moreover, pharyngeal motoneurons found in decerebrate and paralyzed cats did not exhibit a basal constant discharge.62 These results suggest that much of the tone of the UES or CP may be generated by various reflexes, responses, and muscle mechanics rather than a specific tone-generating circuitry of the brainstem.

REFERENCES 1. Lang IM, Dantas RO, Cook IJ, Dodds WJ. Videographic, manometric and electromyographic assessment of upper esophageal sphincter function in the dog. Am J Physiol. 1991;260:G911–G919. 2. Asoh R, Goyal RK. Manometry and electromyography of the upper esophageal sphincter in the opossum. Gastroenterology. 1978;74:514–520. 3. Cook IJ, Dodds WJ, Dantas RO, et al. Opening mechanisms of the upper esophageal sphincter. Am J Physiol. 1989;257:G748–G759. 4. Gerhardt D, Hewett J, Moeschberger M, et al. Human upper esophageal sphincter pressure profile. Am J Physiol. 1980;239:G49–G52. 5. Kahrilas PJ, Dodds WJ, Dent J, et al. Upper esophageal sphincter function during deglutition. Gastroenterology. 1988;95:52–62. 6. Nilsson ME, Isberg A, Schiratzki H. The location of the upper oesophageal sphincter and its behavior during bolus propagation: a simultaneous cineradiographic and manometric investigation. Clin Otolaryngol. 1989;14:61–65.

November 24, 1997 The American Journal of MedicineT Volume 103 (5A)

/ 2312 5513 Mp

53

Friday Dec 05 06:18 PM

EL–AJM (v. 1500)

