Pharmacological control of gastric acid secretion: molecular and cellular aspects.

Bioscience Reports, VoL !2, No. 5, I992

REVIEW

Pharmacological Control of Gastric Acid Secretion" Molecular and Cellular Aspects Ladislav Mirossay, ~ Yolande Di Gioia, Eric Chastre, Shahin Emami, and Christian Gespach 2 Received ls~ version December 6, 1991; revised version May 20, 1992 KEY WORDS: gastric acid secretion; growth factor; harmone; receptor-signal transduction.

INTRODUCTION Chronic ulceration of the gastroduodenal mucosa is one of the most common, so called "civilization diseases" of the gastrointestinal tract in industrially developed countries. Although the primary cause of gastric and duodenal peptic ulcers is unknown, gastric acid secretion is believed to play an important role in this major pathology. Gastric peptic ulcers, which represent 20% of all peptic ulcers (472) are mostly located in the antrum adjacent to the border of the acid producing fundic mucosa. Epidemiologically, gastric cancer is not reported to be increased in gastric ulcer disease. However, gastric endocrine cell hyperplasia and gastric carcinoid tumors have been described in two naturally occurring hypergastrinemic states, gastric atrophy with achlorhydria and Zollinger~Ellison syndrome (44, 45, 64, 363,408). Many hormones, growth factors, and local bioregulators are able to influence gastric secretions and to induce the ulcerogenic cascade or to preserve the integrity of the mucosa. This paper analyses different aspects of the molecular and genetic mechanisms involved in the pathophysiology of gastric secretions. At the same time it describes the complex interconnections between the signal transduction systems implied in the regulation of the secretory activity of parietal cells, and adjacent mucosal cells. Particular reference is focused on the development of the histamine H 2 receptor antagonists and the H +, K+-ATPase inhibitors in the treatment of peptic ulcer disease. Institut National de ia Sant6 et de la Recherche M6dicale INSERM U. 55, Unit6 de Recherches stir les Peptides Neurodigestifs et le Diab~te, H6pital Saint-Antoine, 75571 Paris Cedex 12. France. Present address: Department of Pharmacology, Medical Faculty, P. J. Safarik University, Tr. SNP 1, 04001 Kosice, Czechoslovakia. z To whom all correspondence should be addressed, at INSERM U55. 319

0144-8463/92/1000-0319506,50/0 9 i992 PlenumPublishingCorporation

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Mirossay, Di Gioia, Chastre, Emami and Gespach PATHOPHYSIOLOGICAL BASIS

Gastric glands as a part of the lamina propria, which constitutes a vascularized and innervated conjunctive network, are divided into three sections. The crypt is composed of mucus cells in the antrum and of chief cells (pepsin-secreting cells), mucous and acid- secreting parietal cells in the fundus. The collar neck, also named isthmus, is composed of immature cells which can differentiate and rapidly renew the gastric mucosa (205,238-241). The pit cells or surface mucous cells, originate from this zone and migrate upwards, towards the mucosal surface while the other three types of cells migrate towards the base of the gland. The time required for the newly formed cells to reach the lower end of the gland varies between one hundred and three hundred days. On the other hand, several authors have reported evidence that the chief cells are able to divide, indicating that its renewal is assured by its own mitotic activity. In the mouse, the turnover time for the isthmal cells was estimated to be 16 h, while the renewal time of pit cells was assessed at 3 days in the pyloric antrum (238). The origin of gastric endocrine cells is still a matter of debate. The original A P U D hypothesis (amine precursor uptake and decarboxylation) postulated that some mucosal cells might constitute a separate lineage, derived from the neural crest after migration of the endocrine precursor cells. In this precedent terminology, A P U D cells have the capacity to capture histamine and serotonin precursors, (i.e. histidine and 5-hydroxytryptophane, respectively) and to convert them to bioamines by the action of histidine decarboxylase and DOPAdecarboxylase (228, 445). However, observations of differentiation patterns in cancer and embryological studies indicate that the gut endocrine cells are of endodermal origin, as are the other gastrointestinal epithelial cells. Recent studies have clearly demonstrated the proliferative activity of gastrin and somatostatin cells in the stomach (242). The cells constituting the gastric mucosa are, therefore, a fairly heterogeneous population in terms of proliferation activity and functional differentiation. The gastric epithelium assume a vital protective function since the repair of chemically induced gastric epithelial injury is completed in 30-60 rain by active migration of surviving cells (205). The growth of the gastric mucosa in hypophysectomized rats is partially restored by growth hormone (GH), suggesting atrophic role for G H in the upper gastrointestinal tract and regulation of pepsinogen secretion in gastric glands (254). While it is now recognized that histamine plays a central role in the regulation of acid secretion, the diversity of effectors that can elevate or diminish intragastric pH must also be considered. In man and rodents, histamine of the gastric mucosa is stored in ECL-type enterochromaffin endocrine cells, previously designated histaminocytes (338). In various animal species and human stomach, histamine also accumulates in the mastocytes (mast cells) of the lamina propria, which lie close to the tubular Structures of the mucosa (26,228). The localization of histamine in the human gastric mucosa occurs in two separate cell populations: endocrine ECL cells, restricted to the oxyntic gland area, and mast cells, disseminated throughout the wall of the antrum as welt as in the body of the stomach (255,256). Mucosal cells with hormonal or paracine activity, the

