Scand J Gastroenterol 1992;27:257-62.
REVIEW
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Stress-Induced Gastric Ulceration: Its Aetiology and Clinical Implications Peptic ulceration is one of the common diseases in presentday society. The frequency of its occurrence is about 10% (l), and it occurs in about 1% of the adult population during their lifetime (2,3). However, Weir (4) suggests that the prevalence of peptic ulceration in the general population is approximately 5% to lo%, with regional variations. These observations indicate that peptic ulceration remains a major source of morbidity and mortality. However, the aetiology of human gastric ulceration is still unclear. The pathogenesis of peptic ulcer is also a controversial subject, partly because its cause is unknown, and accumulated evidence suggests a complex multifactorial pathogenesis (5). This article reviews the aetiology of stress-induced ulceration in animals, which may throw light on understanding the pathogenesis of gastric ulcers in man.
General concept of stress and definition of the stress ulcer Stress reaction, defined as ‘nonspecific response of the body to any demand upon it’ ( 6 ) , is considered to involve a complex interaction among the central nervous system, the endocrine system and the immune system. Stress is very frequently accompanied by several functional and structural alterations in the body, as part of a biologic defence mechanism. Selye (7) described the triad of stress as i) enlargement of the adrenal glands, ii) atrophy of the lymph nodes, thymus, and spleen, and iii) acute ulcers or erosions in the gastrointestinal tract, which are now usually termed stress ulcers or acute gastric mucosal lesions. More recently, it has been recognized that stress can play a role in the pathogenesis of either acute or chronic gastric ulcers (8).
The relation between stress and gastric ulcer formation It is known that higher centres in the brain can influence the physiologic functions of the body through the autonomic nervous system and hormonal secretion. The stomach is most influenced by stress (9), and biologic or complex psychosocial agents can induce ulcers in the stomach (7). In the classical observation made on Tom, a patient with a gastric fistula, it was shown that emotion considerably affected gastric function; fear and sadness resulted in inhibition of acid secretion, enhanced gastric motility, and vascular engorgement (10). Prolonged anxiety has been shown to produce mucosal erosions in the stomach, and emotional stress is associated with chronic ulceration (11). Kaplan (12) reported the case of a 41-year-old woman who had recurrent episodes of peptic ulcer disease, which she correlated with
stressful periods. The incidence of peptic ulceration was found to rise markedly during the Second World War (13), and this was stress-related. Stress-induced gastrointestinal bleeding continues to be a clinically observed event, and the cause is still poorly understood (14). Gastric ulcers have been found after surgical operations (15), brain injury (16), burns (17, 18), uraemia (19), infection (20), respiratory failure (21), and after hypotension and jaundice (22). These lesions usually develop soon after the onset of illness; therefore, antacid and histamine H2-receptor antagonists have routinely been given to such patients to prevent gastric bleeding (23). The relationship between stress and gastric ulcer formation has been demonstrated in animals (24). Sawrey & Weisz (25) produced gastric erosions in rats by exposing them to conflict situations for 3 days. Rats subjected to burns have been shown to develop haemorrhagic gastric ulcers (26). Other ulcerogenic manoeuvres involving immobilisation have been shown to generate ulcers in animals (27). A synergistic effect in ulcer production can be obtained when immobilisation is combined with other stressful stimuli, such as restraining the animal in a close-fitting cage in a cold room (28) or immersing the restrained rat in water (29). All these animal experimental models support the notion that gastric ulceration can be induced by either physical or psychologic stress, and this can be found both in animals and man. They may also share similar pathogenetic mechanisms, and, therefore, the use of animal stress-ulcer models could clarify the aetiology of stress ulcers in humans (30).
