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Neural and paracrine regulation of gastrin and gastric acid secretion
September 1996
7. 8.
9.
10.
11.
CORRESPONDENCE 837
of topical oesophageal acidification on human salivary and oesophageal alkali secretion. Gut 1995;36:649–653. Izutsu KT. Theory and measurement of the buffer value of bicarbonate in saliva. J Theor Biol 1981;90:397–403. Helm JF, Dodds WJ, Hogan WJ, Soergel KH, Egide MS, Wood CM. Acid neutralizing capacity of human saliva. Gastroenterology 1982;83:69–74. Rigas B, Levine L. Concentrations of arachidonic-acid metabolites in human mixed saliva are independent of flow rate. Arch Oral Biol 1983;28:1135–1137. Rigas B, Korenberg JR, Merrill WW, Levine L. Prostaglandins E2 and E2 alpha are elevated in saliva of cystic fibrosis patients. Am J Gastroenterol 1989;84:1408–1412. Ohishi K, Ueno R, Nishino S, Sakai T, Hayaishi O. Increased level of salivary prostaglandins in patients with major depression. Biol Psychiatry 1988;23:326–334.
Neural and Paracrine Regulation of Gastrin and Gastric Acid Secretion Dear Sir: We are pleased that GASTROENTEROLOGY has elected to feature on its cover a model describing the neural, hormonal, and paracrine regulation of gastrin and gastric acid secretion proposed by us more than a decade ago1 and extended recently to include a paracrine role for histamine.2,3 We also thank McGowan et al. for bringing the essentials of the model to the attention of your readers.4 However, the simplified model lacks several pathways crucial to understanding normal gastric function and the genesis of Helicobacter pylori–dependent ulcer disease. First, it should be noted that the vagus nerve does not innervate endocrine or parietal cells directly. Its efferent fibers are preganglionic, and they synapse with gastric cholinergic (acetylcholine) and peptidergic (gastrin-releasing peptide [GRP] and vasoactive intestinal peptide [VIP]) neurons in the wall of the stomach that directly innervate various cells. As shown in Figure 1 (inhibition and stimulation are denoted by 0 and / symbols, respectively), gastric cholinergic neurons innervate somatostatin, gastrin, and parietal cells; there is no evidence that they innervate enterochromaffin-like (ECL) cells of the fundus or mast cells of the antrum, even though these cells express muscarinic receptors. GRP neurons innervate gastrin cells but not parietal, ECL, or somatostatin cells, whereas VIP neurons innervate predominantly somatostatin cells and are preferentially activated by low-grade distention.5 Second, reciprocal inhibitory paracrine pathways link somatostatin cells and ECL cells in the fundus and somatostatin cells and mast cells in the antrum.2,3,6 Histamine released from either cell type acts via H3 receptors to inhibit somatostatin secretion. Consequently, a decrease in somatostatin secretion induced by cholinergic stimulation causes an increase in histamine, which, in turn, accentuates the decrease in somatostatin secretion, thereby relieving the inhibitory influence of somatostatin on gastrin and acid secretion. In the fundus, the increase in histamine secretion is further augmented by the action of gastrin on the ECL cell and stimulates acid secretion directly via H2 receptors. The mast cell in the antrum is insensitive to gastrin.3,7 Third, a stimulatory paracrine pathway links gastrin to antral somatostatin cells and acts to restore antral somatostatin secretion after release of gastrin.8 The release of acid into the lumen of the stomach also restores somatostatin secretion in both fundus9 and antrum.10 The neural and paracrine pathways summarized have been characterized in detail in the vascularly perfused stomach and in isolated superfused segments of antral and fundic mucosa.1,2,5,8,11 Physiologically, the pathways can be activated directly by stimuli originating
/ 5e11$$0026
08-14-96 10:17:12
gasa
Figure 1. Model illustrating the neural, hormonal, and paracrine regulation of gastrin secretion from the antrum and acid secretion from the fundus of the stomach. Vagal efferent fibers synapse with intramural gastric cholinergic (acetylcholine [ACh]) and peptidergic (GRP and VIP) neurons. Reciprocal paracine pathways link somatostatin (SST) cells to ECL cells and parietal cells in the fundus and to mast cells and gastrin cells in the antrum. H/, acid; H2 , histamine H2-receptor; H3, histamine H3-receptor; /, stimulatory signal; 0, inhibitory signal. The authors thank Mary Beatty for the artwork.