Pharmacological Control of Gastric Acid Secretion

32'.[

myenteric plexus, and the nerve endings in the smooth muscle layer and submucosa contain somatostatin, gastrin releasing peptide (GRP), vasoactive intestinal peptide (VIP), the human peptide HM with N-terminal histidine and a C-terminal methionine amide (PHM), serotonin in gastric EC cells, tachykinins, and enkephalins (107, 120, 201, 256, 416, 461). Corresponding to these bioamines, hormones and neuropeptides a set of specific receptors regulate exocrine and endocrine secretions in the stomach, as well as gastric emptying (151,160, 359,360). Digestive secretions are regulated by numerous substances, hormones and neurotransmitters, which act through the circulatory system or which are secreted in the interstitial fluid. Paracrine and neuroparacrine regulations involve a single cell or nerve fiber which release their contents in the vicinity of the neighboring effector cell (Fig. 1). For example, the somatostatin-producing D cells have long,

? H+

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EPSIN B I

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A T E

Fig. 1. Hormonal, paracrine and autocrine regulations of gastric secretion. Mast cells (MC) and ECL histaminocytes induce the release of gastrin by antral and duodenal G ceils. Acidification of the intestinal lumen results in secretin release by duodenal secretin S cells and induction of somatostatin release by gastric D cells. Adrenergic (ADR), cholinergic (ACH) or VIPergic neurones regulate endocrine and exocrine secretions by the gastric mucosa. Autocrine activity of prostaglandins (PG) in parietal cells (H+), chief cells (pepsin), and mucous cells participates on this process. (+) and ( - ) : stimulatory and inhibitory effects, respectively.

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Mirossay, Di Gioia, Chastre, Emami and Gespach

nonluminal cytoplasmic processes which establish direct contacts with parietal cells, gastrin (G) cells, and histaminocytes in human and rat gastric epithelium (468). In the fundus, somatostatin secretion is regulated indirectly by gastrinreleasing peptide (GRP), via stimulatory noncholinergic neurons and inhibitory cholinergic neurons (389). In the antrum, GRP acts indirectly on somatostatin cells by stimulating gastrin release and by activating inhibitory cholinergic neurons. In autocrine regulation, the effector cell itself synthesizes or sequesters a product capable of modulating its own function. This is an auto-regulation phenomenon: the prostaglandins (PGs) and the prostacyclins (PGI) are synthesized by parietal cells and surface muciparous cells (283, 332, 405). These metabolites of arachidonic acid contribute to the protection of the mucosa by inhibiting both acid secretion and the activity of the He receptor, which is coupled to adenylate cyclase (AC) in the parietal cells. PGs exert an antisecretory effect via specific PG receptors coupled to Gi (19, 121,268,395). The G proteins serve as intermediaries between activated membrane receptors and their effector enzymes and/or ion channels. The o: subunit of Gi mediates inhibition of adenyl cyclase (vide infra). However, the protective effect of PG on gastric mucosa was observed not to be strictly dependent on the inhibition of gastric acid secretion. It was named cytoprotection, as the property of certain agents to protect the gastric mucosa and the epithelial lining, independently of an anti-secretory effect: mucus secretion, bicarbonate ions, renewal of the surface epithelium, repair, and control of the retrodiffusion of H § ions. The PGs are thus likely to regulate acid secretion, as well as the secretion of bicarbonates and mucus, by acting on the autocrine and paracrine pathways and peripheral circulation. An inhibitory role of PG on acid secretion has been demonstrated after intracisternal injection of PGE2 or its stable analogue 16,16-dimethyl PGE2 in the rat brain (374). By contrast, centrally administered neuropeptide Y (NPY) stimulated gastric acid and pepsin secretions in anesthetized rats (281). While the effect of PGs on gastric acid secretion is quite well defined, the action of leukotrienes (LTs) on the secretory processes in gastric mucosa is controversial. In isolated rabbit fundic glands LTC4 inhibited acid formation in response to histamine and dibutyryl cAMP (264). In contrast, LTC4, LTD4 and LTE4 increased basal, as well as histamine- and carbachol-stimulated acid production in isolated rabbit nmcosal cells (264). In preparations of enriched rat parietal cells, Schepp et al. (1989) observed no effect of either LTC4 or LTD4 on basal acid production. However, they found significant increase in H § formation in prestimulated rat parietal cells (380). The occurrence of platelet activating factor (PAF, paf-acether, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) in glandular gastric mucosa also indicated autocrine and paracrine actions for this phospholipid mediator in the gastrointestinal tract, a family including prostaglandins, leukotrienes and lipoxins (124,421). It has been demonstrated that PAF is formed from membrane phospholipids by phospholipase Ae and causes the release of other mediators such as tumor necrosis factor a; (TNFo:), leukotriene C4 and norepinephrine during bowel necrosis (198,423). In the gastrointestinal tract, PAF is a potent ulcerogenic factor and stimulates aminopyrine uptake, as an index of H + accumulation, by isolated guinea pig parietal cells (315). The PAF