Current concepts of the aetiology of stress ulceration The aetiology of stress ulcers has been widely studied. Peptic ulceration and gastric secretion can be produced by direct electric stimulation of the anterior or posterior hypothalamus (31,32). Nishizaki & Watanabe (33) suggest that the anterior hypothalamus may be the origin of parasympathetic impulses, whereas the posterior hypothalamus is concerned with the sympathetic outflow. It has been postulated that there are three possible pathways for the development of stress ulceration: the anterior hypothalamo-vagal system, the posterior hypothalamo-sympathetic axis, and the posterior hypothalamepituitary-adrenal system (34). It is not known whether the central effect of stress is transmitted through these routes, either simultaneously or independently. Gastric acid. It is generally believed that gastric ulcer formation in man results from an imbalance between aggress-
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ive factors such as acid-pepsin digestion and the defensive factors, which include gastric mucus and mucosal blood flow (35-38). liyperactivity of the vagus is observed during stress (27.39,40), and direct electricvagal stimulation can increase acid secretion in pylorus-ligated rats (40). Acid hypersecretion, accompanied by gastric ulceration, has also been observed in stressed animals (41). However, others have found either no change (42) or even a decrease in acid secretion under stress conditiorls (43. 44); furthermore, effective gastric acid neutralisation by intragastric perfusion with sodium bicarbonate or pretreatment with antacid has failed to prevent ulceration (39, 41, 42, 45). Singh (42) has shown that strcss ulcers occur even in the absence of gastric secretion. Patients with type-1 gastric ulcer, as defined by Johnson (46). show either normal or low gastric secretion. Therefore, the question of whether gastric acid plays a major role in stress-induccd ulccration is still debatable. It appears that gastric acidity may not be the sole causative factor in the pathogenesis of stress ulcer formation; it is more likely to play only a permissive role (47,4H). IIowever, one should consider the possibility that endogenous and exogenous acid may act differently in the formation of acute gastric ulceration (49). Must cells. Another effect of stress is the induction of mast cell degranulation (50-52), The vagal fibres directly innervate the parietal cells (53, 54) and possibly the mast cells (55, 56). R a s h e n & Hirvonen (57) have shown that electric vagal stimulation degranulates the mast cells in the gastrointestinal tract and markedly activates acid secretion. Mast cell degranulation in rats releases histamine (58), heparin (59), 5-hydroxytryptamine (5-HT) (60),dopamine (61), leukotrienes (62), and various enzymes and compounds (6365); other workers (66) have found that vagal-mediated mast cell degranulation could be the major factor involved in stress-induced glandular ulceration in rats. However, Guth & Kozbun (67) and Guth (68) are of the view that there is no correlaticin between gastric wall mast cell degranulation and gastric ulceration. Histamine. Stimulation of histamine H , and H, receptors in the blood vessels and gastric submucosal arterioles of rats (69-71) dilates the precapillary sphincters (72) but constricts microvessels larger than 80pm in diameter (72). These effects increase the postcapillary venular intravascular pressure (73) and attenuate vasomotion of the precapillary sphincters and meta-arterioles (74). The amine appears to affect selectively the venular end of the microcirculatory bed (7U, 73) and has also been shown to produce vasodilation in the stomach. Histamine increases gastric microvascular permeability (75) and produces local oedema (76). This could be caused by contraction of actomyosin fibrils in the venular endothelial cells, which stimulates the cells to move apart (77), or by an increase in size and turnover of the endothelial vesicles (78). Therefore, it is possible that histamine stimulates molecular transport by both increasing the number of available pores and enhancing the rate of vesicular transport.
