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Spontaneous transient lower esophageal sphincter relaxations: A target for treatment of gastroesophageal reflux disease
November 1995
EDITORIALS
1703
Spontaneous Transient Lower Esophageal Sphincter Relaxations: A Target for Treatment of Gastroesophageal Reflux Disease See article on page 1 5 4 7 .
n previous studies in asymptomatic subjects with normal lower esophageal sphincter (LES) pressure, Dent et al., Holloway et al., and Mittal and McCallum have shown that gastroesophageal reflux almost always occurs during spontaneous transient relaxations of the LES (TLESRs)) -3 In this issue of GASTROENTEROLOGY,the same investigators report on their studies on the mechanisms of gastroesophageal reflux in healthy subjects under the experimental condition of low LES pressure induced by atropine. 4 LES pressure, esophageal pH, and crural diaphragm electromyogram were recorded in the postprandial period. Although basal LES pressure was experimentally reduced by atropine, they showed that reflux only occurred during TLESRs, which were characterized by a further small decrease in the already lowered LES pressure and by an inhibition of the activity of the crural diaphragm. Unexpectedly, atropine also provoked a reduction in frequency of reflux episodes apparently related to a significant decrease in the number of postprandial TLESRs. The effect of atropine on the rate of TLESRs observed in the present study and recent experimental data, showing that cholecystokinin A receptor antagonists are able to reduce the number of TLESRs induced by gastric distention in dogs, 5 focus our attention on TLESRs as a possible target for the treatment of gastroesophageal reflux disease. Several factors are involved in the pathogenesis of gastroesophageal reflux disease. Every reflux episode occurs as a consequence of a failure of the antireflux barrier at the gastroesophageal junction. When gastroesophageal reflux occurs, the amount of reflux that rises into the esophagus is at least partially determined by the contractile status of the esophageal body. When the refluxed material succeeds to move up into the esophagus, volume clearing by gravity and esophageal peristalsis and chemical clearing by swallowed saliva will determine the time during which the refluxed bolus is in contact with the esophageal mucosa. Intragastric volumes and, thus, gastric emptying and esophageal mucosal defense mechanisms are other important but less well understood factors. Of all of these mechanisms, incompetence of the antireflux barrier is considered to be the key factor. The
I
resting LES tone, the number of TLESRs, and the contraction of the crural diaphragm during increased intraabdominal pressure are the most important components of the antireflux barrier. 6 Studies in normal subjects 1'7 and in patients with esophagitis 8'9 have shown that gastroesophageal reflux can occur in the case of a very low basal LES pressure (socalled free reflux), during TLESRs, or as a consequence of increased intra-abdominal pressure in the presence of normal or decreased basal LES tone (straining or stress reflux). Recent studies by Schoeman et al. 7 have shown that a low resting LES pressure gives rise to reflux only in the extreme case of pressures of < 3 m m Hg, which is very rare in healthy subjects even during the postprandial period. The present study by Mittal et al. is in agreement with these findings and showed that a low basal LES pressure induced by atropine is insufficient to provoke free reflux in healthy subjects. Although one would expect more straining-induced reflux in the case of a low basal LES pressure, the study by Mittal et al. showed that this is not the case, at least not in healthy subjects, because of the significant role of the crural diaphragm, which seems to not be affected by atropine. As a group, patients with gastroesophageal reflux disease have lower basal LES pressures than controls. 8 Some patients have a normal or slightly diminished basal LES pressure, but a subset of patients may have a very low basal LES pressure. Recent data from prolonged ambulatory p H and pressure recordings in patients with esophagitis showed that almost 10% of all reflux episodes occurred as free reflux during very low LES tone and that straining was present in 25 % of all reflux events. 9 Therefore, unlike healthy subjects, a subset of patients with esophagitis and very low basal LES pressure apparently lack an effective crural diaphragmatic function. In 1980, Dent et al. showed for the first time that a significant number of gastroesophageal reflux episodes occur during complete relaxations of the LES that are not induced by swallowing. These type of LES relaxations were called spontaneous TLESRs to distinguish them from swallow-induced LES relaxations. 1 Spontaneous TLESRs differ from swallow-induced LES relaxations because they are not accompanied by pharyngeal contraction and subsequent esophageal peristalsis; they usually
