Acid suppression: Optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome
2000; Elsevier BV; Volume: 118; Issue: 2 Linguagem: Inglês
10.1016/s0016-5085(00)70004-7
ISSN1528-0012
AutoresM. Michael Wolfe, George Sachs,
Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoOne of the hallmarks of the mammalian stomach is its ability to secrete large quantities of concentrated (0.16 mol/L) hydrochloric acid (HCl).1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Although it is generally assumed that gastric acid and the proteolytic enzyme pepsin are required to initiate digestion, achlorhydric individuals generally do not develop malabsorption unless small bowel bacterial overgrowth is present. It is thus likely that the ability of the stomach to secrete acid evolved primarily from a need to sustain a sterile intragastric milieu. Organisms that possessed the capacity to kill ingested bacteria and other microbes were able to avoid the development of enteric colonization, and thereby ensure both efficient absorption of nutrients and prevention of systemic infections.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Nevertheless, when present, gastric acid does play a significant role in protein hydrolysis and other aspects of the digestive process, and under various conditions, acid may play an etiologic role in producing various forms of discomfort and inciting esophageal and gastroduodenal mucosal injury. The normal human stomach contains approximately 1 billion parietal cells that secrete hydrogen ions into the gastric lumen in response to various physiological stimuli. The generation of H+ ions is mediated by 3 pathways: neurocrine, paracrine, and endocrine (Figure 1). The principal neurocrine transmitter is acetylcholine, which is released by vagal postganglionic neurons and appears to stimulate H+ ion generation directly via a parietal cell muscarinic M3 receptor. Histamine is the primary paracrine transmitter that binds to H2-specific receptors on parietal cells. Adenylate cyclase is then activated, leading to an increase in adenosine 3′,5′-cyclic monophosphate (cAMP) levels and subsequent generation of H+ ions. The secretion of gastrin from antral G cells comprises the endocrine pathway and stimulates H+ ion generation both directly and indirectly, the latter by stimulating histamine secretion from enterochromaffin-like (ECL) cells of the corpus and fundus. Interactions among neurocrine, paracrine, and endocrine pathways are coordinated to promote or inhibit H+ ion generation. Histamine appears to represent the dominant route, because gastrin stimulates acid secretion principally by promoting histamine release from ECL cells.2Waldum HL Sandvik AK. The enterochromaffin-like (ECL) cells.Acta Oncol. 1993; 32: 141-147Crossref PubMed Google Scholar, 3Prinz C Scott DR Hurwitz D Helander HF Sachs G. Gastrin effects on isolated rat enterochromaffin-like cells in primary culture.Am J Physiol. 1994; 267: G663-G675PubMed Google Scholar Thus, ECL cells are often referred to as "controller" cells in the process of gastric acid secretion. A negative feedback loop governs both gastrin release and the return of acid secretion to basal level.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar, 4Van Dam J Wolfe MM. Gastrin and other peptide hormones. In Pharmacology of peptic ulcer disease.in: eds Collen MJ Benjamin SB Springer-Verlag,, Berlin1991: 55-58Google Scholar, 5Brand SJ Stone D. Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria.J Clin Invest. 1988; 82: 1059-1066Crossref PubMed Google Scholar, 6Schubert ML Saffouri B Makhlouf GM. Identical patterns of somatostatin secretion from isolated antrum and fundus of rat stomach.Am J Physiol. 1988; 254: G20-G24PubMed Google Scholar This autoregulatory mechanism prevents postprandial acid hypersecretion. After ingestion of a meal, gastrin release stimulates secretion of gastric acid. The intraluminal pH begins to decrease, which stimulates release of somatostatin from antral D cells, possibly through the activation of calcitonin gene-related peptide (CGRP) neurons.5Brand SJ Stone D. Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria.J Clin Invest. 1988; 82: 1059-1066Crossref PubMed Google Scholar, 7Ren J Dunn ST Tang Y Wang Y Gao J Brewer K Harty RF. Effects of calcitonin gene-related peptide on somatostatin and gastrin gene expression in rat antrum.Regul Pep. 1998; 73: 75-82Crossref PubMed Scopus (9) Google Scholar Somatostatin then appears to act via a paracrine mechanism to inhibit further release of gastrin from G cells.8Wolfe MM Jain DK Reel GM McGuigan JE. Effects of carbachol on gastrin and somatostatin release in rat antral tissue culture.Gastroenterology. 1984; 87: 86-93Abstract Full Text PDF PubMed Google Scholar Somatostatin produced by D cells in the gastric corpus and fundus may also directly inhibit acid secretion from parietal cells and may suppress histamine release from ECL cells (Figure 1).6Schubert ML Saffouri B Makhlouf GM. Identical patterns of somatostatin secretion from isolated antrum and fundus of rat stomach.Am J Physiol. 1988; 254: G20-G24PubMed Google Scholar, 9Short GM Reel GM Doyle JW Wolfe MM. Effect of GRP on β-adrenergic-stimulated gastrin and somatostatin release in the isolated rat stomach.Am J Physiol. 1985; 249: G197-G202PubMed Google Scholar Other recent observations indicate that several other neurotransmitters, including vasoactive intestinal peptide (VIP), galanin, and pituitary adenylate cyclase-activating peptide, may play important roles in regulating gastric acid secretion, both directly and indirectly, under physiological conditions.10Athmann C Zeng N Sachs G. An integrated model of paracrine regulation of acid secretion.Gastroenterology. 1999; 116 (abstr): A590Google Scholar The treatment of duodenal ulcer (DU) has served as the basis (correctly or incorrectly) for the management of nearly all acid-related disorders. This supposition in all likelihood contributed to delays in the optimal management of other gastrointestinal (GI) disorders in which acid plays an etiologic role in producing symptoms and causing mucosal injury, such as gastroesophageal reflux disease (GERD). Although patients with gastric ulcers (GUs) tend to have normal or reduced levels of acid secretion,11Feldman M Richardson CT. Total 24-hour gastric acid secretion in patients with duodenal ulcer: comparison with normal subjects and effects of cimetidine and parietal cell vagotomy.Gastroenterology. 1986; 90: 540-544Abstract Full Text PDF PubMed Google Scholar the average DU patient is an acid hypersecretor. When compared with age-matched controls, DU patients secrete ~70% more acid during the day (meal-stimulated) and about 150% more acid at night (basal secretion) (Figure 2).11Feldman M Richardson CT. Total 24-hour gastric acid secretion in patients with duodenal ulcer: comparison with normal subjects and effects of cimetidine and parietal cell vagotomy.Gastroenterology. 1986; 90: 540-544Abstract Full Text PDF PubMed Google Scholar Postprandial gastric acid secretion is regulated primarily by increases in gastrin expression, which is controlled by a negative feedback loop. Individuals infected with Helicobacter pylori have been shown to have a diminished number of somatostatin-secreting D cells, which decreases the magnitude of the response to luminal acidification.12Moss SF Legon S Bishop AE Polak JM Calam J. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease.Lancet. 1992; 340: 930-932Abstract PubMed Scopus (187) Google Scholar, 13Graham DY Lew GM Lechago J. Antral G-cell and D-cell numbers in Helicobacter pylori infection: effect of H. pylori eradication.Gastroenterology. 