Histamine released from the mast cell interferes with local gastric blood flow by causing vasodilatation and vascular stasis through histamine-receptor activation (79). Stressinduced gastric ulceration is frequently associated with mucosal blood vessel engorgement (68), and this could possibly be due to the effccts of histamine. Gastric hyperaemia is also frequently observed in stressed animals. However, this could reflect either incrcased gastric mucosal blood flow or simply vascular engorgement (SO, 80, 81). Experimental evidence indicates that mucosal blood flow plays an important role in the pathogenesis and in the healing of gastric ulcers (82, 83); it is therefore necessary to clarify the importance of gastric mucosal blood flow in stress-induced ulceration. Hepurin. The release of heparin together with histamine from the mast cells inhibits mitotic activity of gastric epithelial cells, and this effect is probably due to inhibition of DNA polymerase activity (84, 85). Therefore, heparin can reduce mucosal epithelial cell regeneration after mucosal damage, and this effect could be an important factor contributing to prolongation of mucosal lesion healing. Motility. Gastric hypermotility is postulated to be induced by stress through vagal overactivity and has been considered to contribute to ulcer formation (86, 87). Yano et al. (88) showed that hypermotility per se caused gastric ulceration, and this was thought to be due to excessive rubbing and compression of the mucosal tissues, leading to cell damage and stasis of mucosal blood flow. In fact, atropine and verapamil decrease gastric motility and decrease ulceration; however, bethanechol treatment, which increases stomach contractions, does not aggravate stress-induced ulcer formation. It has also been found that the amplitude of gastric contractions is reduced throughout the stress period (89). These findings reinforce the idea that gastric hypermotility is unlikely to contribute substantially to stress-induced ulceration, although the possibility that it has a role in ulcer formation cannot be cxcluded. Mucus. Gastric mucus glycoproteins are believed to play an important role in the defensive mechanism against gastric ulceration (90); the mucus layer acts as an unstirred mucusbicarbonate mucosal barrier to acid and pepsin digestion (91). Stress has been shown to decrease the amount of mucus adhering to the gastric mucosa (89,92,93); thus, the underlying epithelial cells are more exposed to the aggressive ulcerogenic action of luminal gastric acid (94). Furthermore. reduccd mucus by N-acetylcysteine is accompanied by gastric lesion formation in nonstressed rats or by aggravation of stress ulceration (95). These observations reinforce the conclusion that stomach wall mucus is likely to play an important role in stress-induced glandular lesions. Leukotrienes. The role of leukotrienes (LTs) in the stomach has been described by Goldberg & Subers (96). They found that the dose-dependent contractile response with LTC4was inhibited by a specific antagonist, FPL55712. Because the duodenum and ileum failed to respond to LTC4,
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a.
Labilization of mast cclls or other sources .c
Gastric con traction
1
Biogenic amines and leukotriene release
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Vascular engorgement
these workers concluded that specific LT receptors were present in the stomach. This finding was confirmed by Piper & Samhoun (97), Magous et al. (98), and Pendleton & Stavorski (99). Peck et al. (100) showed that LTs induce vasoconstriction in the vascular bed of the stomach, which is followed by leakage of macromolecules from the postcapillary venules. Whittle (101) reported that LTC4 can induce vasoconstriction in both the venous and arteriolar vessels in the rat submucosa and that this potent vasoconstriction of submucosal microvessels of the rat stomach causes tissue necrosis (102). It could therefore serve as a potential pro-ulcerogenic agent. Studies on the gastric antiulcer action of drugs suggest that LTs may participate in stress-induced gastric glandular ulceration (103-105). This idea was later supported by Konturek et al. (106), who suggested that LTC4 may facilitate mucosal damage produced in rats stressed by restraint and immersion in water. However, it is unclear what the proportion is of the individual contributions of the various LTs in the pathogenesis of stress-induced gastric ulcers in rats. Previous studies on 5-lipoxygenase (5-LO) inhibition in the gastric mucosa (107, 108) suggest that blockade of 5-LO may divert metabolism of arachidonic acid from the 5-LO pathway to that mediated by cyclo-oxygenase, to result in more prostanoid formation. However, it appears unlikely that prostaglandins (PG), if indeed influenced by 5-LO antagonism, do play a significant role in stress ulcer prevention because raised stomach tissue levels of PEG2 do not prevent this type of ulcer formation (105). Mucosal blood flow. Gastric mucosal microcirculation is involved in the maintenance of mucosal integrity and plays an important part in the mucosal protection (109, 110). The functional and morphologic alteration in microcirculation can result in the reduction of blood flow and oxygen saturation in the gastric mucosa and may produce haemorrhages, erosions, and even ulcers (111). Yabana et al. (112) have