1704
EDITORIALS
last longer than swallow-induced relaxations and they are frequently followed by gastroesophageal reflux. 1° Since 1980, several studies using stationary perfused manometry with a Dent sleeve to measure LES pressure have confirmed that spontaneous TLESRs are the main mechanism for reflux in recumbent healthy subjects and are also an important mechanism for reflux in patients with gastroesophageal reflux disease. 8'11 In healthy subjects, 8 0 % - 9 5 % of reflux events occur during spontaneous TLESRs. The literature is more controversial about the relative importance of spontaneous TLESRs in patients with gastroesophageal reflux disease. The percent of reflux episodes occurring during spontaneous TLESRs in patients with reflux disease ranges from 4 0 % 12 tO 77.1%. i3 Only recently, the development of a miniaturized pneumohydraulic water-perfused sleeve device combined with a solid-state recording system allowed prolonged studies in ambulatory healthy subjects and patients with gastroesophageal reflux disease. These studies confirmed previous observations: the majority of reflux episodes occur in the postprandial period, and the main mechanisms for reflux are spontaneous TLESRs (82% in normals and 67% in patients with gastroesophageal reflux disease), v'9 Looking more closely to the mechanism of reflux in individual patients, the studies showed considerable variation in between patients: in some, the mechanism was almost exclusively spontaneous TLESRs; in others, it was mainly stress reflux or free reflux or a combination of both. The authors concluded that, generally spoken, reflux in patients with normal resting LES pressure was mainly due to spontaneous TLESRs, whereas patients with low resting LES pressure had a high degree of free reflux. The present study by Mittal et al. shows that spontaneous TLESRs may even be more important for the induction of reflux than already accepted and that they are also responsible for the occurrence of reflux episodes in the presence of a low resting LES tone. A close inspection of the period preceding reflux events showed an additional small decrease in pressure (representing a spontaneous TLESR) together with inhibition of the crural diaphragm. These small spontaneous changes in LES pressure may have been missed in previous studies in patients with gastroesophageal reflux disease; thus, reflux episodes may have erroneously been labeled as free reflux. In any case, there is now sufficient evidence to consider TLESRs as an important mechanism for reflux in patients with gastroesophageal reflux disease. Therefore, as suggested by Mittal et al., the reduction in the number of TLESRs may have significant therapeutic implications. Reflux occurs as discrete events during a period of absent basal LES pressure or during a spontaneous
GASTROENTEROLOGY Vol. 109, No. 5
TLESR. Moreover, some spontaneous TLESRs are not accompanied by reflux, suggesting that another intermittent process must be involved for reflux to occur. Mittal et al. suggest that a sudden inhibition of crural diaphragm contraction during spontaneous TLESRs or a failure of the crural diaphragm to compensate for small sudden increases in intra-abdominal pressure can be the events that represent this intermittent process. Some studies indicate that the proportion of spontaneous TLESRs accompanied by reflux is higher in patients with gastroesophageal reflux disease than in normals.n Is the crural diaphragmatic function impaired in these patients? Prolonged measurements ofcrural diaphragmatic function in patients with gastroesophageal reflux disease are certainly needed to answer this question. Are there other mechanisms that may explain why reflux occurs more frequently in patients than in normals during spontaneous TLESRs? Preliminary studies have shown an active tonic contraction of the esophageal body at the time of reflux during TLESRs in normals but not in patients with reflux disease. 