3~

receptor from guinea pig lung belongs to the G protein-coupled receptors, vide infra (195). Several products are secreted into the lumen by the salivary glands and the gastric mucosa or are derived from milk and digested food. Examples include epidermal growth factor (EGF), transforming growth factor o~ (TGF~), bradykinin, kininogens, triiodothyronine, parathyroid hormone-related peptide, neurotensin, pro-,/-melanotropin, colony stimulating factor, calcitonin- and gastrin releasing peptide (GRP)-like peptides, prolactin, gastrin, somatostatin, PG, morphiceptin, fi-endorphin, c~-melanocyte stimulating hormone (c~-MSH), and caseinomacropeptide (109, 125, 314, 316, 398, 404, 426, 433,458, 463). Milk products, digestive products and mucosal secretions can regulate acid secretion, gastrointestinal motility or exert their trophic effects on different segments of the digestive tract via the luminal fluid and specific mucosal receptors, for instance opioid receptors activated by fl-casomorphins (70, 90, 94, 151, 171). The microvascnlarization system in gastric gland also participates in the control of stomach secretory activity and gastric mucosal protection (136, 137, 191). Histamine receptors are involved in the microvascular permeability to macromolecules, the reduction of blood flow by vasoconstrictio~ via the H~ receptors, and the increase in blood flow and acid secretion via the H2 receptors (69, 85, 191, 276, 303, 304). The increase of gastric mucosal blood flow may be the principal mechanism of protective effect of some gastroprotective agents. For example, intragastric administration of capsaicin protects against ethanol-induced rat gastric mucosal lesions (330). The effect of capsaicin seems to be mediated by stimulation of afferent sensory nerve endings followed by local release of neuropeptides (193). Since it was shown that substance P induces endotheliumdependent vasodilation (132) it is likely that these neuropeptides could in turn release nitric oxide (NO). Finally, it is possible that NO is involved in capsaicin-induced gastric protection by increasing blood flow (194). The catcitonin gene-related peptide is also abundantly distrubuted in the capsaicin-sensitive afferent innervation of the rat stomach, and may contribute to the protective effects produced by acute administration of capsaicin on gastric acid secretion. As shown in Fig. 1 and 2, the secretory activity of the parietal celt is controlled by three principal effectors which can act in synergy (57, 160). 1) Histamine activates Ha receptors, which are coupled to adenylate cyclase via G proteins (25, 103, 172, 268) and to intracellular caldum (309, 310) 2) Cholecystokinin (CCK) and gastrin may share the same receptor (409) or may activate two distinct receptors (266) 3) Acetylcholine, which activates cholinergic M2 receptors. These last effectors mobilize cGMP, the inositol cycle, PKC and Ca 2+ in the gastric epithelium (29, 68, 76, 83). Histamine and cAMP activate protein kinases in parietal cells (74, 268). A protein of 80kD, situated at the apical pole, is then phosphorylated and H+/K§ the proton pump, is activated (261,270, 431,442, 443, 464). In the resting celt the proton pump is localized in the membrane of intracellular tubovesicular structures, which undergo remarkable rearrangements when acid secretion is stimulated and may fuse with the apical membrane to form secretory canaliculi (28, 205,288). Histamine and cAMP are also involved in the regulation

324


ion

Fig. 2. Membrane receptors and signaling pathways involved in the regulation of acid secretion by parietal cells.

of glycoprotein synthesis and release of mucous glycoproteins from gastric nonparietal cells (181). This observation is also consistent with the functional expression of H2 receptors in gastric cell fractions enriched in 87% of mucous cells (145). The histaminergic pathway involves a variety of pathophysiological and pharmacological mechanisms in the digestive tract: 1) histamine secretion; 2) its degradation by histamine methyltransferase (HMT); 3) the activation of the H2 receptor transducer system; 4) H2 receptor desensitization and the capture of bioamines by the histaminocyte or the effector cell, 5) control of receptor activation either by drugs or biological regulators of the histaminergic signaling pathway, such as somatostatins and PG (113, 116, 150, 160), and 6) inhibition of gastric acid secretion by both neural and hormonal mechanisms during acidification in the upper small intestine. The hormonal mechanism is mediated by somatostatin and CCK (321). Histamine receptors have been characterized, according to their pharmacological specificity, vis ~ vis selective agonists and antagonists and the transducers that they mobilize (7-9, 36, 104, 156). In the central nervous system, the H3 receptors are autoreceptors which inhibit the biosynthesis and the secretion of histamine by the histaminergic neurones (7). In the periphery, these receptors inhibit acetylcholine secretion in the trachea (199), the tonus of the sympathetic nervous system, causing the vasodilation of the mesenteric artery and the contraction of the guinea pig ileum (438). H~ receptors are coupled to the IP3-Ca 2+ cascade, while the H2 and H2h receptors are coupled to cAMP and to