shown that exposure to stress results in a rapidly developing vascular injury in subepithelial capillaries and increased vascular permeability; these lead to functional impairment of gastric microcirculation (113). It has been found that the degree of decrease in mucosal blood flow correlates with the extent of haemorrhagic erosion (113, 114). Conclusion It is concluded that cholinergic activation and the release of several biogenic amines and the metabolites of arachidonic acid through 5-LO-for example, leukotrienes-could play a significant role in stress-induced ulceration in animals. Their labilisation from mast cells and/or from other sources could contribute to ulcer formation. The effects produced by these biologically active mediators and cholinergic stimulation include increased gastric contractions, vascular engorgement, acid secretion, and, possibly, mucus depletion (Fig. 1). It is therefore likely that the modulation of these effects, by blocking mediator release or action at receptor sites, may have therapeutic benefits in stress-evoked ulceration in man. Indeed, several mast cell stabilisers, histamine, and leukotriene antagonists have been proved to be effective against stress-induced ulceration in animals and may possibly be of benefit in man (23, 63, 115-119). Acknowledgements The authors are grateful to W. L. Lau and P. Y. Lam for their secretarial assistance. C. H. C H O M. W. L. K o o G. P. GARG C. W. OGLE Dept. of Pharmacology Faculty of Medicine University of Hong Kong 5 Sassoon Road Hong Kong
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102. Wallace JL, Whittle BJR. Role of prostanoids in the protective actions of BW775C on the gastric mucosa. Eur J Pharmacol 1985;115:45-S2. 103. Boughton-Smith NK, Whittle BJR. Prostaglandin inhibition o f ethanol-induced release of gastric mucosal leukotrienes. Gastroenterology 1987;92:1325. 104. Ogle CW, Cho CH. FPL55712, a leukotriene-receptor antagonist. protects against stress-induced gastric ulcers in rats. IKCS Med Sci 1986;14:114-5. 105. Ogle CW, Cho CH, Dai S. Sulphasalazine and experimental stress ulcers. Agents Actions 1985;17:153-7. 106. Konturek SJ, Brzozowski T, Drozdowicz D, Garlicki J, Beck G. Role of leukotrienes and platelet activating factor in acute gastric mucosal lesions in rats. Eur J Pharmacol 1989;164:28592. 107. Boughton-Smith N K , Whittle BJR. Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in uitro by anti-inflammatory agents. Br J Pharmacol1983;78: 1 7 s 80. 108. Flernstrom G, Bergman A , Rriden S. Stimulation of mucosal bicarbonatc secretion in rat duodenum in oiuo by BW75SC. Acta Physiol Scand 1984;121:3+43. 109. Cho CH, Ogle CW. Modulatory action of adenosine on gastric [unction and ethanol-induced mucosal damagc in rats. Dig Dis Sci 1090;35:13349. 110. Jacobson E, Lanciault G. The gastrointestinal vasculature. In: Duthic HL, Wormsley KG, editors. Scientific basis of gastroenterology. New York: Churchill Livingstone, 1979:26 48.
111. Sat0 N , Kawano S, Kamada T, Takeda M. Hemodynamics of the gastric mucosa and gastric ulceration in rats and in patients with gastric ulcer. Dig Dis Sci 1986;31 Suppl: 35S-41S. 112. Yabana T, Kondo Y, Tujia K, Yachi A, Szabo S. Role of increased rnucosal vascular pcrmeability and vascular iniury ion pathogenesis of peptic ulcer. Exerpia Med Int CongiSer 1985;704:11526. 113. Pihan G, Rogers C, Szabo S. Seminars on gastric mucosal injury. V. Vascular injury in acute gastric rnucosal damage: Mediatory role of leukotrienes. Dig Dis Sci 1988;33:625-32. 114. Wong SH, Cho CH, Ogle CW. The role of serotonin in ethanolinduced gastric glandular damage in rats. Digestion 1990;45:5260. 115. Cho CH. Current views of zinc as a gastro-hepatic protective agent. Drug Develop Res 1989;17:185-97. 116. Cho CH, Pfeiffer CJ. The developing role of zinc as an antiulcer agent. In: Pfciffer CJ, editor. Drugs and peptic ulcer. Boca Raton, Fla.: CRC Press, 1982:147-58. 117. Ogle CW, Cho CH. Thc protcctive mechanism of FPL55712 against stress-induced gastric ulceration in rats. Agents Actions 1989;26:350-4. 118. Ogle CW, Lau HK. Disodium cromoglycate: its influence on gastric ulcers produced by stress in rats. IRCS Med Sci 1979;7:393-4. 119. Pfeiffer CJ, Bulbena 0 ,Esplugues JV, Escolar G , Navarro C, Esplugucs J. Antiulcer and membrane stabilizing actions of zinc acexamate J. Arch Int Pharmacodyn Ther 1987;285:14% 57.