14 An abnormal function of the crural diaphragm and/or a different motor behavior of the esophageal body in response to acid entering the lower esophagus may be important factors that warrant further studies. It is widely believed that anticholinergic agents increase gastroesophageal reflux and that they are contraindicated in patients prone to gastroesophageal reflux disease. Several studies evaluated the effect of anticholinergic drugs on LES pressure in humans 1%17 and found them to reduce basal LES pressure. Although most investigators suggest that this effect may increase the risk for gastroesophageal reflux, only few studies have been performed to confirm this hypothesis by directly measuring intraesophageal pH after the administration of anticholinergic agents. In 1960, Bettarello et al. t8 showed that atropine reduced LES tone and increased the incidence ofgastroesophageal reflux in patients with cirrhosis or gastric or duodenal ulcers. Skinner and Camp, however, found no increase in reflux episodes in healthy subjects after atropine administration. 19 In pregnant women with or without heartburn, atropine decreased LES pressure without increasing free or stress reflux. 2° There is even less information available in patients with gastroesophageal reflux disease. Only Fisher et al., using combined esophageal manometry and gastroesophageal scintigraphy, showed that atropine decreased LES pressure and significantly increased reflux as shown by scintigraphy in patients with heartburn. 21 In the present study by Mittal et al., atropine unexpectedly reduced the frequency of reflux in healthy subjects by decreasing the rate of spontaneous TLESRs. A spontaneous TLESR is a neurogenic reflex in which,
November 1995
after triggering, afferent information is transmitted to the central nervous system and a subsequent efferents discharge travels via the vagus and activates intramural inhibitory neurons that release nitric oxide (and/or vasoactive intestinal peptide) to relax the LES. 5'22 Atropine did not affect swallow-induced relaxations, and the spontaneous TLESRs persisting after atropine administration were complete relaxations; thus, the authors suggested that the effect of atropine on spontaneous TLESRs was on the afferent limb and/or receptor rather than on the efferent pathway of the reflex. It is unknown whether swallow-induced and spontaneous TLESRs share the same efferent pathway. The fact that cooling the cervical vagosympathetic trunk in dogs abolished both swallowinduced LES relaxations and spontaneous TLESRs 23 is not proof for a common efferent pathway. It only means that the efferent discharge responsible for both phenomena travels via vagal fibers that are not necessarily the same. Muscarinic M1 receptors are present on the soma or dendrites of NANC inhibitory neurons in the I.ES. 24 An effect of atropine on these receptors cannot be excluded, and the action of a more specific M1 antagonist such as pirenzepine on spontaneous TLESRs needs to be tested. Unlike atropine, pirenzepine inhibits gastric acid secretion without significantly affecting the resting LES pressure or esophageal peristalsis. 25 Gastric distention and subthreshold pharyngeal stimulus have been proposed as trigger sites for the afferent stimulus that elicits spontaneous TLESRs. 26'27 Mittal et al. suggest that atropine may have raised the threshold for stimulation of spontaneous TLESRs by decreasing gastric tone or increasing gastric compliance. The effect of atropine on gastric tone has recently been studied in humans during the fasting state. Unlike in previous experiments in dogs, 28 basal gastric tone in humans was not significantly changed by atropine administration. 29 Different doses of atropine, however, were used in these studies. The effect of atropine administration on gastric tone during the postprandial period has not been investigated thus far. In the opossum, electrical stimulation of the superior laryngeal nerve, which carries afferent information from the pharynx, provokes swallowing, esophageal peristalsis, and LES relaxation. Depending on the frequency and duration of the stimulus, it is possible to induce isolated LES relaxations. These experiments led to the suggestion that spontaneous TLESRs were the consequence of an incomplete swallow provoked by a subthreshold pharyngeal stimulation. 26 It is possible that movement of the manometric catheter or minute amounts of saliva stimulate pharyngeal mechanoreceptors and trigger spontaneous TLESRs. 27 Therefore, atropine may have diminished the frequency of spontaneous TLESRs by decreasing salivary secretion.