in the brain or reflexly by stimuli originating in the stomach, such as mechanical distention5 or chemical stimulation11 after ingestion of a meal. The pathways in the antrum involve cholinergic and peptidergic (via GRP neurons) stimulation of gastrin secretion and cholinergic inhibition of somatostatin secretion. The resultant decrease in somatostatin eliminates its inhibitory influence on gastrin secretion (disinhibition). It also causes an increase in antral histamine that acts via H3 receptors to cause a further decrease in somatostatin secretion: the net effect is suppression of all inhibitory influence on gastrin secretion. The pathways in the fundus involve (1) direct cholinergic stimulation of acid secretion, (2) cholinergic inhibition of somatostatin secretion, (3) direct hormonal stimulation of parietal cells by gastrin, and (4) gastrin-induced stimulation of histamine release from ECL cells. The release of histamine from these cells is accentuated by the decrease in somatostatin secretion. The net effect in the fundus is suppression of all paracrine inhibitory influence (i.e., somatostatin) and enhancement of paracrine stimulatory influence (i.e., histamine acting via H2 receptors) on parietal cells. An appreciation of these pathways provides some insight into the mechanism(s) whereby H. pylori infection may lead to ulceration. In patients with ulcer disease and infection, antral somatostatin expression and content are low, whereas basal and stimulated gastrin secretion are elevated.4,12 – 14 Courillon-Mallet et al.15 have recently provided evidence that H. pylori synthesizes Na-methyl histamine, a potent and selective H3 -receptor agonist. One may speculate that the H3 -receptor agonist could diffuse across the antral mucosa where it interacts with H3 receptors on antral somatostatin cells, causing inhibition of somatostatin secretion, and, thus, stimulation of both histamine and gastrin secretion. The increase in gastrin secretion stimulates the release of histamine from fundic ECL cells. The net effect is sustained suppression of inhibitory influences (somatostatin) and sustained stimulation of two secretagogues (histamine and gas-
WBS-Gastro
838 CORRESPONDENCE
GASTROENTEROLOGY Vol. 111, No. 3
trin), one of which is the main trophic hormone of the stomach. As other triggers are uncovered, their putative mechanisms should be examined in light of the pathways outlined in this model. MITCHELL L. SCHUBERT, M.D.
Division of Gastroenterology Medical College of Virginia and McGuire VAMC Richmond, Virginia GABRIEL M. MAKHLOUF, M.D., Ph.D.
Division of Gastroenterology Medical College of Virginia Richmond, Virginia 1. Duval JW, Saffouri B, Weir GC, Walsh JH, Arimura A, Makhlouf GM. Stimulation of gastrin and somatostatin secretion from the isolated rat stomach by bombesin. Am J Physiol 1981;241: G242–G247. 2. Schubert ML, Harrington L, Makhlouf GM. Reciprocal paracrine pathways link histamine and somatostatin secretion in the fundus of rat stomach (abstr). Gastroenterology 1993;104:A188. 3. Vuyyuru L, Schubert ML, Harrington L, Arimura A, Makhlouf GM. Dual inhibitory pathways link antral somatostatin and histamine secretion in human, dog, and rat stomach. Gastroenterology 1995;109:1566–1574. 4. McGowan CC, Cover TL, Blaser MJ. Helicobacter pylori and gastric acid: biological and therapeutic implications. Gastroenterology 1996;110:926–938. 5. Schubert ML, Makhlouf GM. Gastrin secretion induced by distention is regulated by cholinergic and vasoactive intestinal peptide neurons in rats. Gastroenterology 1993;104:834–839. 6. Sandvik AK, Holst JJ, Waldum HL. The effect of gastrin-releasing peptide on acid secretion and the release of gastrin, somatostatin, and histamine in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 1989;24:9–15. 7. Soll A, Lewin K, Beaven M. Isolation of histamine-containing cells from rat gastric mucosa: biochemical and morphological differences from the mast cells. Gastroenterology 1981;80:717– 727. 8. Schubert ML, Jong MJ, Makhlouf GM. Bombesin/GRP-stimulated somatostatin secretion is mediated by gastrin in the antrum and intrinsic neurons in the fundus. Am J Physiol 1991;261:G885– G889. 9. Schubert ML, Edwards NF, Makhlouf GM. Regulation of gastric somatostatin secretion in the mouse by luminal acid: a local feedback mechanism. Gastroenterology 1988;94:317–322. 10. Manela FD, Ren JY, Gao JS, McGuigan JE, Harty RF. Calcitonin gene-related peptide modulates acid-mediated regulation of somatostatin and gastrin release from rat antrum. Gastroenterology 1995;109:701–706. 11. Schubert ML, Coy DH, Makhlouf GM. Peptone stimulates gastrin secretion from the stomach by activating bombesin/GRP and cholinergic neurons. Am J Physiol 1992;262:G685–G689. 12. Calam J. Effects of H. pylori on hormones. Reg Pep Letter 1996; VII:9–12. 13. Moss SF, Legon S, Bishop AE, Polak JM, Calam J. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 1992;340:930–932. 14. El-Omar EM, Penman ID, Ardill JES, Chittajallu RS, Howie C, McColl KEL. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995;109:681–691. 15. Courillon-Mallet A, Launay J, Roucayrol A, Callebert J, Emond J, Tabuteau F, Cattan D. Helicobacter pylori infection: physiopathologic implication of Na-methyl histamine. Gastroenterology 1995; 108:959–966.