5513

53S

SYMPOSIUM ON GASTROESOPHAGEAL REFLUX DISEASE/LANG AND SHAKER 7. Zaino C, Jacobsen HG, Lepow H, Oziurk CH. The Pharyngoesophageal Sphincter. Springfield, Illinois: Charles C. Thomas, 1970. 8. Goyal RK, Martin SB, Shapiro J, Spechler SJ. The role of cricopharyngeus muscle in pharyngoesophageal disorders. Dysphagia. 1993;8:252– 258. 9. Sokol EM, Heitman P, Wolf B, Cohen B. Simultaneous cineradiographic and manometric study of the pharynx, hypopharynx, and cervical esophagus. Gastroenterology. 1966;51:960–974. 10. Ekberg O, Lindstrom C. The upper esophageal sphincter area. Acta Radiol. 1987;28:173–176. 11. Medda BK, Lang IM, Layman R, et al. Characterization and quantification of a pharyngo–UES contractile reflex in cats. Am J Physiol. 1994;267:G972– G983. 12. Car A, Roman C. L’activite spontanee du sphincter oesophagien superieur chez le mouton. J Physiol (Paris). 1970;62:505–511. 13. Lang IM, Sarna SK, Dodds WJ. The pharyngeal, esophageal, and gastrointestinal responses associated with vomiting. Am J Physiol. 1993;265:G963– G972. 14. Tanaka E, Palmer J, Siebens A. Bipolar suction electrodes for pharyngeal electromyography. Dysphagia. 1986;1:39–40. 15. Elidan J, Gonen B, Shochina M, Gay I. Electromyography of the inferior constrictor and cricopharyngeal muscles during swallowing. Ann Otol Rhinol Laryngol. 1990;99:46–49. 16. Shipp T, Deatsch WW, Robertson K. Pharyngoesophageal muscle activity during swallowing in man. Laryngoscope. 1970;80:1–16. 17. Van Overbeek JJM, Wit HP, Paping RHL Segenhout HM. Simultaneous manometry and electromyography in the pharyngoesophageal segment. Laryngoscope. 1985;95:582–584. 18. Jacob P, Kahrilas PJ, Herzon, McLaughlin B. Determinants of upper esophageal sphincter pressure in dogs. Am J Physiol. 1990;259:G245–G251. 19. Lang IM, Marvig J, Sarna SK. The contractile correlates of belching and their mechanisms of initiation. Gastroenterology. 1988;95:876A. 20. Monges H, Salducci J, Naudy B. The upper esophageal sphincter during vomiting, eructation, and distension of the cardia: an electromyographic study in the unanesthetized dog. In: Duthie HL, ed. Gastrointestinal Motility in Health and Disease. Lancaster, UK: MTP Press, 1978:575–583. 21. Medda BK, Lang IM, Dodds WJ. Control of UES tone by lung inflation reflexes. Gastroenterology. 1990;99:1219A. 22. Murakami Y, Fukuda H, Kirchner JA. The cricopharyngeus muscle. An electrophysiological and neuropharmacological study. Acta Otolaryngol Suppl. 1973;311:4–19. 23. Lang IM, Marvig J, Sarna SK. Electromyography (EMG) of the pharyngoesophageal junction (PEJ) during various physiologic states. Gastroenterology. 1988;94:249A. 24. Brownlow H, Whitmore I, Willan P. A quantitative study of the histochemical and morphometric characteristics of the human cricopharyngeus muscle. J Anat. 1989;166:67–75. 25. Miller ME, Christensen GC, Evans HE. Chapter 3. Myology. In: Anatomy of the Dog. Philadelphia: Saunders, 1984. 26. McClure RC, Dallman MJ, Garrett PG. Section 9. The cephalic region and central nervous system. In: Cat Anatomy. An Atlas, Text, and Dissection Guide. Philadelphia: Lea and Fibiger, 1973. 27. Bonington A, Whitmore I, Mahon M. A histological and histochemical study of the cricopharyngeus muscle in the guinea pig. J Anat. 1987; 153:151–161. 28. Kristmundsdottir F, Mahon M, Froes MMQ, Cumming WJK. Histomorphometric and histopathological study of the human cricopharyngeus muscle: in health and in motor neuron disease. Neuropathol Appl Neurobiol. 1990;16:461–475. 29. Bonington A, Mahon M, Whitemore I. A histological and histochemical study of the cricopharyngeus muscle in man. J. Anat. 1988;156:27–37. 30. Bonington A. The histochemical characteristics of the human cricopharyngeus muscle. J Anat. 1986;146:251–251. 31. Ibebunjo C. Histochemical and morphometric properties of muscles of the upper airway of goats. Res Vet Sci. 1993;55:215–223. 32. Dick TE, Van Lunteren. Fiber subtype distribution of pharyngeal dilator muscles and diaphragm in the cat. J Appl Physiol. 1990;68:2237–2240. 54S