EDITORIALS 1705
Although the study by Mittal et al. showed a reduced number of reflux episodes after atropine administration in healthy subjects, it does not mean that anticholinergics are indicated in the treatment of reflux disease. It remains to be proven that the effect of anticholinergics on spontaneous TLESRs and on the amount of reflux in patients with reflux disease is similar to that in controls. It is possible that a further reduction of an already low basal LES pressure in patients, even if the number of spontaneous TLESRs is reduced, may result in an increase in stress reflux in the case of impaired crural diaphragmatic function. Anticholinergics decrease gastric acid secretion but also slow down gastric emptying3°'3~; they affect the strength of primary and secondary peristaltic contractions 16'32 and may deteriorate volume clearing of the reflux33; anticholinergics reduce salivary secretion and thus prolong the process of chemical neutralization of the refluxed acid. 3°'34 The study by Mittal et al. puts additional emphasis on the key role of spontaneous TLESRs in the pathogenesis of gastroesophageal reflux. Moreover, the study shows for the first time that medical therapy that diminishes the number of spontaneous TLESRs also decreases reflux. A challenge for the future will be the development of new pharmacological agents that reduce the frequency of postprandial TLESRs without affecting swallow-induced LES relaxations or other mechanisms involved in the natural protection against gastroesophageal reflux. JOZEF JANSSENS DANIEL SIFRIM Centerfor Gastroenterological Research Department of Medical Research University of Leuven Leuven, Belgium
References 1. Dent J, Dodds WJ, Friedman RH, Toshikazu S, Hogan WJ, Arndoffer RC, Petrie DJ. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980;65:256-267. 2. Holloway RH, Hongo M, Berger K, McCallum RW. Gastric distention: a mechanism for postprandial gastroesophageal reflux. Gastroenterology 1 9 8 5 ; 8 9 : 7 7 9 - 7 8 4 . 3. Mittal RK, McCallum RW. Characteristics of transient lower esophageal sphincter relaxation in humans. Am J Physiol 1987; 252:G636-G641. 4. Mittal RK, Holloway R, Dent J. Effect of atropine on the frequency of reflux and transient lower esophageal sphincter relaxation in normal subjects. Gastroenterology 1995; 109:1547-1554. 5. Boulant J, Fioramonti J, Dapoigny M, Bommelaer G, Bueno L. Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distention in dogs. Gastroenterology 1994; 1 0 7 : 1 0 5 9 - 1 0 6 6 . 6. Mittal RK. Current concepts of the antirreftux barrier. Gastroenterol Clin North Am 1 9 9 0 ; 1 9 : 5 0 1 - 5 1 6 . 7. Schoeman MN, Tippett MD, Akkermans LMA, Dent J, Holloway
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RH. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology 1995; 108:83-91. Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser R, Patel GK, Egide MS. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547-1552. Penagini R, Schoeman M, Holloway R, Dent J, Tippet M. Mechanisms of reflux in ambulant patients with reflux esophagitis (abstr). Gastroenterology 1994; 106:A159. Holioway RH, Penagini R, ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 1995; 268:G128-G133. Mittal RK, McCallum RW. Characteristics and frequency of transient relaxations of the lower esophageal sphincter in patients with reflux esophagitis. Gastroenterology 1988;95:593-599. Freidin N, Fisher MJ, Taylor W, Boyd D, Surrat P, McCallum RW, Mittat RK. Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis. Gut 1991;32:1275-1279. Cucchiara S, Bortolotti M, Minella R, Auricchio S. Fasting and postprandial mechanisms of gastroesophageal reflux in children with gastroesophageal reflux disease. Dig Dis Sci 1993;38:8692. Janssens J, Sifrim D, Lerut A. Esophageal motility disorders: a pathophysiological concept (abstr). Gastroenterology 1995; 108: A621. Lind JF, Crispin JS, Mclver DK. The effect of atropine on the gastroesophageal sphincter. Can J Physiol Pharmacol 1968; 46:233-238. Dodds WJ, Dent J, Hogan WJ, Arndorfer RC. Effect of atropine on esophageal motor function in humans. Am J Physiol 1981; 240:G290-G296. Fournet J, Bost R, Hostein J, Lachet B. Effect of propantheline on esophageal motor activity in humans. Gastroenterol Clin Biol 1983; 7:457-464. Bettarello A, Tuttle SG, Grossman MI. Effect of autonomic drugs on gastroesophageal reflux. Gastroenterology 1960;39:340346. Skinner DB, Camp TF. Relation of esophageal reflux to lower esophageal sphincter pressures decreased by atropine. Gastroenterology 1968; 54:543-551. Dow TGB, Brock-Utne JG, Rubin J, Welman S, Dimopoulus GE, Moschal MG. The effect of atropine on the lower esophageal sphincter in late pregnancy. Obstet Gynecol 1978; 51:426-430. Fisher RS, Malmud LS, Roberts GS, Lobis IF. The lower esophageal sphincter as a barrier to gastroesophageal reflux. Gastroenterology 1977; 72:19-22. Conklin JL, Christensen J. Motor functions of the pharynx and