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gasa
The Gastrin-Histamine Sequence Dear Sir: It was fascinating to see the cover of GASTROENTEROLOGY (March 1996) showing that gastrin stimulates acid secretion by releasing histamine from the enterochromaffin-like (ECL) cell and with no gastrin receptor on the parietal cell. However, it was very disappointing to see that this figure referred to a paper1 referring to two other papers, one from Hirschowitz et al. from 19952 and a hypothesis from Blaser from 1992.3 If McGowan et al.1 had had sufficient knowledge of the literature, they would have known that this figure was originally published by us in 19914 and slightly modified later.5 Moreover, the role of histamine in gastrin- and food-stimulated acid secretion was described as early as in the sixties.6 Later in the same decade, Ha˚kanson and Owman described histamine production by the ECL cell.7 In the 1980s we showed that maximal histamine-stimulated acid secretion was higher than that stimulated by gastrin8 and that gastrin evoked an immediate and concentration-dependent histamine release9 sufficient to explain the acid stimulatory effect of gastrin.10 Later, by studying isolated oxyntic mucosal cells, we could show that gastrinstimulated aminopyrine uptake in parietal cells depended on histamine release from the ECL cell.11 Studies on histamine release from oxyntic mucosal cells more enriched in ECL cells were later elaborated by the group of Sachs.12 The nearly 100-year dispute concerning the interaction between gastrin and histamine in the regulation of acid secretion is full of misinterpretations13 – 15 and should again tell us that it is necessary to have an open mind in science. We have experienced the refusal of manuscripts showing the fundamental role of histamine in the gastrin and thereby food-stimulated acid secretion16 by reviewers claiming that the main points in the regulation of gastric acid secretion were settled and that there without doubt was a gastrin receptor on the parietal cell. It is sad to see that articles that clarified this question nearly 10 years ago9 are not referred to, whereas more recent publications are mentioned.2,3 HELGE L. WALDUM ARNE K. SANDVIK EILIY BRENNA PER M. KLEVELAND
Department of Medicine Trondheim University Hospital N-7006 Trondheim, Norway 1. McGowan CC, Cover TL, Blaser MJ. Helicobacter pylori and gastric acid: biological and therapeutic implications. Gastroenterology 1996;110:926–938. 2. Hirschowitz BI, Keeling D, Lewin M, Okabe S, Parsons S, Sewing K, Wallmark B, Sachs G. Pharmacological aspects of acid secretion. Dig Dis Sci 1995;40(Suppl):3S–23S. 3. Blaser MJ. Hypothesis on the pathogenesis and natural history of Helicobacter pylori –induced inflammation. Gastroenterology 1992;102:720–727. 4. Waldum HL, Sandvik AK, Brenna E, Petersen H. Gastrin-histamine sequence in the regulation of gastric acid secretion. Gut 1991;32:698–701. 5. Waldum HL, Sandvik AK. Gastric functional and trophic receptors for CCK. In: Stone TW, ed. Aspects of synaptic transmission. 2. Acetylcholine, sigma receptors, CCK and eicosanoids, neurotoxins. Longon, Taylor & Francis, 1993:157–172. 6. Kahlson G, Rosengren E, Svahn D, et al. Mobilization and formation of histamine in the gastric mucosa as related to acid secretion. J Physiol (Lond) 1964;174:400–416. 7. Ha˚kanson R, Owman C. Argyrophilic reaction of histamine-con-
WBS-Gastro
7. 8.