REVIEW
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Stress-Induced Gastric Ulceration: Its Aetiology and Clinical Implications Peptic ulceration is one of the common diseases in presentday society. The frequency of its occurrence is about 10% (l), and it occurs in about 1% of the adult population during their lifetime (2,3). However, Weir (4) suggests that the prevalence of peptic ulceration in the general population is approximately 5% to lo%, with regional variations. These observations indicate that peptic ulceration remains a major source of morbidity and mortality. However, the aetiology of human gastric ulceration is still unclear. The pathogenesis of peptic ulcer is also a controversial subject, partly because its cause is unknown, and accumulated evidence suggests a complex multifactorial pathogenesis (5). This article reviews the aetiology of stress-induced ulceration in animals, which may throw light on understanding the pathogenesis of gastric ulcers in man.
General concept of stress and definition of the stress ulcer Stress reaction, defined as ‘nonspecific response of the body to any demand upon it’ ( 6 ) , is considered to involve a complex interaction among the central nervous system, the endocrine system and the immune system. Stress is very frequently accompanied by several functional and structural alterations in the body, as part of a biologic defence mechanism. Selye (7) described the triad of stress as i) enlargement of the adrenal glands, ii) atrophy of the lymph nodes, thymus, and spleen, and iii) acute ulcers or erosions in the gastrointestinal tract, which are now usually termed stress ulcers or acute gastric mucosal lesions. More recently, it has been recognized that stress can play a role in the pathogenesis of either acute or chronic gastric ulcers (8).
The relation between stress and gastric ulcer formation It is known that higher centres in the brain can influence the physiologic functions of the body through the autonomic nervous system and hormonal secretion. The stomach is most influenced by stress (9), and biologic or complex psychosocial agents can induce ulcers in the stomach (7). In the classical observation made on Tom, a patient with a gastric fistula, it was shown that emotion considerably affected gastric function; fear and sadness resulted in inhibition of acid secretion, enhanced gastric motility, and vascular engorgement (10). Prolonged anxiety has been shown to produce mucosal erosions in the stomach, and emotional stress is associated with chronic ulceration (11). Kaplan (12) reported the case of a 41-year-old woman who had recurrent episodes of peptic ulcer disease, which she correlated with
stressful periods. The incidence of peptic ulceration was found to rise markedly during the Second World War (13), and this was stress-related. Stress-induced gastrointestinal bleeding continues to be a clinically observed event, and the cause is still poorly understood (14). Gastric ulcers have been found after surgical operations (15), brain injury (16), burns (17, 18), uraemia (19), infection (20), respiratory failure (21), and after hypotension and jaundice (22). These lesions usually develop soon after the onset of illness; therefore, antacid and histamine H2-receptor antagonists have routinely been given to such patients to prevent gastric bleeding (23). The relationship between stress and gastric ulcer formation has been demonstrated in animals (24). Sawrey & Weisz (25) produced gastric erosions in rats by exposing them to conflict situations for 3 days. Rats subjected to burns have been shown to develop haemorrhagic gastric ulcers (26). Other ulcerogenic manoeuvres involving immobilisation have been shown to generate ulcers in animals (27). A synergistic effect in ulcer production can be obtained when immobilisation is combined with other stressful stimuli, such as restraining the animal in a close-fitting cage in a cold room (28) or immersing the restrained rat in water (29). All these animal experimental models support the notion that gastric ulceration can be induced by either physical or psychologic stress, and this can be found both in animals and man. They may also share similar pathogenetic mechanisms, and, therefore, the use of animal stress-ulcer models could clarify the aetiology of stress ulcers in humans (30).