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esophagus. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven, 1994:903-923. Martin CH J, Patrikios J, Dent J. Abolition of gas reflux and transient lower esophageal sphincter relaxation by vagal blockade in the dog. Gastroenterology 1986; 91:890-896. Gilbert R, Rattan S, Goyal RK. Pharmacologic identification, activation and antagonism of two muscarine receptors subtypes in the LES. J Pharmacol Exp Ther 1984;230:284-291. Denis P, Galmiche JP, Gibon JF, Colin R, Pasquis P, Lefran£ois R. Effect of pirenzepine on human esophageal motility. Gastroenterol Clin Biol 1982;6:27-31. Paterson W, Rattan S, Goyal RK. Experimental induction of isolated lower esophageal sphincter relaxation in anesthetized opossums. J Clin Invest 1986;77:1187-1193. Mittal RK. Stewart W, Schirmer B. Effect of catheter in the pharynx on the frequency of transient lower esophageal sphincter relaxation. Gastroenterology 1992; 103:1236-1240. Azpiroz F, Malagelada J-R. Physiologic variation in canine gastric tone measured by electronic barostat. Am J Physiol 1985;248: G229-G237. Parys V, Bruley des Varannes S, Ropert A, Roze C, Galmiche JP. Use of an electronic barostat for measurement of proximal gastric motor response to feeding and to various nervous stimuli in humans. Gastroenterol Clin Biol 1993;17:321-328. Rashid MU, Bateman DN. Effect of intravenous atropine on gastric emptying, paracetamol absortion, salivary flow and heart rate in young and fit elderly volunteers. Br J Clin Pharmacol 1990; 30:25-34. Maes B, Hiele M, Geypens B, Rutgeerts P, Ghoos Y, Vantrappen G. Pharmacological modulation of gastric emptying rate of solids as measured by carbon labelled octanoic acid breath test: influence of erythromycin and propantheline. Gut 1994; 35:333-337. Schoeman MN, Holloway RH. Stimulation and characteristics of secondary oesophageal peristalsis in normal subjects. Gut 1994;35:152-158. Phaosawasdi K, Malmud LS, Tolin RD, Stelzer F, Appledate G, Fisher RS. Cholinergic effects on esophageal transit and clearance. Gastroenterology 1981;81:915-920. Kharilas PJ. Esophageal motor activity and acid clearence. Gastroenterol Clin North Am 1990;19:537-550.
Address requests for reprints to: Jozef Janssens, M.D., Ph.D., Department of Internal Medicine, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Fax: (32)16-34-43-08. © 1995 by the American GastroenterologicalAssociation 0016-5085/95/$3.00
Regulation of Secretion and Absorption by Recruitment and Recycling of Primary Transport Proteins I
See article on page 1 6 0 0 .
I
uch of homeostasis, at the cellular level and within the whole organism, is directed at regulating membrane transport events. Voluminous secretory and absorptive activity in the gastrointestinal tract are prominent examples of up-regulation and down-regulation of fundamental transport processes. Extrinsic regulation of transport is under neural and hormonal control via trans-
M
duction by intracellular messengers. Although the mechanics for operating transport proteins are diverse, e.g., conductive channels, exchangers, cotransporters, and primary active pumps, the means to regulate transport activity can occur only by changes in turnover frequency and/ or total number of transporters available. It was once thought that transport activity was exclusively modulated in the short-term through kinetic parameters, i.e., availability of and affinity for substrates, and/or specific modification of the transporter protein, such as by phos-
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1703
Spontaneous Transient Lower Esophageal Sphincter Relaxations: A Target for Treatment of Gastroesophageal Reflux Disease See article on page 1 5 4 7 .