PharmacologicalControl of Gastric Acid Secretion

325

cGMP, respectively. In contrast, the H 3 receptors are not coupled to adenytate cyclase (153, 156, 160, 204). The localization of the H2 receptors in parietal cells does not exclude a role for histamine in cAMP synthesis nor in the secretion of chief cells and mucus cells at the mucosal surface in the antrum and the fundus (145, 155,366, 386). In the gastrointestinal mucosa the secretion of histamine by mastocytes (MC) (Fig. 1) is induced by pentagastrin, acetylcholine, phorbol esters, calcium and ethanol, whereas it is inhibited by somatostatin, PG and /3-adrenergic receptors (100, 351, 365, 410-413). The histaminergic Ha receptors and the adrenergic 13-receptors are involved in the regulation of both acid and pepsin secretion (41, 98, 185). In the gastric mucosa, tetragastrin induces the secretion of histamine by the histaminocytes (364). Histamine can exert a negative feedback on its own secretion from ECL cells via the histamine H3 autoreceptors (17, 185). Alternatively, the H3 receptor located on parietal cells may regulate in a negative manner the acid secretory processes (17). Although it is now well known that gastrin has its own receptors on the surface of parietal cells, which stimulate acid secretion (352, 412, 413), there is some evidence that this peptide also partly controls the metabolism of histamine in gastric mucosa. It has been shown that gastrin injection increases histidine decarboxylase activity in the guinea pig (30) and pentagastrin induced decrease of histamine content in dog gastric mucosa, accompanied by an increase of histidine decarboxylase activity (259). Pentagastrin administration in humans induces a significant decrease of histamine content in the oxyntic part of the gastric mucosa. This effect if most pronounced in patients with duodenal and gastric ulcers (257). The effect of gastrin and CCK on the secretory activity of the parietal cell seems to be transmitted by two distinct receptors. In vitro, when the agonists act directly on parietal cell receptors, both gastrin and CCK-8 (octapeptide of cholecystokinin) stimulate the acid secretion with the same potency and efficacy in canine parietal cells (409). The same effect was observed on (14C) aminopyrine uptake (an index of H + accumulation in intracellular, intravesicular spaces), and the formation of inositol phosphates in isolated rabbit parietal cells (357). On the other hand, gastrin is a potent stimulator of H + production in vivo, whereas CCK-8 appears as a weak stimulator capable of inhibiting pentagastrin-stimulated acid secretion (91). These effects influence indirectly parietal cell activity and may be explained by the existance of "gastrin-type" CCK receptors on the gastric "non parietal cell" population. Histamine or somatostatin release could be induced after the stimulation of different receptors by gastrin or CCK, respectively (354). By using specific CCK receptor and gastrin receptor antagonists it was concluded that both gastrin (1-17) and CCK (1-33) stimulate histamine and acid secretion by gastrin receptors, and that gastrin stimulates acid secretion by releasing histamine (354,373). On the other hand, the release of somatostatin, which can be stimulated by CCK-8 or gastrin, is very likely controted by the CCK-type receptor (354) (Fig. 1). Some substances like GRP, secretin, carbachol, and cAMP stimulate the secretion of gastrin in normal antral mucosa as well as in the ZoUinger-Ellison syndrome (110,447). Somatostatin inhibits the transcription of the gene encoding gastrin in the mucosa of the gastric antrum (217).

326


Recent biochemical studies, using isolated rabbit parietal cells, suggest that the muscarinic receptor which controls acid secretion in parietal cells appears to be of M3 subtype (244). Of the five muscarinic receptors that have been cloned, the ml, m3 and m5 subtypes are closely related in sequence and appear to be functionally equivalent (42,349). The M3 receptors potently activate PtdIns hydrolysis and stimulate large, rapid, and transient chloride currents by a pertussis toxin- insensitive G-protein pathway (236). The importance of C1currents in gastric acid secretion (414) was confirmed in a recent study using the patch-clamp technique. In apical membranes of isolated rabbit parietal cells, chloride channels were observed in histamine-stimulated acid-secreting cells but not in resting parietal cells treated by cimetidine (369). M2 muscarinic receptors and nicotinic receptors in the gastric epithelium have been previously characterized (105,265,312, 331). Different second messengers effects were observed in their dependence of ligand concentration. Stimulation of M2-muscarinic receptors by 0.1/~M carbachol 1) inhibits the formation of cAMP by activating the Gi subunit of adenylate cyclase and 2) activates phospholipase C ( P L C ) when the carbachot concentration is raised to 3 #M (10, 417). It was shown that the M2 receptors, which couple to a pertussis toxin-sensitive G protein, weakly activatephosphatidylinositol (PtDlns) hydrolysis and stimulate small, delayed and oscillatory chloride channels. Muscarinic acetylcholine receptors possess sequence homology with the mas oncogene (206,475), and may induce oncogenic progression when expressed in immature cells with proliferating activity (166). Interleukin-1, gastric inhibitory peptide (GIP) and the peptides related to pancreatic glucagon (GLP), including glicentin, truncated glucagon-like peptide (TGLP-1), oxyntomodulin and its C-terminal octapeptide, all inhibit acid secretion induced by histamine, pentagastrin, or by a meal in humans (12, 21, 95, 160, 221, 383, 451). Pancreatic glucagons (G-29), oxyntomodulin, and TGLP-1 stimulate the production of cAMP in the human gastric cell line HGT-1 (Fig. 2) and in isolated rat gastric glands (21, 143, 147, 152, 170). As a function of the ligand concentration (0.25 or 6 nM), G-29 can successively mobilize PLC and the inositol cycle, by the intermediary of glucagon GR1 receptors, and AC by the glucagon GR2 receptors (450). Glucagons thus have a twofold cytoprotective role. They inhibit acid secretion, by a mechanism which controls the gastrindependent activation of PLC and of IP3 in the parietal cell (Fig. 2), and also cause the release of mucus from surface epithelial cells in the gastric mucosa, via cAMP. In humans and in rat, G-29 activates adenylate cyclase in partially purified parietal cells. This paradoxical effect (143,291,382) may be explained by a role played glucagons on the metabolism of the parietal cell, which consumes both ATP and oxygen in large quantities (143). This last mechanism is under the control of somatostatin. Similar results were obtained by Schmidtler et al. (384) who showed that TGLP-1 and its variants exerted a direct stimulatory effect on H + production in isolated rat parietal cells. The effect of these peptides was mediated by a cAMP-dependent regulatory pathway, but independent of H2 receptors. The stimulation of acid secreting cells by TGLP-1 was not observed in vivo. T h e direct effect of this peptide might be counterbalanced by indirect inhibitory mechanisms which are excluded under in vitro conditions (384).