9.
10.
11.
CORRESPONDENCE 837
of topical oesophageal acidification on human salivary and oesophageal alkali secretion. Gut 1995;36:649–653. Izutsu KT. Theory and measurement of the buffer value of bicarbonate in saliva. J Theor Biol 1981;90:397–403. Helm JF, Dodds WJ, Hogan WJ, Soergel KH, Egide MS, Wood CM. Acid neutralizing capacity of human saliva. Gastroenterology 1982;83:69–74. Rigas B, Levine L. Concentrations of arachidonic-acid metabolites in human mixed saliva are independent of flow rate. Arch Oral Biol 1983;28:1135–1137. Rigas B, Korenberg JR, Merrill WW, Levine L. Prostaglandins E2 and E2 alpha are elevated in saliva of cystic fibrosis patients. Am J Gastroenterol 1989;84:1408–1412. Ohishi K, Ueno R, Nishino S, Sakai T, Hayaishi O. Increased level of salivary prostaglandins in patients with major depression. Biol Psychiatry 1988;23:326–334.
Neural and Paracrine Regulation of Gastrin and Gastric Acid Secretion Dear Sir: We are pleased that GASTROENTEROLOGY has elected to feature on its cover a model describing the neural, hormonal, and paracrine regulation of gastrin and gastric acid secretion proposed by us more than a decade ago1 and extended recently to include a paracrine role for histamine.2,3 We also thank McGowan et al. for bringing the essentials of the model to the attention of your readers.4 However, the simplified model lacks several pathways crucial to understanding normal gastric function and the genesis of Helicobacter pylori–dependent ulcer disease. First, it should be noted that the vagus nerve does not innervate endocrine or parietal cells directly. Its efferent fibers are preganglionic, and they synapse with gastric cholinergic (acetylcholine) and peptidergic (gastrin-releasing peptide [GRP] and vasoactive intestinal peptide [VIP]) neurons in the wall of the stomach that directly innervate various cells. As shown in Figure 1 (inhibition and stimulation are denoted by 0 and / symbols, respectively), gastric cholinergic neurons innervate somatostatin, gastrin, and parietal cells; there is no evidence that they innervate enterochromaffin-like (ECL) cells of the fundus or mast cells of the antrum, even though these cells express muscarinic receptors. GRP neurons innervate gastrin cells but not parietal, ECL, or somatostatin cells, whereas VIP neurons innervate predominantly somatostatin cells and are preferentially activated by low-grade distention.5 Second, reciprocal inhibitory paracrine pathways link somatostatin cells and ECL cells in the fundus and somatostatin cells and mast cells in the antrum.2,3,6 Histamine released from either cell type acts via H3 receptors to inhibit somatostatin secretion. Consequently, a decrease in somatostatin secretion induced by cholinergic stimulation causes an increase in histamine, which, in turn, accentuates the decrease in somatostatin secretion, thereby relieving the inhibitory influence of somatostatin on gastrin and acid secretion. In the fundus, the increase in histamine secretion is further augmented by the action of gastrin on the ECL cell and stimulates acid secretion directly via H2 receptors. The mast cell in the antrum is insensitive to gastrin.3,7 Third, a stimulatory paracrine pathway links gastrin to antral somatostatin cells and acts to restore antral somatostatin secretion after release of gastrin.8 The release of acid into the lumen of the stomach also restores somatostatin secretion in both fundus9 and antrum.10 The neural and paracrine pathways summarized have been characterized in detail in the vascularly perfused stomach and in isolated superfused segments of antral and fundic mucosa.1,2,5,8,11 Physiologically, the pathways can be activated directly by stimuli originating
/ 5e11$$0026
08-14-96 10:17:12
gasa
Figure 1. Model illustrating the neural, hormonal, and paracrine regulation of gastrin secretion from the antrum and acid secretion from the fundus of the stomach. Vagal efferent fibers synapse with intramural gastric cholinergic (acetylcholine [ACh]) and peptidergic (GRP and VIP) neurons. Reciprocal paracine pathways link somatostatin (SST) cells to ECL cells and parietal cells in the fundus and to mast cells and gastrin cells in the antrum. H/, acid; H2 , histamine H2-receptor; H3, histamine H3-receptor; /, stimulatory signal; 0, inhibitory signal. The authors thank Mary Beatty for the artwork.