n previous studies in asymptomatic subjects with normal lower esophageal sphincter (LES) pressure, Dent et al., Holloway et al., and Mittal and McCallum have shown that gastroesophageal reflux almost always occurs during spontaneous transient relaxations of the LES (TLESRs)) -3 In this issue of GASTROENTEROLOGY,the same investigators report on their studies on the mechanisms of gastroesophageal reflux in healthy subjects under the experimental condition of low LES pressure induced by atropine. 4 LES pressure, esophageal pH, and crural diaphragm electromyogram were recorded in the postprandial period. Although basal LES pressure was experimentally reduced by atropine, they showed that reflux only occurred during TLESRs, which were characterized by a further small decrease in the already lowered LES pressure and by an inhibition of the activity of the crural diaphragm. Unexpectedly, atropine also provoked a reduction in frequency of reflux episodes apparently related to a significant decrease in the number of postprandial TLESRs. The effect of atropine on the rate of TLESRs observed in the present study and recent experimental data, showing that cholecystokinin A receptor antagonists are able to reduce the number of TLESRs induced by gastric distention in dogs, 5 focus our attention on TLESRs as a possible target for the treatment of gastroesophageal reflux disease. Several factors are involved in the pathogenesis of gastroesophageal reflux disease. Every reflux episode occurs as a consequence of a failure of the antireflux barrier at the gastroesophageal junction. When gastroesophageal reflux occurs, the amount of reflux that rises into the esophagus is at least partially determined by the contractile status of the esophageal body. When the refluxed material succeeds to move up into the esophagus, volume clearing by gravity and esophageal peristalsis and chemical clearing by swallowed saliva will determine the time during which the refluxed bolus is in contact with the esophageal mucosa. Intragastric volumes and, thus, gastric emptying and esophageal mucosal defense mechanisms are other important but less well understood factors. Of all of these mechanisms, incompetence of the antireflux barrier is considered to be the key factor. The
I
resting LES tone, the number of TLESRs, and the contraction of the crural diaphragm during increased intraabdominal pressure are the most important components of the antireflux barrier. 6 Studies in normal subjects 1'7 and in patients with esophagitis 8'9 have shown that gastroesophageal reflux can occur in the case of a very low basal LES pressure (socalled free reflux), during TLESRs, or as a consequence of increased intra-abdominal pressure in the presence of normal or decreased basal LES tone (straining or stress reflux). Recent studies by Schoeman et al. 7 have shown that a low resting LES pressure gives rise to reflux only in the extreme case of pressures of < 3 m m Hg, which is very rare in healthy subjects even during the postprandial period. The present study by Mittal et al. is in agreement with these findings and showed that a low basal LES pressure induced by atropine is insufficient to provoke free reflux in healthy subjects. Although one would expect more straining-induced reflux in the case of a low basal LES pressure, the study by Mittal et al. showed that this is not the case, at least not in healthy subjects, because of the significant role of the crural diaphragm, which seems to not be affected by atropine. As a group, patients with gastroesophageal reflux disease have lower basal LES pressures than controls. 8 Some patients have a normal or slightly diminished basal LES pressure, but a subset of patients may have a very low basal LES pressure. Recent data from prolonged ambulatory p H and pressure recordings in patients with esophagitis showed that almost 10% of all reflux episodes occurred as free reflux during very low LES tone and that straining was present in 25 % of all reflux events. 9 Therefore, unlike healthy subjects, a subset of patients with esophagitis and very low basal LES pressure apparently lack an effective crural diaphragmatic function. In 1980, Dent et al. showed for the first time that a significant number of gastroesophageal reflux episodes occur during complete relaxations of the LES that are not induced by swallowing. These type of LES relaxations were called spontaneous TLESRs to distinguish them from swallow-induced LES relaxations. 1 Spontaneous TLESRs differ from swallow-induced LES relaxations because they are not accompanied by pharyngeal contraction and subsequent esophageal peristalsis; they usually
1704