327

Certain natural substances, such as the PGs, somatostatins 14 and 28, oxyntomodulin, glicentin, EGF, and the tachykinins inhibit acid secretion by blocking the activation of the histaminergic or gastrin-dependent pathways (21, 119, 120, 148, 223, 329). The calcitonin gene-related peptide (CGRP), as well as vasoactive intestinal peptide (VIP), secretin, acetylcholine, pentagastrin, ~.eukotrienes and EGF induce the secretion and biosynthesis of these natural substances (160, 176,202,224, 320). Somatostatin receptors are coupled to the Gi subunit of adenylate cyclase or to other transduction systems (2, 11, 148, 154, 290, 387). Some evidence exists for the expression of cytosolic somatostatin binding sites activating phosphoprotein phosphatases in the digestive tract (345,346). The molecular cloning of genes encoding two different somatostatin receptors with higher affinity for somatostatin-14 than somatostatin-28, and their tissue-specific distribution has been recently reported by Yamada and his colleagues (469). Still unknown are the internalization and intracellular transport mechanisms for this peptide as well as the physiological roles for the membranous, cytosolic and nuclear somatostatin receptors (46, 345, 346) (Fig. 2). The possibility that somatostatin autoregulates the secretion of gastric epithelium D cells has been suggested by in v i v o experiments in dogs. In humans, the half-life of somatostatin-14 is three rain, whereas that of the somatostatin analogue SMS 201-995 (Sandostatin R) is 60 rain. This drug has thus a potential importance in ulcer treatment when anti-H2 medication is found to be insufficient. Unfortunately, this analogue does not appear to be effective in treating the bleeding that occurs subsequently to a peptic ulcer (78, 148, 151, 154, 155,370). A recent discovery established that VIP causes a weak, transient increase in basal and histamine-stimulated acid secretion and sustained increase in somatostatin secretion. This sustained increase in somatostatin, despite the return of acid secretion to basal levels, indicated that VIP directly exerts a stimulatory and an indirectly inhibitory effect on acid secretion. The indirect effect was mediated by released somatostatin in response to VIP stimulation of nonparietal cells (388), as shown in Fig. 1. The physiological role of catecholamines in acid secretion is still poorly understood. There is a human fi2 adrenergic receptor localized preferentially in the gastric fundus, which is under the control of somatostatin-14 (41). fi adrenergic receptor activation of the parietal cell is coupled to H + secretion in isolated rat gastric glands (60, 160). The stimulation of presynaptic o:2 adrenergic receptors, localized in the vagus, lowers basal gastric acid secretion by inhibiting the release of acetylcholine (72,209,473). This is confirmed by the results of Savola et al. (375) with the highly specific a~2-adrenoceptor agonist, medetomidine. Its action was blocked by atipamezol, a novel 0:~-adrenergic receptor antagonist. The EGF receptors were also identified on isolated gastric glands of guinea pig (126) and basolateral membranes of parietal cells (297). Increase in EGF immunoreactivity and the inhibition of gastric acid secretion during the healing of gastric ulcers, argue for a possible role of EGF in the ulcer healing process (171). PGs and certain peptides when injected into the central nervous system, may indirectly mediate acid secretion, gastric contractibility and alimentary supply

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(183,243,424). This is well established for thyrotropin-releasing hormone (TRH), corticotropin-releasing factor (CRF), and basic fibroblast growth factor (bFGF). Injection of TRH into the central nervous system increases the gastric acid secretion and induces the development of gastric lesions in the rat. Contrarily, intracisternally injected bFGF inhibits the secretion of both gastric acid and pepsin and has a mucosal protective effect through a mechanism involving the central nervous system (318,319). The central application of CRF inhibits gastric acid secretion, motility, and emptying, augments bicarbonate content and confers protection against cold restraint-induced gastric mucosal damage in rats (165). On the other hand, peripheral administration of CRF does not enhance alkaline secretion and is not able to inhibit acid-induced villous damage in duodenum (246). Acid secretion is thus integrated into an extremely complex regulatory network (Fig. 1 and 2), in which stimulations, inhibitions, and potentializations all intervene (35,289). The occurrence of these processes depends on chronological factors and on the coordination between agressive digestive secretions (acid, proteases, lipases) and those that are protective (water, bicarbonate, mucus). The integrity of the mucosa is directly linked to the repair systems of the protective barrier and to the healing and rapid renewal of gastric epithelial cells, which are themselves dependent on growth factors and on genes controlling cellular proliferation and differentiation.

RECEPTOR-SIGNAL TRANSDUCTION Biological substances regulate cellular activity via cell surface, cytoplasmic, and nuclear membrane receptors. There are at least five principal pathways which allow information to be communicated by the receptor- signal transduction systems: 1) adenylate cyclase and guanylate cyclase (GC); 2) the IP3-calciumdiacylglycerol-protein kinase C; 3) phospholipase A2; 4) the tyrosine kinases; and 5) the calcium channel-coupled receptors.