1993; 104: 1655-1660PubMed Google Scholar, 14Odum L Petersen HD Andersen IB Hansen BF Rehfeld JF. Gastrin and somatostatin in Helicobacter pylori infected antral mucosa.Gut. 1994; 35: 615-618Crossref PubMed Google Scholar Thus, in patients with H. pylori infection limited to the antrum, the negative feedback inhibition of gastrin release is attenuated, resulting in higher postprandial gastrin levels and hypersecretion of acid. Despite the existence of meal-induced hyperchlorhydria in DU patients, the presence of food in the stomach has a buffering effect that may protect the gastroduodenal mucosa from acid-induced injury. However, at night and during other prolonged periods of fasting, acid bathes the "bare" mucosa, and in DU patients, the increase in nocturnal acid secretion magnifies this effect. Duodenal bicarbonate secretion also appears to be impaired in patients with DU,15Isenberg JI Selling JA Hogan DL Koss MA. Impaired proximal duodenal mucosa bicarbonate secretion in patients with duodenal ulcer.N Engl J Med. 1987; 316: 374-1379Crossref PubMed Google Scholar as well as in those infected with H. pylori, making the mucosal exposure to acid even greater. These observations, as discussed below, form the rationale for single nocturnal dosing of H2-receptor antagonists in the treatment of DU, a mode of therapy that is at least as effective as multiple dosing regimens. Clearly, factors other than acid and pepsin are involved in the pathogenesis of peptic ulcer disease (PUD), because only 30% of patients with DUs and very few patients with GUs are hyperchlorhydric.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar The balance between aggressive factors that act to injure the gastroduodenal mucosa and defensive factors that normally protect against corrosive agents is also important. When this delicate balance is disrupted for any reason, mucosal injury may ensue.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar These defensive properties appear to be mediated to a large extent by endogenous prostaglandins, nitric oxide, and trefoil proteins, and when the synthesis of any or all are diminished, the ability of the gastroduodenal mucosa to resist injury is decreased. Thus, even normal rates of acid secretion may be sufficient to injure the mucosa and produce gastroduodenal ulcers. Nevertheless, even in DU patients who are normal secretors of acid, a reduction in the rate of acid secretion is the most efficient means of healing ulcers.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Although a large number of gastroduodenal ulcers are associated with H. pylori infection, at least 60% of individuals with complicated ulcers (e.g., hemorrhage or perforation) report the use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin.16Wolfe MM Lichtenstein DR Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.N Engl J Med. 1999; 340: 1888-1899Crossref PubMed Scopus (1372) Google Scholar Mucosal injury associated with NSAID use is initiated topically by the acidic nature of NSAIDs.17Schoen RT Vender RJ. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage.Am J Med. 1989; 86: 449-459Abstract Full Text PDF PubMed Google Scholar Topical mucosal injury may also occur as a result of indirect mechanisms, mediated through the biliary excretion and subsequent duodenogastric reflux of active NSAID metabolites.18Graham DY Smith JL Holmes GI Davies RO. Nonsteroidal anti-inflammatory effect of sulindac sulfoxide and sulfide on gastric mucosa.Clin Pharmacol Ther. 1985; 38: 65-70Crossref PubMed Google Scholar, 19Carson JL Strom BL Morse L West Sl Soper KS Stolley PD Jones JK. The relative gastrointestinal toxicity of the nonsteroidal anti-inflammatory drugs.Arch Intern Med. 1987; 147: 1054-1059Crossref PubMed Google Scholar Topical injury caused by NSAIDs certainly contributes significantly to the development of gastroduodenal mucosal injury, but the systemic effects of these agents appear to play the predominant role,17Schoen RT Vender RJ. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage.Am J Med. 1989; 86: 449-459Abstract Full Text PDF PubMed Google Scholar, 20Soll AH Weinstein WM Kurata J McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.Ann Intern Med. 1991; 114: 307-319Crossref PubMed Google Scholar, 21Needleman P Isakson PC. The discovery and function of COX-2.J Rheumatol. 