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last longer than swallow-induced relaxations and they are frequently followed by gastroesophageal reflux. 1° Since 1980, several studies using stationary perfused manometry with a Dent sleeve to measure LES pressure have confirmed that spontaneous TLESRs are the main mechanism for reflux in recumbent healthy subjects and are also an important mechanism for reflux in patients with gastroesophageal reflux disease. 8'11 In healthy subjects, 8 0 % - 9 5 % of reflux events occur during spontaneous TLESRs. The literature is more controversial about the relative importance of spontaneous TLESRs in patients with gastroesophageal reflux disease. The percent of reflux episodes occurring during spontaneous TLESRs in patients with reflux disease ranges from 4 0 % 12 tO 77.1%. i3 Only recently, the development of a miniaturized pneumohydraulic water-perfused sleeve device combined with a solid-state recording system allowed prolonged studies in ambulatory healthy subjects and patients with gastroesophageal reflux disease. These studies confirmed previous observations: the majority of reflux episodes occur in the postprandial period, and the main mechanisms for reflux are spontaneous TLESRs (82% in normals and 67% in patients with gastroesophageal reflux disease), v'9 Looking more closely to the mechanism of reflux in individual patients, the studies showed considerable variation in between patients: in some, the mechanism was almost exclusively spontaneous TLESRs; in others, it was mainly stress reflux or free reflux or a combination of both. The authors concluded that, generally spoken, reflux in patients with normal resting LES pressure was mainly due to spontaneous TLESRs, whereas patients with low resting LES pressure had a high degree of free reflux. The present study by Mittal et al. shows that spontaneous TLESRs may even be more important for the induction of reflux than already accepted and that they are also responsible for the occurrence of reflux episodes in the presence of a low resting LES tone. A close inspection of the period preceding reflux events showed an additional small decrease in pressure (representing a spontaneous TLESR) together with inhibition of the crural diaphragm. These small spontaneous changes in LES pressure may have been missed in previous studies in patients with gastroesophageal reflux disease; thus, reflux episodes may have erroneously been labeled as free reflux. In any case, there is now sufficient evidence to consider TLESRs as an important mechanism for reflux in patients with gastroesophageal reflux disease. Therefore, as suggested by Mittal et al., the reduction in the number of TLESRs may have significant therapeutic implications. Reflux occurs as discrete events during a period of absent basal LES pressure or during a spontaneous
GASTROENTEROLOGY Vol. 109, No. 5
TLESR. Moreover, some spontaneous TLESRs are not accompanied by reflux, suggesting that another intermittent process must be involved for reflux to occur. Mittal et al. suggest that a sudden inhibition of crural diaphragm contraction during spontaneous TLESRs or a failure of the crural diaphragm to compensate for small sudden increases in intra-abdominal pressure can be the events that represent this intermittent process. Some studies indicate that the proportion of spontaneous TLESRs accompanied by reflux is higher in patients with gastroesophageal reflux disease than in normals.n Is the crural diaphragmatic function impaired in these patients? Prolonged measurements ofcrural diaphragmatic function in patients with gastroesophageal reflux disease are certainly needed to answer this question. Are there other mechanisms that may explain why reflux occurs more frequently in patients than in normals during spontaneous TLESRs? Preliminary studies have shown an active tonic contraction of the esophageal body at the time of reflux during TLESRs in normals but not in patients with reflux disease. 14 An abnormal function of the crural diaphragm and/or a different motor behavior of the esophageal body in response to acid entering the lower esophagus may be important factors that warrant further studies. It is widely believed that anticholinergic agents increase gastroesophageal reflux and that they are contraindicated in patients prone to gastroesophageal reflux disease. Several studies evaluated the effect of anticholinergic drugs on LES pressure in humans 1%17 and found them to reduce basal LES pressure. Although most investigators suggest that this effect may increase the risk for gastroesophageal reflux, only few studies have been performed to confirm this hypothesis by directly measuring intraesophageal pH after the administration of anticholinergic agents. In 1960, Bettarello et al. t8 showed that atropine reduced LES tone and increased the incidence ofgastroesophageal reflux in patients with cirrhosis or gastric or duodenal ulcers. Skinner and Camp, however, found no increase in reflux episodes in healthy subjects after atropine administration. 19 In pregnant women with or without heartburn, atropine decreased LES pressure without increasing free or stress reflux. 2° There is even less information available in patients with gastroesophageal reflux disease. Only Fisher et al., using combined esophageal manometry and gastroesophageal scintigraphy, showed that atropine decreased LES pressure and significantly increased reflux as shown by scintigraphy in patients with heartburn. 21 In the present study by Mittal et al., atropine unexpectedly reduced the frequency of reflux in healthy subjects by decreasing the rate of spontaneous TLESRs. A spontaneous TLESR is a neurogenic reflex in which,
November 1995