in the brain or reflexly by stimuli originating in the stomach, such as mechanical distention5 or chemical stimulation11 after ingestion of a meal. The pathways in the antrum involve cholinergic and peptidergic (via GRP neurons) stimulation of gastrin secretion and cholinergic inhibition of somatostatin secretion. The resultant decrease in somatostatin eliminates its inhibitory influence on gastrin secretion (disinhibition). It also causes an increase in antral histamine that acts via H3 receptors to cause a further decrease in somatostatin secretion: the net effect is suppression of all inhibitory influence on gastrin secretion. The pathways in the fundus involve (1) direct cholinergic stimulation of acid secretion, (2) cholinergic inhibition of somatostatin secretion, (3) direct hormonal stimulation of parietal cells by gastrin, and (4) gastrin-induced stimulation of histamine release from ECL cells. The release of histamine from these cells is accentuated by the decrease in somatostatin secretion. The net effect in the fundus is suppression of all paracrine inhibitory influence (i.e., somatostatin) and enhancement of paracrine stimulatory influence (i.e., histamine acting via H2 receptors) on parietal cells. An appreciation of these pathways provides some insight into the mechanism(s) whereby H. pylori infection may lead to ulceration. In patients with ulcer disease and infection, antral somatostatin expression and content are low, whereas basal and stimulated gastrin secretion are elevated.4,12 – 14 Courillon-Mallet et al.15 have recently provided evidence that H. pylori synthesizes Na-methyl histamine, a potent and selective H3 -receptor agonist. One may speculate that the H3 -receptor agonist could diffuse across the antral mucosa where it interacts with H3 receptors on antral somatostatin cells, causing inhibition of somatostatin secretion, and, thus, stimulation of both histamine and gastrin secretion. The increase in gastrin secretion stimulates the release of histamine from fundic ECL cells. The net effect is sustained suppression of inhibitory influences (somatostatin) and sustained stimulation of two secretagogues (histamine and gas-
WBS-Gastro
838 CORRESPONDENCE
GASTROENTEROLOGY Vol. 111, No. 3
trin), one of which is the main trophic hormone of the stomach. As other triggers are uncovered, their putative mechanisms should be examined in light of the pathways outlined in this model. MITCHELL L. SCHUBERT, M.D.
Division of Gastroenterology Medical College of Virginia and McGuire VAMC Richmond, Virginia GABRIEL M. MAKHLOUF, M.D., Ph.D.
Division of Gastroenterology Medical College of Virginia Richmond, Virginia 1. Duval JW, Saffouri B, Weir GC, Walsh JH, Arimura A, Makhlouf GM. Stimulation of gastrin and somatostatin secretion from the isolated rat stomach by bombesin. Am J Physiol 1981;241: G242–G247. 2. Schubert ML, Harrington L, Makhlouf GM. Reciprocal paracrine pathways link histamine and somatostatin secretion in the fundus of rat stomach (abstr). Gastroenterology 1993;104:A188. 3. Vuyyuru L, Schubert ML, Harrington L, Arimura A, Makhlouf GM. Dual inhibitory pathways link antral somatostatin and histamine secretion in human, dog, and rat stomach. Gastroenterology 1995;109:1566–1574. 4. McGowan CC, Cover TL, Blaser MJ. Helicobacter pylori and gastric acid: biological and therapeutic implications. Gastroenterology 1996;110:926–938. 5. Schubert ML, Makhlouf GM. Gastrin secretion induced by distention is regulated by cholinergic and vasoactive intestinal peptide neurons in rats. Gastroenterology 1993;104:834–839. 6. Sandvik AK, Holst JJ, Waldum HL. The effect of gastrin-releasing peptide on acid secretion and the release of gastrin, somatostatin, and histamine in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 1989;24:9–15. 7. Soll A, Lewin K, Beaven M. Isolation of histamine-containing cells from rat gastric mucosa: biochemical and morphological differences from the mast cells. Gastroenterology 1981;80:717– 727. 8. Schubert ML, Jong MJ, Makhlouf GM. Bombesin/GRP-stimulated somatostatin secretion is mediated by gastrin in the antrum and intrinsic neurons in the fundus. Am J Physiol 1991;261:G885– G889. 9. Schubert ML, Edwards NF, Makhlouf GM. Regulation of gastric somatostatin secretion in the mouse by luminal acid: a local feedback mechanism. Gastroenterology 1988;94:317–322. 10. Manela FD, Ren JY, Gao JS, McGuigan JE, Harty RF. Calcitonin gene-related peptide modulates acid-mediated regulation of somatostatin and gastrin release from rat antrum. Gastroenterology 1995;109:701–706. 11. Schubert ML, Coy DH, Makhlouf GM. Peptone stimulates gastrin secretion from the stomach by activating bombesin/GRP and cholinergic neurons. Am J Physiol 1992;262:G685–G689. 12. Calam J. Effects of H. pylori on hormones. Reg Pep Letter 1996; VII:9–12. 13. Moss SF, Legon S, Bishop AE, Polak JM, Calam J. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 1992;340:930–932. 14. El-Omar EM, Penman ID, Ardill JES, Chittajallu RS, Howie C, McColl KEL. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995;109:681–691. 15. Courillon-Mallet A, Launay J, Roucayrol A, Callebert J, Emond J, Tabuteau F, Cattan D. Helicobacter pylori infection: physiopathologic implication of Na-methyl histamine. Gastroenterology 1995; 108:959–966.