1997; 24: 6-8PubMed Google Scholar largely through the decreased synthesis of mucosal prostaglandins.22Lanza FL Royer GL Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa.N Engl J Med. 1980; 303: 136-138Crossref PubMed Google Scholar Avoidance of topical mucosal injury by enteric-coated aspirin preparations22Lanza FL Royer GL Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa.N Engl J Med. 1980; 303: 136-138Crossref PubMed Google Scholar or by the parenteral23Lanza FL Karlin DA Yee JP. A double-blind placebo controlled endoscopic study comparing the mucosal injury seen with orally and parenterally administered nonsteroidal analgesic ketorolac tromethamine at therapeutic and supratherapeutic doses.Am J Gastroenterol. 1987; 82: 939Google Scholar or rectal24Henry D Dobson A Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs.Gastroenterology. 1993; 105: 1078-1088Abstract PubMed Google Scholar administration of NSAIDs does not prevent the development of ulcer complications. Moreover, doses of aspirin as low as 10 mg are sufficient to significantly suppress gastric mucosal prostaglandin synthesis.25Cryer B Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans.Gastroenterology. 1999; 117: 17-25Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar A decrease in the above protective mechanisms normally stimulated by prostaglandins enables endogenous gastric acid to incite mucosal injury. In recent years, it has become evident that the actual percentage of ulcers associated with H. pylori may not be 90%–95% as often reported, but may be as low as 32% in non-referral-based populations.26Kurata JH Nogawa AN. Meta-analysis of risk factors for peptic ulcers.J Clin Gastroenterol. 1997; 24: 2-17Crossref PubMed Scopus (174) Google Scholar Furthermore, despite the inclination to ascribe the etiology of ulcers in such individuals to NSAIDs, the use of these agents clearly does not account for the balance of the cases. Finally, the vast majority of remaining individuals do not have the Zollinger-Ellison syndrome (ZES) or another unusual cause of gastroduodenal ulcer. Thus, while peptic ulceration involves the participation of several factors, as first stated by Karl Schwarz27Schwarz K. Über penetrierende magen-und jejunalgeschwüre.Beitr Klin Chirurgie. 1910; 5: 96-128Google Scholar in 1910: "Ohne sauren Magensaft, kein peptisches Geschwür," i.e., "No acid, no ulcer." The erosive properties of acid continue to play a central role in the pathogenesis of gastroduodenal mucosal ulceration, and conversely, acid suppression therapy remains the cornerstone of therapy. Although the principal aggressive factor involved in causing heartburn and the other clinical manifestations of GERD is the presence of acid in the esophagus, the disorder does not usually result from the hypersecretion of gastric acid.28Hirschowitz BI. A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis.Gastroenterology. 1991; 101: 1149-1158PubMed Google Scholar Rather, GERD occurs as a result of several abnormalities in motor function of the lower esophagus and the lower esophageal sphincter (LES). Despite the etiologic role played by these important motor abnormalities, the severity of symptoms, most notably heartburn, and esophageal mucosal injury can be correlated with the total time that the esophageal mucosa is exposed to acid. Gastric acid thus also constitutes a critical element in the pathogenesis of GERD, and acid suppression comprises the principal mechanism for therapy. However, the optimal timing and degree of acid suppression differ significantly in GERD patients compared with the treatment of gastroduodenal ulcer (see below). Many terms have been used to describe this entity, including stress ulcer syndrome, stress gastritis, stress-related mucosal disease, and stress-related erosive syndrome (SRES).29Lucas CE Sugawa C Riddle J Rector F Rosenberg B Wah AJ. Natural history and surgical dilemma of "stress" gastric bleeding.Arch Surg. 1971; 102: 266-273Crossref PubMed Google Scholar, 30Goldin GF Perra DA. Stress-related mucosal damage. What to do or not to do.Gastrointest Clin North Am. 1996; 6: 505-526PubMed Google Scholar The principal feature of SRES is its relationship to serious systemic disease, such as sepsis, massive burn injury, head injury associated with increased intracranial pressure, severe trauma, and multiple-system organ failure. A meta-analysis of 2252 patients by Cook et al.31Cook DJ Fuller HD Guyatt GH Marshall JC Leasa D Hall R Winton TL Rutledge F Todd TJR Roy P LaCroix J Griffith L Willan A. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian critical care trials group.N Engl J Med. 1994; 330: 377-381Crossref PubMed Scopus (474) Google Scholar identified mechanical ventilation and coagulopathy as the 2 singlemost important risk factors. Although the pathophysiology is multifactorial and definitely includes a component of ischemia, which compromises gastric mucosal integrity, luminal acid plays a dominant role in producing the multiple erosive lesions characteristic of the entity. Fiddian-Green et al.32Fiddian-Green RG McGough E Pittenger G Rothman E. Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration.Gastroenterology. 1983; 85: 613-620PubMed Google Scholar emphasized the importance of H+ ion back-diffusion by demonstrating a high correlation between the degree of intramural pH and the development of SRES. Furthermore, most, but not all, methods for preventing massive hemorrhage-associated SRES include the alkalinization of gastric contents.33Wolfe M. Stress-related erosive syndrome. In Current therapy in gastroenterology and liver disease.in: ed Bayless T Mosby-Year Book,, St. Louis1994: 139-143Google Scholar The parietal cell possesses a unique morphology that differs markedly between the resting and stimulated states.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Mitochondria occupy 34% of its cell volume, indicative of the importance of adenosine triphosphate (ATP) synthesis as an energy source required for the active transport of H+ ions out of the cell against a 3,000,000:1 ionic gradient. A large percentage of resting cell volume is also occupied by tubulovesicles, which are elongated tubes with smooth surface membranes, and by the secretory canaliculus, a small invaginated area of the apical membrane. Upon stimulation, which is generally accomplished by eating a meal, the tubulovesicles decrease in number and become transformed into microvilli around the secretory canaliculus, which serves to greatly expand the surface area of the parietal cell in preparation for the secretion of large quantities of HCl. The parietal cell also possesses several different receptors for stimulatory and inhibitory ligands on its basolateral membrane (Figure 1). The histamine receptor belongs to a large family of G protein-linked receptors possessing 7 transmembrane domains.34Ganz I Schaeffer M Del Valle J Logsdon C Campbell V Uhler M Yamada T. Molecular cloning of a gene encoding the histamine H2-receptor.Proc Natl Acad Sci USA. 1991; 488: 429-433Crossref Scopus (104) Google Scholar Despite the recognition that histamine stimulates gastric acid secretion, it was not until 1966, when Ash and Schield35Ash A Schild H. Receptors mediating some of the actions of histamine.Br J Pharmacol. 1996; 27: 427-439Google Scholar described H1 and H2 receptors for histamine, that the possibility of inhibiting acid secretion with histamine antagonists was proposed. In 1970, Black et al.36Black JW Duncan WAM Durant CJ Ganellin CR Parsons ME. Definition and antagonism of histamine H2 receptors.Nature. 1972; 236: 385-390Crossref PubMed Scopus (439) Google Scholar described selective histamine H2-receptor inhibition and initiated the search for pharmacological agents that could effectively suppress the secretion of acid. Within 10 years of the release of cimetidine in the United States in 1977, 3 additional H2-receptor antagonists—ranitidine, famotidine, and nizatidine—became available for use throughout the world. All 4 drugs (Figure 3) suppress basal and meal-stimulated acid secretion, albeit to a lesser degree than proton pump inhibitors (PPIs) discussed below. Despite similar therapeutic profiles, some differences do exist with regard to the agents' pharmacokinetic properties (Table 1), most of which are clinically insignificant.37Lichtenstein DR Wolfe MM. Histamine H2-receptor antagonists. In Gastrointestinal pharmacotherapy.in: ed Wolfe MM Saunders,, Philadelphia1993: 