33. Braund KG, Steiss JE, Marshall AE, et al. Morphologic and morphometric studies of the intrinsic laryngeal muscles in clinically normal adult dogs. Am J Vet Res. 1988;49:2105–2110. 34. Medda BK, Lang IM, Dodds WJ, et al. Correlations of electrical and contractile activities of the cricopharyngeous muscle in the cut. Am J Physiol. 1997;273:G470–G479. 35. Spiro D, Sonenblick EH. Comparison of the ultrastructural basis of the contractile process in heart and skeletal muscle. Circ Res. 1964;15(suppl 11):14–37. 36. Wilkie DR. The mechanical properties of muscle. Br Med Bull. 1956;12:177–182. 37. Hill AV. The heat of shortening and the dynamic contraction of muscle. Proc Roy Soc Ser B. 1938;126:136–195. 38. Grimm AF, Whitehorn WV. Characteristics of resting tension of myocardium and localization of its elements. Am J Physiol. 1966;210:1362–1368. 39. Kobler JB, Datta S, Goyal RK, Benecchi EJ. Innervation of the larynx, pharynx, and upper esophageal sphincter of the rat. J Comp Neurol. 1994;349:129–147. 40. Mebis J, Geboes K, Desmet V. Innervation of the human esophagus. In: Janssens J, ed. Gastrointestinal Motility Disorders. Belgium: KU Leuven, 1993. 41. Sprague JM. The innervation of the pharynx in the rhesus monkey and the formation of the pharyngeal plexus in primates. Anat Rec. 1944;90:197–208. 42. Steinberg JL, Khane GJ, Fernandes CMC, Nel JP. Anatomy of the recurrent laryngeal nerve: a redescription. J Laryngol Otol. 1986;100:919–927. 43. Lemere F. Innervation of the larynx. I. Innervation of the laryngeal muscles. Am J Anat. 1932;51:417–437. 44. Mu L, Sanders I. The innervation of the human upper esophageal sphincter. Dysphagia. 1996;11:234–238. 45. Lund WS, Adran GM. The motor nerve supply of the cricopharyngeal sphincter. Ann Otol Rhinol Laryngol. 1964;73:599–617. 46. Hwang K, Grossman, MI, Ivy AC. Nervous control of the cervical portion of the esophagus. Am J Physiol. 1948;154:343–357. 47. Lund WS. A study of the cricopharyngeal sphincter in man and in the dig. Ann Roy Coll Surg Engl. 1965;37:225–246. 48. Venker-van Haagen AJ, Hartman W, Wolvekamp WTC. Contributions of the glossopharyngeal nerve and the pharyngeal branch of the vagus nerve to the swallowing process in dogs. Am J Vet Res. 1986;47:1300–1307. 49. Venker-van Haagen AJ, Hartman W, Van den Brom WE, Wolvekamp WTC. Continuous elctromyographic recordings of pharyngeal muscle activity in normal and previously denervated muscles in dogs. Am J Vet Res. 1989;50:1725– 1728. 50. Levitt MN, Dedo HH, Ogura JH. The cricopharyngeus muscle, an electromyographic study in the dog. Laryngoscope. 1965;75:122–136. 51. Kirchner JA. The motor activity of the cricopharyngeus muscle. Laryngoscope. 1958;68:1119–1159. 52. Tadaki N, Hisa Y, Uno T, et al. Neurotransmitters for the canine inferior pharyngeal constrictor muscle. Otolaryngol Head Neck Surg. 1995;113:755– 759. 53. Ternghi G, Polak JM, Rodrigo J, et al. Calcitonin gene-related peptide-immunoreactive nerves in the tongue, epiglottis and pharynx of the rat: occurrence, distribution and origin. Brain Res. 1986;365:1–14. 54. Rodrigo J, Polak JM, Fernandez L, et al. Calcitonin gene-related peptide immunoreactive sensory and motor nerves of the rat, cat, and monkey esophagus. Gastroenterol. 1985;88:444–451. 55. Altschuler SM, Bao, X, Miselis RR. Dendritic architecture of nucleus ambiguus motoneurons projecting to the upper alimentary tract in the rat. J Comp Neurol. 1991;309:402–414. 56. Bieger D, Hopkins DA. Viscerotopic representation of the upper alimentary tract in the medulla oblongata in the rat: the nucleus ambiguus. J Comp Neurol. 1987;262:546–562. 57. Bao X, Wiedner EB, Altschuler SM. Transsynaptic localization of pharyngeal premotor neurons in rat. Brain Res. 1995;696:246–249. 58. Hudson LC. The origins of innervation of the canine caudal pharyngeal muscles: an HRP study. Brain Res. 1986;374:413–418. 59. Lawn AM. The localization, by means of electrical stimulation, of the origin and path in the medulla oblongata of the motor nerve fibres of the rabbit oesophagus. J Physiol. 1964;174:232–244.