Current concepts of the aetiology of stress ulceration The aetiology of stress ulcers has been widely studied. Peptic ulceration and gastric secretion can be produced by direct electric stimulation of the anterior or posterior hypothalamus (31,32). Nishizaki & Watanabe (33) suggest that the anterior hypothalamus may be the origin of parasympathetic impulses, whereas the posterior hypothalamus is concerned with the sympathetic outflow. It has been postulated that there are three possible pathways for the development of stress ulceration: the anterior hypothalamo-vagal system, the posterior hypothalamo-sympathetic axis, and the posterior hypothalamepituitary-adrenal system (34). It is not known whether the central effect of stress is transmitted through these routes, either simultaneously or independently. Gastric acid. It is generally believed that gastric ulcer formation in man results from an imbalance between aggress-
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ive factors such as acid-pepsin digestion and the defensive factors, which include gastric mucus and mucosal blood flow (35-38). liyperactivity of the vagus is observed during stress (27.39,40), and direct electricvagal stimulation can increase acid secretion in pylorus-ligated rats (40). Acid hypersecretion, accompanied by gastric ulceration, has also been observed in stressed animals (41). However, others have found either no change (42) or even a decrease in acid secretion under stress conditiorls (43. 44); furthermore, effective gastric acid neutralisation by intragastric perfusion with sodium bicarbonate or pretreatment with antacid has failed to prevent ulceration (39, 41, 42, 45). Singh (42) has shown that strcss ulcers occur even in the absence of gastric secretion. Patients with type-1 gastric ulcer, as defined by Johnson (46). show either normal or low gastric secretion. Therefore, the question of whether gastric acid plays a major role in stress-induccd ulccration is still debatable. It appears that gastric acidity may not be the sole causative factor in the pathogenesis of stress ulcer formation; it is more likely to play only a permissive role (47,4H). IIowever, one should consider the possibility that endogenous and exogenous acid may act differently in the formation of acute gastric ulceration (49). Must cells. Another effect of stress is the induction of mast cell degranulation (50-52), The vagal fibres directly innervate the parietal cells (53, 54) and possibly the mast cells (55, 56). R a s h e n & Hirvonen (57) have shown that electric vagal stimulation degranulates the mast cells in the gastrointestinal tract and markedly activates acid secretion. Mast cell degranulation in rats releases histamine (58), heparin (59), 5-hydroxytryptamine (5-HT) (60),dopamine (61), leukotrienes (62), and various enzymes and compounds (6365); other workers (66) have found that vagal-mediated mast cell degranulation could be the major factor involved in stress-induced glandular ulceration in rats. However, Guth & Kozbun (67) and Guth (68) are of the view that there is no correlaticin between gastric wall mast cell degranulation and gastric ulceration. Histamine. Stimulation of histamine H , and H, receptors in the blood vessels and gastric submucosal arterioles of rats (69-71) dilates the precapillary sphincters (72) but constricts microvessels larger than 80pm in diameter (72). These effects increase the postcapillary venular intravascular pressure (73) and attenuate vasomotion of the precapillary sphincters and meta-arterioles (74). The amine appears to affect selectively the venular end of the microcirculatory bed (7U, 73) and has also been shown to produce vasodilation in the stomach. Histamine increases gastric microvascular permeability (75) and produces local oedema (76). This could be caused by contraction of actomyosin fibrils in the venular endothelial cells, which stimulates the cells to move apart (77), or by an increase in size and turnover of the endothelial vesicles (78). Therefore, it is possible that histamine stimulates molecular transport by both increasing the number of available pores and enhancing the rate of vesicular transport.
Histamine released from the mast cell interferes with local gastric blood flow by causing vasodilatation and vascular stasis through histamine-receptor activation (79). Stressinduced gastric ulceration is frequently associated with mucosal blood vessel engorgement (68), and this could possibly be due to the effccts of histamine. Gastric hyperaemia is also frequently observed in stressed animals. However, this could reflect either incrcased gastric mucosal blood flow or simply vascular engorgement (SO, 80, 81). Experimental evidence indicates that mucosal blood flow plays an important role in the pathogenesis and in the healing of gastric ulcers (82, 83); it is therefore necessary to clarify the importance of gastric mucosal blood flow in stress-induced ulceration. Hepurin. The release of heparin together with histamine from the mast cells inhibits mitotic activity of gastric epithelial cells, and this effect is probably due to inhibition of DNA polymerase activity (84, 85). Therefore, heparin can reduce mucosal epithelial cell regeneration after mucosal damage, and this effect could be an important factor contributing to prolongation of mucosal lesion healing. Motility. Gastric hypermotility is postulated to be induced by stress through vagal overactivity and has been considered to contribute to ulcer formation (86, 87). Yano et al. (88) showed that hypermotility per se caused gastric ulceration, and this was thought to be due to excessive rubbing and compression of the mucosal tissues, leading to cell damage and stasis of mucosal blood flow. In fact, atropine and verapamil decrease gastric motility and decrease ulceration; however, bethanechol treatment, which increases stomach contractions, does not aggravate stress-induced ulcer formation. It has also been found that the amplitude of gastric contractions is reduced throughout the stress period (89). These findings reinforce the idea that gastric hypermotility is unlikely to contribute substantially to stress-induced ulceration, although the possibility that it has a role in ulcer formation cannot be cxcluded. Mucus. Gastric mucus glycoproteins are believed to play an important role in the defensive mechanism against gastric ulceration (90); the mucus layer acts as an unstirred mucusbicarbonate mucosal barrier to acid and pepsin digestion (91). Stress has been shown to decrease the amount of mucus adhering to the gastric mucosa (89,92,93); thus, the underlying epithelial cells are more exposed to the aggressive ulcerogenic action of luminal gastric acid (94). Furthermore. reduccd mucus by N-acetylcysteine is accompanied by gastric lesion formation in nonstressed rats or by aggravation of stress ulceration (95). These observations reinforce the conclusion that stomach wall mucus is likely to play an important role in stress-induced glandular lesions. Leukotrienes. The role of leukotrienes (LTs) in the stomach has been described by Goldberg & Subers (96). They found that the dose-dependent contractile response with LTC4was inhibited by a specific antagonist, FPL55712. Because the duodenum and ileum failed to respond to LTC4,
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a.