after triggering, afferent information is transmitted to the central nervous system and a subsequent efferents discharge travels via the vagus and activates intramural inhibitory neurons that release nitric oxide (and/or vasoactive intestinal peptide) to relax the LES. 5'22 Atropine did not affect swallow-induced relaxations, and the spontaneous TLESRs persisting after atropine administration were complete relaxations; thus, the authors suggested that the effect of atropine on spontaneous TLESRs was on the afferent limb and/or receptor rather than on the efferent pathway of the reflex. It is unknown whether swallow-induced and spontaneous TLESRs share the same efferent pathway. The fact that cooling the cervical vagosympathetic trunk in dogs abolished both swallowinduced LES relaxations and spontaneous TLESRs 23 is not proof for a common efferent pathway. It only means that the efferent discharge responsible for both phenomena travels via vagal fibers that are not necessarily the same. Muscarinic M1 receptors are present on the soma or dendrites of NANC inhibitory neurons in the I.ES. 24 An effect of atropine on these receptors cannot be excluded, and the action of a more specific M1 antagonist such as pirenzepine on spontaneous TLESRs needs to be tested. Unlike atropine, pirenzepine inhibits gastric acid secretion without significantly affecting the resting LES pressure or esophageal peristalsis. 25 Gastric distention and subthreshold pharyngeal stimulus have been proposed as trigger sites for the afferent stimulus that elicits spontaneous TLESRs. 26'27 Mittal et al. suggest that atropine may have raised the threshold for stimulation of spontaneous TLESRs by decreasing gastric tone or increasing gastric compliance. The effect of atropine on gastric tone has recently been studied in humans during the fasting state. Unlike in previous experiments in dogs, 28 basal gastric tone in humans was not significantly changed by atropine administration. 29 Different doses of atropine, however, were used in these studies. The effect of atropine administration on gastric tone during the postprandial period has not been investigated thus far. In the opossum, electrical stimulation of the superior laryngeal nerve, which carries afferent information from the pharynx, provokes swallowing, esophageal peristalsis, and LES relaxation. Depending on the frequency and duration of the stimulus, it is possible to induce isolated LES relaxations. These experiments led to the suggestion that spontaneous TLESRs were the consequence of an incomplete swallow provoked by a subthreshold pharyngeal stimulation. 26 It is possible that movement of the manometric catheter or minute amounts of saliva stimulate pharyngeal mechanoreceptors and trigger spontaneous TLESRs. 27 Therefore, atropine may have diminished the frequency of spontaneous TLESRs by decreasing salivary secretion.
EDITORIALS 1705
Although the study by Mittal et al. showed a reduced number of reflux episodes after atropine administration in healthy subjects, it does not mean that anticholinergics are indicated in the treatment of reflux disease. It remains to be proven that the effect of anticholinergics on spontaneous TLESRs and on the amount of reflux in patients with reflux disease is similar to that in controls. It is possible that a further reduction of an already low basal LES pressure in patients, even if the number of spontaneous TLESRs is reduced, may result in an increase in stress reflux in the case of impaired crural diaphragmatic function. Anticholinergics decrease gastric acid secretion but also slow down gastric emptying3°'3~; they affect the strength of primary and secondary peristaltic contractions 16'32 and may deteriorate volume clearing of the reflux33; anticholinergics reduce salivary secretion and thus prolong the process of chemical neutralization of the refluxed acid. 3°'34 The study by Mittal et al. puts additional emphasis on the key role of spontaneous TLESRs in the pathogenesis of gastroesophageal reflux. Moreover, the study shows for the first time that medical therapy that diminishes the number of spontaneous TLESRs also decreases reflux. A challenge for the future will be the development of new pharmacological agents that reduce the frequency of postprandial TLESRs without affecting swallow-induced LES relaxations or other mechanisms involved in the natural protection against gastroesophageal reflux. JOZEF JANSSENS DANIEL SIFRIM Centerfor Gastroenterological Research Department of Medical Research University of Leuven Leuven, Belgium
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Address requests for reprints to: Jozef Janssens, M.D., Ph.D., Department of Internal Medicine, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Fax: (32)16-34-43-08. © 1995 by the American GastroenterologicalAssociation 0016-5085/95/$3.00
Regulation of Secretion and Absorption by Recruitment and Recycling of Primary Transport Proteins I
See article on page 1 6 0 0 .
I
uch of homeostasis, at the cellular level and within the whole organism, is directed at regulating membrane transport events. Voluminous secretory and absorptive activity in the gastrointestinal tract are prominent examples of up-regulation and down-regulation of fundamental transport processes. Extrinsic regulation of transport is under neural and hormonal control via trans-
M
duction by intracellular messengers. Although the mechanics for operating transport proteins are diverse, e.g., conductive channels, exchangers, cotransporters, and primary active pumps, the means to regulate transport activity can occur only by changes in turnover frequency and/ or total number of transporters available. It was once thought that transport activity was exclusively modulated in the short-term through kinetic parameters, i.e., availability of and affinity for substrates, and/or specific modification of the transporter protein, such as by phos-