November 24, 1997 The American Journal of MedicineT Volume 103 (5A)

/ 2312 5513 Mp

54

Friday Dec 05 06:18 PM

EL–AJM (v. 1500)

5513

SYMPOSIUM ON GASTROESOPHAGEAL REFLUX DISEASE/LANG AND SHAKER 60. Lawn AM. The localization, in the nucleus ambiguus of the rabbit, of the cells of origin of motor nerve fibers in the glossopharyngeal nerve and various branches of the vagus nerve by means of retrograde degeneration. J Comp Neurol. 1966;127:293–306. 61. Kitamura S, Ogata K, Nishiguchi T, et al. Location of the motoneurons supplying the rabbit pharyngeal constrictor muscles and the peripheral course of their axons: a study using the retrograde HRP or flourescent labeling technique. Anat Rec. 1991;229:399–406. 62. Grelot L, Barillot JC, Bianchi AL. Pharyngeal motoneurons: respiratory-related activity and responses to laryngeal afferents in the decerebrate cat. Exp Brain Res. 1989;78:336–344. 63. Doty RW, Richmond WH, Storey AT. Effect of medullary lesions on coordination of deglutition. Exp Neurol. 1967;17:91–106. 64. Lang IM, Medda BK, Hogan WJ, Shaker R. Brainstem control of the upper esophageal sphincter in the cat. J Neurogastrointestinal Mot. 1995;7:268. 65. Hayakawa T, Yajima Y, Zyo K. Ultrastructural characterization of pharyngeal and esophageal motoneurons in the nucleus ambiguus of the rat. J Comp Neurol. 1996;370:135–146. 66. Reynolds RPE, Effer GW, Bendeck MP. The upper esophageal sphincter in the cat: the role of central innervation assessed by transient vagal blockade. Can J Physiol Pharmacol. 1987;65:96–99. 67. Freiman JM, El-Sharkay TY, Diamant NE. Effect of bilateral vagosympathetic nerve blockade on response of the dog upper esophageal sphincter (UES) to intraesophageal distension and acid. Gastroenterology. 1981;812:78–84.

68. Enzmann DR, Harell GS, Zboralske FF. Upper esophageal responses to intraluminal distension in man. Gastroenterology. 1977;72:1292–1298. 69. Sengupta JN, Saha JK, Goyal RK. Stimulus–response function studies of esophageal mechanosensitive nociceptors in sympathetic afferents of opossum. J Neurophysiol. 1990;64:796–812. 70. Gerhardt DC, Shuck TJ, Bordeaux RA, et al. Human upper esophageal sphincter response to volume, osmotic and acid stimuli. Gastroenterology. 1978;75:268–274. 71. Wallin L, Boesby S, Madsen T. The effect of HCl infusion in the lower part of the esophagus on the pharyngo-oesophageal sphincter pressure in normal subjects. Scand J Gastroenterol. 1978;13:821–826. 72. Vakil NB, Kahrilas PJ, Dodds WJ, Vanagunas A. Absence of an upper esophageal sphincter response to acid reflux. Am J Gastroenterol. 1989;84:606–610. 73. Wilson JA, Pryde A, Macintyre CCA, Heading RC. Effect of esophageal acid exposure on upper esophageal sphincter pressure. J GI Motil. 1990;2:117–120. 74. Ren J, Shaker R, Lang IM, et al. Effect of volume, temperature and anesthesia on the pharyngo–UES contractile reflex in humans. Gastroenterology. 1995;108:A677. 75. Kawasaki M, Ogura JH, Takenouchi S. Neurophysiologic observation of normal deglutition. I. Its relationship to the respiratory cycle. Laryngoscope. 1964;74;1747–1765. 76. Kahrilas PJ, Dodds WJ, Dent J, et al. Effect of sleep, spontaneous gastroesophageal reflux, and a meal on upper esophageal sphincter pressure in normal human volunteers. Gastroenterology. 1987;92:466–471.

November 24, 1997 The American Journal of MedicineT Volume 103 (5A)

/ 2312 5513 Mp

55

Friday Dec 05 06:18 PM

EL–AJM (v. 1500)

5513

55S