47-84Google Scholar The elimination of these drugs occurs by a combination of hepatic metabolism and urinary excretion, and although hepatic dysfunction does not alter their pharmacokinetic properties, dose reductions are recommended for all individuals with varying degrees of renal impairment (Table 2).37Lichtenstein DR Wolfe MM. Histamine H2-receptor antagonists. In Gastrointestinal pharmacotherapy.in: ed Wolfe MM Saunders,, Philadelphia1993: 47-84Google Scholar H2-receptor antagonists as a class possess an unsurpassed safety record, and in 1995 became available for use in the United States without prescription. aTable 1.Comparison of the Histamine H2-Receptor AntagonistsCimetidineRanitidineFamotidineNizatidineBioavailability (%)80504070Relative potency15–10325–10Circulatory t½ (h)1.5–2.31.6–2.42.5–41.1–1.6Biological t½aaApproximate values. (h)68128Relative effect on cytochrome P450 metabolism10.100t½, half-life.Adapted and reprinted with permission.37Lichtenstein DR Wolfe MM. Histamine H2-receptor antagonists. In Gastrointestinal pharmacotherapy.in: ed Wolfe MM Saunders,, Philadelphia1993: 47-84Google Scholara aApproximate values. Open table in a new tab aTable 2.Histamine H2-Receptor Antagonist Dosing Adjustments With Renal InsufficiencyDrugCreatinine clearance (mL/min)Dose (mg/day)aaDosing for gastroduodenal ulcer.Cimetidine>3080015–30600 7530030–7522515–30150 754030–753015–3020 7530030–7522515–30150<1575Adapted and reprinted with permission.37Lichtenstein DR Wolfe MM. Histamine H2-receptor antagonists. In Gastrointestinal pharmacotherapy.in: ed Wolfe MM Saunders,, Philadelphia1993: 47-84Google Scholara aDosing for gastroduodenal ulcer. Open table in a new tab t½, half-life. Adapted and reprinted with permission.37Lichtenstein DR Wolfe MM. Histamine H2-receptor antagonists. In Gastrointestinal pharmacotherapy.in: ed Wolfe MM Saunders,, Philadelphia1993: 47-84Google Scholar Adapted and reprinted with permission.37Lichtenstein DR Wolfe MM. Histamine H2-receptor antagonists. In Gastrointestinal pharmacotherapy.in: ed Wolfe MM Saunders,, Philadelphia1993: 47-84Google Scholar The central nervous system, particularly via the vagus nerve, plays a dominant role in regulating basal acid secretion, as well as the cephalic phase of meal-stimulated acid secretion. Extracts of belladonna were used to treat dyspepsia since the time of the Roman empire, and in the recent past, nonspecific antimuscarinic agents such as atropine and propantheline bromide were used as inhibitors of gastric acid secretion. These drugs were associated with many adverse effects, including drowsiness, dry mouth, blurry vision, and urinary retention, and as a result are rarely used today. To date, however, 5 muscarinic receptors have been subtyped and cloned, and although all are G protein coupled, they signal different intracellular pathways. In vitro characterization of gastric acid secretion has indicated that the parietal cell normally expresses the M3 subtype.38Kajimura M Reuben M Sachs G. The muscarinic receptor gene expressed in rabbit parietal cells is the M3 subtype.Gastroenterology. 1992; 103: 870-875PubMed Google Scholar Clinically, the M1 antagonists, pirenzepine and telenzepine, are effective inhibitors of acid secretion and probably exert their effect by interaction with a postsynaptic neuronal M1 receptor.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar These 2 agents are available in other countries for the treatment of duodenal ulcer, but they have not been approved for use in the United States. As stated above, gastrin stimulates acid secretion via an endocrine pathway and induces H+ ion generation both directly and indirectly. The precise location and density of the gastrin receptor have been subjects of debate and may be somewhat species dependent. Several studies in rats and other rodents have suggested that gastrin stimulates acid secretion by enhancing the release of histamine from ECL cells.39Håkanson R Böttcher G Ekblad F Panula P Simonsson M Dohlsten M Hallberg T Sundler F. Histamine in endocrine cells in the stomach.Histochemistry. 