Labilization of mast cclls or other sources .c
Gastric con traction
1
Biogenic amines and leukotriene release
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Vascular engorgement
these workers concluded that specific LT receptors were present in the stomach. This finding was confirmed by Piper & Samhoun (97), Magous et al. (98), and Pendleton & Stavorski (99). Peck et al. (100) showed that LTs induce vasoconstriction in the vascular bed of the stomach, which is followed by leakage of macromolecules from the postcapillary venules. Whittle (101) reported that LTC4 can induce vasoconstriction in both the venous and arteriolar vessels in the rat submucosa and that this potent vasoconstriction of submucosal microvessels of the rat stomach causes tissue necrosis (102). It could therefore serve as a potential pro-ulcerogenic agent. Studies on the gastric antiulcer action of drugs suggest that LTs may participate in stress-induced gastric glandular ulceration (103-105). This idea was later supported by Konturek et al. (106), who suggested that LTC4 may facilitate mucosal damage produced in rats stressed by restraint and immersion in water. However, it is unclear what the proportion is of the individual contributions of the various LTs in the pathogenesis of stress-induced gastric ulcers in rats. Previous studies on 5-lipoxygenase (5-LO) inhibition in the gastric mucosa (107, 108) suggest that blockade of 5-LO may divert metabolism of arachidonic acid from the 5-LO pathway to that mediated by cyclo-oxygenase, to result in more prostanoid formation. However, it appears unlikely that prostaglandins (PG), if indeed influenced by 5-LO antagonism, do play a significant role in stress ulcer prevention because raised stomach tissue levels of PEG2 do not prevent this type of ulcer formation (105). Mucosal blood flow. Gastric mucosal microcirculation is involved in the maintenance of mucosal integrity and plays an important part in the mucosal protection (109, 110). The functional and morphologic alteration in microcirculation can result in the reduction of blood flow and oxygen saturation in the gastric mucosa and may produce haemorrhages, erosions, and even ulcers (111). Yabana et al. (112) have
shown that exposure to stress results in a rapidly developing vascular injury in subepithelial capillaries and increased vascular permeability; these lead to functional impairment of gastric microcirculation (113). It has been found that the degree of decrease in mucosal blood flow correlates with the extent of haemorrhagic erosion (113, 114). Conclusion It is concluded that cholinergic activation and the release of several biogenic amines and the metabolites of arachidonic acid through 5-LO-for example, leukotrienes-could play a significant role in stress-induced ulceration in animals. Their labilisation from mast cells and/or from other sources could contribute to ulcer formation. The effects produced by these biologically active mediators and cholinergic stimulation include increased gastric contractions, vascular engorgement, acid secretion, and, possibly, mucus depletion (Fig. 1). It is therefore likely that the modulation of these effects, by blocking mediator release or action at receptor sites, may have therapeutic benefits in stress-evoked ulceration in man. Indeed, several mast cell stabilisers, histamine, and leukotriene antagonists have been proved to be effective against stress-induced ulceration in animals and may possibly be of benefit in man (23, 63, 115-119). Acknowledgements The authors are grateful to W. L. Lau and P. Y. Lam for their secretarial assistance. C. H. C H O M. W. L. K o o G. P. GARG C. W. OGLE Dept. of Pharmacology Faculty of Medicine University of Hong Kong 5 Sassoon Road Hong Kong
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