Cyclic AMP- and Cyclic GMP-Dependent Regulatory Pathways Three types of mammalian particulate adenylate cyclases have been biochemically distinguished and isolated from various tissues: a brain-specific, calmodulin-sensitive form (type I), a calmodulin-insensitive form identified in brain and lung (type II), and an olfactory-specific, calmodulin-activated cyclase (18). Particulate adenylate cyclases are regulated by G proteins, but the soluble form is independent of these regulatory proteins (427). The general structure of adenylate cyclase resembles those of membrane channels, leading to the speculation that these transmembrane proteins might have dual roles, as both enzymes and transporters. The particulate, calmodulin-sensitive adenylate cyclase from bovine brain has been found to have 1134 aminoacid residues with both the N- and C-terminal ends being intracellular. Its sequence consists of two large hydrophobic and two large hydrophilic domains. Each hydrophobic domain


329

consists of 6 putative transmembrane spans which are interconnected by short, alternatingly extracellular and intracellular, hydrophobic sequences. The hydrophobic domains themselves are connected at the intracellular side, by one of the large (43 kD) hydrophilic domains (226). The cloning and characterization of a type IV adenylate cyclase has been recently described. It is insensitive to calmodulin and appears to be widely distributed (140). Adenylate cyclase activity is regulated after receptor stimulation by two regulatory subunits (Fig. 3). One of the regulatory subunits has a stimulatory effect (Gs) on the formation of cyclic AMP (cAMP), while the other has an inhibitory effect (Gi) on this process (187,358). The binding of ligand to its receptor exerts a stimulatory effect on the coupling reaction between the receptor cytoplasmic domain and Gs, a heterotrimer composed of o6 fi and 7 subunits. This coupling process is followed by increased exchange of bound GDP for GTP on the G protein. The excess of G-GTP protein complex allows the Gcr-GTP subunit to dissociate from the fi, 7 dimer. The Gsoc-GTP complex subsequently activates the catalytic subunit of adenylate cyclase, while the inhibitory activity of

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Fig. 3. Activation of adenylate cyclase (AC) via the histamine H2 receptor and the Gs subunits ols, fi, and y.

330


Gia~ is weakened. The /~, y dimer of Gi is predominantly responsible for adenylate cyclase inhibition (227). There exist three different y subunits isoforms: y1, y2, y3, each encoded by three distinct genes. The o~subunits can be grouped into four distinct classes (248,420). The activity of adenylate cyclase catalytic subunit remains unchanged as long as GTP is not hydrolyzed. The intrinsic GTP-ase activity terminates the signal. Breakdown of GTP to GDP at the Gc~ nucleotide binding site causes the release of Gol-GDP, restoration of the or, /3, y trimer, and restitution of basal level of adenylate cyclase activity. This cycle is generally followed by all naturally occurring ligands, except the diterpene forskolin, which directly activates adenylate cyclase in the absence of Gs (394). Cell surface receptor activation and adenylate cyclase stimulation induce subsequent cAMP accumulation and cAMP-dependent protein kinase (PKA) activation (74). In the resting cell, PKA forms a heterotetramer which is catalytically inactive. The regulatory subunit (PKA-R) liberates two catalytic subunits (PKA-C) after cAMP-binding. Two PKA-C monomers are then capable of phosphorylating a large number of cellular proteins, whereas PKA-R conserves its dimeric form. Mammalian tissues contain two categories of PKA regulatory subunits: type I and type II. Several isoforms of each PKA-R have been cloned. PKA-RIo: and PKA-RIIol are expressed in most cells (237,393), while the expression of PKA-RI/3 and PKA-RII/3 is more tissue-dependent (79,207). An inverse relationship was observed between types I and II isoform expression during ontogenic development, cell differentiation, and neoplastic transformation. It has been proposed that PKA-RI overexpression is responsible for the augmentation of cellular growth and malignancy, whereas the elevation of cellular levels of PKA-RH isoenzyme is associated with tissue differentiation and growth arrest (77). The activation and inhibition of PKA by histamine and its antagonists mimic the functional characteristics and the pharmacological specificity of H2 receptors (151). Cyclic AMP is hydrolyzed to adenosine monophosphate by a phosphodiesterase (PDE), localized either in the cytosol or in the membrane. Multiple forms of PDE with distinct properties are present in mammalian tissues. The unique among them is the PDE II isoenzyme family, because of its cGMP-induced ability to hydrolyse cAMP (459). Guanylate cyclases exists both in cytosolic and particulate forms (141,390). The membrane-bound guanylate cyclase appears to span the membrane bilayer as a single polypeptide chain, with an intracellular catalytic domain and an extracellular binding domain for the series of atrial natriuretic peptides. Recently, an endogenous activator of the intestinal guanylate cyclase has been recently purified and designated guanylin (84). Guanylin appears to act in a manner similar to the heat-stable enterotoxins in stimulating cGMP levels in intestine and other tissues, through the same extracellular binding region of the particulate enzyme. At least five independent membrane guanylate cyclases, showing a similar pattern have been cloned (162). Detergent- insoluble forms of guanylate cyclase appear to predominate in gastrointestinal mucosa (391). The cytosolic form of guanylate cyclase is found in most mammalian tissues. The soluble guanylate cyclase is a heterodimer of 70 and 82 kD subunits containing catalyticlike domains (Fig. 4). They must interact with each other in order to generate the


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t

Fig. 4. Intracellular and transcellular signaling via the NO synthase and the soluble guanylate cyclase pathways. Activation of membrane receptors by prostacyclins (PGIs), histamine, platelet activating factor (PA) or acetylcholine (ACh) results in Ca2 + uptake by target cells, stimulation of cytosolic NO synthase (nitric oxide synthase: NOS) by the Ca2+-calmodutin complex (Ca2+-CaM), production of nitric oxide (NO), i.e. the endothelium-derived relaxing factor (NO/EDRF). The release of NO, derived from the oxidative metebolism of one of the guanidinonitrogens of L-arginine, or produced after the uptake of sodium nitroprusside (SNP) induces activation of the soluble form of guanylate cyclase and mobilization of the cGMP cascade: membrane channels, cGMP-dependent protein kinases (cGMP-PK), cAMP phosphodiesterases (cAMP-PDE). NO is a gaseous oxide of nitrogen that diffuses through cell membranes and reacts with adjacent effector cells.