1986; 86: 5-17Crossref PubMed Scopus (158) Google Scholar, 40Prinz C Kajimura M Scott DR Mercier F Helander HF Sachs G. Histamine secretion from rat enterochromaffin-like cells.Gastroenterology. 1993; 105: 449-461Abstract PubMed Scopus (279) Google Scholar Conversely, receptors for gastrin receptors on canine parietal cells have been demonstrated by Soll et al.41Soll AH Amirian DA Thomas LP Reedy TJ Elashoff JD. Gastrin receptors on isolated canine parietal cells.J Clin Invest. 1984; 73: 1434-1447Crossref PubMed Google Scholar by employing the analogue 125I-[Leu15]gastrin, and by Kopin et al.,42Kopin AS Lee YM McBride EW Miller LJ Lu M Lin HY Kolakowski Jr, LF Beinborn M. Expression cloning and characterization of the canine parietal cell gastrin receptor.Proc Natl Acad Sci USA. 1992; 89: 3605-3609Crossref PubMed Google Scholar who cloned and expressed the gastrin receptor from a purified canine parietal cell complementary DNA library. Moreover, single-cell video imaging has provided direct evidence for a functional gastrin receptor on the parietal cells of rats and rabbits.43Geibel J Abraham R Modlin I Sachs G. Gastrin-stimulated changes in Ca2+ in individual, acid-secreting rat parietal cells.Biochem Biophys Res Commun. 1992; 183: 1097-1102Crossref PubMed Google Scholar The gastrin receptor belongs to the above-mentioned family of G protein-linked receptors possessing 7 transmembrane domains.42Kopin AS Lee YM McBride EW Miller LJ Lu M Lin HY Kolakowski Jr, LF Beinborn M. Expression cloning and characterization of the canine parietal cell gastrin receptor.Proc Natl Acad Sci USA. 1992; 89: 3605-3609Crossref PubMed Google Scholar It is closely related to the receptor for cholecystokinin ("CCK-A" or "CCK-1") and is thus often referred to as the "CCK-B" or "CCK-2" receptor. Gastrin-specific receptor antagonists have been developed, which include L365,260 and YM022.44Lotti VJ Pendleton RG Gould RJ Hanson HM Chang RSL Clineschmidt BV. In vivo pharmacology of L-364,718, a new potent nonpeptide peripheral cholecystokinin antagonist.J Pharmacol Exp Ther. 1987; 241: 103-109PubMed Google Scholar The former is a benzodiazepine derivative that was derived from the fungus Aspergillus alliaceus and has been demonstrated to effectively antagonize gastrin-stimulated gastric acid secretion.44Lotti VJ Pendleton RG Gould RJ Hanson HM Chang RSL Clineschmidt BV. In vivo pharmacology of L-364,718, a new potent nonpeptide peripheral cholecystokinin antagonist.J Pharmacol Exp Ther. 1987; 241: 103-109PubMed Google Scholar Despite this effect, these antagonists have not been used clinically as inhibitors of acid secretion. However, they may ultimately prove useful in the treatment of panic and anxiety disorders by virtue of binding to gastrin receptors in the brain.45Pande AC Greiner M Adams JB Lydiard B Pierce MW. Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder.Biol Psychiatry. 1999; 46: 860-862Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Other receptors on the parietal cell basolateral membrane have been suggested by the ability of various agents to inhibit gastric acid secretion. For example, prostaglandins inhibit H+ ion generation by binding to their EP3 G protein-linked receptor on the parietal cell, which appears to inhibit adenylate cyclase, and thereby decrease intracellular cAMP generation when activated.46Chen MC Amirian DA Toomey M Sanders MJ Soll AH. Prostanoid inhibition of canine parietal cells: mediation by the inhibitory guanosine triphosphate-binding protein of adenylate cyclase.Gastroenterology. 1988; 94: 1121-1129Abstract PubMed Scopus (101) Google Scholar As discussed below, the acid-inhibitory properties of prostaglandin analogues such as misoprostol, while not potent, are nevertheless critical for exerting any beneficial clinical effects.16Wolfe MM Lichtenstein DR Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.N Engl J Med. 1999; 340: 1888-1899Crossref PubMed Scopus (1372) Google Scholar The gastric enzyme H+,K+-adenosine triphosphatase (ATPase) is a member
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