/ 5e11$$0026
08-14-96 10:17:12
gasa
The Gastrin-Histamine Sequence Dear Sir: It was fascinating to see the cover of GASTROENTEROLOGY (March 1996) showing that gastrin stimulates acid secretion by releasing histamine from the enterochromaffin-like (ECL) cell and with no gastrin receptor on the parietal cell. However, it was very disappointing to see that this figure referred to a paper1 referring to two other papers, one from Hirschowitz et al. from 19952 and a hypothesis from Blaser from 1992.3 If McGowan et al.1 had had sufficient knowledge of the literature, they would have known that this figure was originally published by us in 19914 and slightly modified later.5 Moreover, the role of histamine in gastrin- and food-stimulated acid secretion was described as early as in the sixties.6 Later in the same decade, Ha˚kanson and Owman described histamine production by the ECL cell.7 In the 1980s we showed that maximal histamine-stimulated acid secretion was higher than that stimulated by gastrin8 and that gastrin evoked an immediate and concentration-dependent histamine release9 sufficient to explain the acid stimulatory effect of gastrin.10 Later, by studying isolated oxyntic mucosal cells, we could show that gastrinstimulated aminopyrine uptake in parietal cells depended on histamine release from the ECL cell.11 Studies on histamine release from oxyntic mucosal cells more enriched in ECL cells were later elaborated by the group of Sachs.12 The nearly 100-year dispute concerning the interaction between gastrin and histamine in the regulation of acid secretion is full of misinterpretations13 – 15 and should again tell us that it is necessary to have an open mind in science. We have experienced the refusal of manuscripts showing the fundamental role of histamine in the gastrin and thereby food-stimulated acid secretion16 by reviewers claiming that the main points in the regulation of gastric acid secretion were settled and that there without doubt was a gastrin receptor on the parietal cell. It is sad to see that articles that clarified this question nearly 10 years ago9 are not referred to, whereas more recent publications are mentioned.2,3 HELGE L. WALDUM ARNE K. SANDVIK EILIY BRENNA PER M. KLEVELAND
Department of Medicine Trondheim University Hospital N-7006 Trondheim, Norway 1. McGowan CC, Cover TL, Blaser MJ. Helicobacter pylori and gastric acid: biological and therapeutic implications. Gastroenterology 1996;110:926–938. 2. Hirschowitz BI, Keeling D, Lewin M, Okabe S, Parsons S, Sewing K, Wallmark B, Sachs G. Pharmacological aspects of acid secretion. Dig Dis Sci 1995;40(Suppl):3S–23S. 3. Blaser MJ. Hypothesis on the pathogenesis and natural history of Helicobacter pylori –induced inflammation. Gastroenterology 1992;102:720–727. 4. Waldum HL, Sandvik AK, Brenna E, Petersen H. Gastrin-histamine sequence in the regulation of gastric acid secretion. Gut 1991;32:698–701. 5. Waldum HL, Sandvik AK. Gastric functional and trophic receptors for CCK. In: Stone TW, ed. Aspects of synaptic transmission. 2. Acetylcholine, sigma receptors, CCK and eicosanoids, neurotoxins. Longon, Taylor & Francis, 1993:157–172. 6. Kahlson G, Rosengren E, Svahn D, et al. Mobilization and formation of histamine in the gastric mucosa as related to acid secretion. J Physiol (Lond) 1964;174:400–416. 7. Ha˚kanson R, Owman C. Argyrophilic reaction of histamine-con-
WBS-Gastro