basal and stimulated guanylate cyclase activity (51). It contains heme, which is thought to be the recognition site of nitric oxide (NO) and other NO-generating agents (nitroprusside, nitroglycerin). NO is formed from arginine in a reaction catalyzed by the enzyme NO synthase, the activity of which is regulated by calmodulin and calcium (Ca2+-Cam). Thus, agonist-induced cGMP accumulation presumably results from agonist-stimulated Ca 2+ influx through calcium channels in the plasma membrane, activation of NO synthase (48), and stimulation of the soluble guanylate cyclase by NO. Various substances may activate specific receptors and induce the formation of NO. This found to be the case for substances such as acetylcholine (ACh), adrenaline, noradrenaline, histamine, prostacyclins (PG12) arginine-vasopressin, 5-hydroxytryptamine, ADP, thrombin, PAF, and bradykinin (444). As mentioned above, the stimulation of sensory nerves by some agents, with subsequent release of substance P, may be one of the protective components in the gastric mucosa mediated by NO-dependent vasodilatation (330). The remarkable difference between cAMP-dependent and cGMP-dependent

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Mirossay, Di Gioia, Chastre, Emamiand Gespach

transduction systems is that the molecular sites of action of cGMP are not exclusively the protein kinases, but also cAMP-PDE, ion channels, and possibly other target proteins involved in cellular responses, as shown in Fig. 4.

Phosphatidylinositol / PKC Pathway Receptor-mediated phosphoinositide breakdown is catalyzed by agonist activation of PLC (Fig. 2). There are at least four or five types of PLC in mammalian tissues (or, /3, y, 6 and e) activated by the Gp-linked receptors, such as muscarinic M2 receptors, and gastrin/CCK receptors (80, 347, 348, 353,368). Three types of Gp proteins are involved in this process, and have been described according to their sensitivity to pertussis and cholera toxins (47, 279, 302, 385, 400, 406, 440). In parietal cells, at least one cholera toxin-insensitive Gp protein(s) appeared to be involved in gastrin receptor coupling to PLC (353). Each PLC has similar catalytic properties and hydrolyzes three, common phosphoinositides: phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIPz). PLC transforms PIP2 into two messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DG), the latter is also the product of phosphatidylcholine hydrolysis (33,277). When IP3 is released into the cytoplasm, it mobilizes Ca 2+ stores from the endoplasmic reticulum (ER), as shown in Fig. 2. The transitory rise in free calcium and/or its binding to calmodulin induces the activation of specific protein kinases. In parietal cells, both gastrin and CCK receptors mediate phosphoinositide breakdown accompanied by a rise in free intracellular calcium (Ca 2+) (357). In isolated rabbit parietal cells, gastrin induces a rapid rise in IP3 concomitant with acid formation (356). The kinetics of gastrin-induced rise in IP3 is biphasic with a rapid increase occurring within the first 15 seconds, followed by a sustained increase. While the first event is insensitive to pertussis toxin and extracellular calcium the latter is affected by these two factors. The physiological role of the sustained increased level of IP3 is not clear (355). Recent studies have also indicated that the CaZ+-calmodulin pathway may have a critical role in the secretion of pepsinogen induced by carbachol and CCK in rabbit mucosa maintained in organ culture (295). Evidence is now accumulating to indicate that other membrane phospholipids are also degraded following receptor activation. This is the case for phosphatidyl-choline which is probably hydrolyzed by both a phospholipase C and a receptor-coupled phospholipase D (PLD), producing phosphatidic acid or phosphatidylbutanol (432). In various tissues, PLD might be activated by: 1) G protein-coupled receptors, 2) phosphorylation by a receptor tyrosine kinase, 3) the DG/PKC cascade, or 4) the IP3/Ca 2+ cascade. Lipidsoluble diacylglycerol allows protein kinase C (PKC), localized in the cytoplasm in its inactive form, to translocate towards the plasma membrane, where it is activated (Fig. 2). PKC is a Ca 2+ and phospholipid-dependent serine-threonine protein kinase, which is ubiquitously distributed in tissues and organs, with the highest level of activity observed in brain cells (229,292). The family of PKC enzymes consists of at least 7 isotypes o~, /31,/311, y, 6, e, ~, which exhibit distinct tissue-specific patterns of expression (219). The 7 isotype appears


333

to be expressed predominantly in the central nervous tissue, whereas the 0~and isotypes are differentially expressed in a wide variety of cell types (219). The presence of elevated levels of Ca 2+ and phosphatidyl serine are required for the stabilization of the binding of PKC to the membrane. Phorbol esters and certain mutagens directly stimulate the C kinases in the presence of calcium in a fashion similar to diacylglycerol (311). The PKC contains 2 phorbol ester binding domains which may have interactive functions (55). The hydrolysis of diacylglycerol produces arachidonic acid (AA), which is metabol~ed by the lipo-oxygenase pathway (L-ox) into leukotrienes and by the cyclo-oxygenase pathway (C-ox) into thromboxane A 2 and the series of prostaglandins D2, E2 and F2 (Fig. 2). It is now generally accepted that the PKC enzymatic complex plays a crucial role in a number of cellular responses related to differentiation, proliferation, tumor promotion and membrane protein functions (190,313). Several other G proteins, possessing a GTPase activity, couple a large number of other cell surface receptors to other transducers and ion channels (308). The following proteins may be cited as examples: transducin Gt, which activates cGMP-dependent phosphodiesterases in the retina during the photoreceptor cascade, the Go proteins isolated in the central nervous system and the heart, and the pertussis-insensitive Goal6 protein specifically expressed in hematopoietic cells (3,269, 308,418, 428).

Phospholipases A2 and Phospholipases D Phospholipases A2 (PLA2) are enzymes responsible for the release of arachidonic acid (AA) from membrane phospholipids (PL) and hydrolyze the 2-acyl ester bond of phosphoglycerides. Investigation of the subcellular distribution of these enzymes revealed the existence of both cytosolic and membranebound forms. In cytosol of various cells and tissues including blood cells and kidney, a cytosolic PLA2 preferentially hydrolyses phospholipids containing arachidonic acid esterified in the 2-position. The activity of cytoslic PLAa is calcium-dependent and may be reulated by physiological Ca 2+ intracellular levels (99). Because simultaneous increase in Ca2+-dependent activity and PLA2 membrane translocation have been observed, it was suggested that membranebound and cytosolic PLA2 activities represent one enzyme and that the membrane-bound form is the biologically active PLA2 (343). Recent molecular cloning of the human Ca2+-sensitive cytosolic PLA2 gene demonstrates that the corresponding cDNA encodes the functional 85 kD cytosolic PLA2. The cytosolic PLA2 protein contains a structural element homologous with the conserved region C2 of the regulatory domain of PKC (339). In rabbit platelets, the histamine Ha receptor is coupled to PLA2 via pertussis toxin-sensitive G proteins (301). Taken together, these results suggest that PLA2 is coupled to receptors through G proteins and is stimulated by an activated PKC in concomitance with intracellular Ca a+ elevation (43,167,325). In addition, a source of diglycerides different from phosphatidylinositol has been detected in various ce~l types. The role of phosphatidylcholine as a

334


precursor for second messengers in signal transduction was suggested to be mediated via phospholipase C or phospholipase D.

Tyrosine Kinase Transduction Systems The fourth type of communication may be illustrated by two types of protein-tyrosine kinases: 1) the receptor type tyrosine kinase complex of insulin, EGF, or platelet-derived growth factor (PDGF), and 2) the non-receptor types of protein-tyrosine kinases encoded by different (proto)oncogenes, which are membrane associated enzymes without any ligand binding domain: pp60 ..... , pp160 gag-abl, pp130 gag-fps and pp59 c-fyn (63). The receptor tyrosine kinases have a similar molecular topology. All possess a large glycosylated, extracellular ligand binding domain, a single hydrophobic transmembrane region, and a cytosolic domain that contains a tyrosine kinase catalytic unit (168, 462, 471). It is possible to classify these receptors into 4 subclasses according to their distinct structural characteristics (441). The activity of the receptor type protein-tyrosine kinase is regulated by ligand binding and the subsequent conformational alteration at the extracellular domain (371). This process induces receptor oligomerization, which stabilizes interactions between adjacent cytoplasmic domains and leads to activation of kinase function by molecular interaction. Receptor oligomerization is an universal phenomenon among growth factor receptors. Receptor tyrosine kinases catalyze the phosphorylation of exogenous substrates as well as tyrosine residues within their own polypeptide chain. The ligand-stimulated autophosphorylation (or cross-phosphorylation) on tyrosine not only enhances the tyrosine kinase activity of the receptors but also creates binding sites for recruitment of specific cellular enzymes (reviewed in 441). These enzymes then transduce signals to the cell interior. For example, PLCy1 and phosphatidylinositol 3-kinase (PtdIns 3-kinase), the cytosolic enzymes in resting cell, are recruited by the PDGF receptor after its activation (216,446). The stimulation of PLC-~I, an isoenzyme of PLC, is responsible for PIP2 turnover after EGF and PDGF receptor stimulation. This activation of PLC-y1 is accompanied by tyrosine phosphorylation (348). Activation of PtdIns-specific PLC-1 would stimulate the classical PtdIns turnover pathway, leading to elevation of cytosolic Ca 2+ and stimulation of PKC with subsequent activation of a multitude of cellular events including changes in cytosolic pH, potassium levels, and transcription. A newly discovered enzyme implicated in the cross-talk of the transduction pathways, is PtdIns-3 kinase. This enzyme was shown to be composed of two subunits of 85 and 110 kD (460). The 85 kD subunit is a direct substrate of the PDGF receptor and pp60 ..... . PtdIns 3-kinase was the first enzyme found to be associated with tyrosine kinase. Upon activation, PtdIns 3-kinase phosphorylates the D-3 position of the inositol ring. Until recently, phosphatidylinositol was thought to be phosphorylated only at the D-4 and D-5 positions of the inositol ring. The discovery of PtdIns 3-kinase uncovered a family of D-3-phosphorylated phosphoinositides (65,460). The phosphoinositides that are phosphorylated at the 3 position are not substrates for any of the known PtdIns-specific PLCs (253),

Pharmacological Control of Gastric Add Secretion

335

indicating that they are not converted to inositol phosphates in response to activators of the classical pathway. It appears to be possible that they act in a new signalling pathway distinct from the clasical Ptdins turnover pathway (13, 66). Some other enzymes, such as the ras GTPase-activating protein (GAP) or c-raf proto-oncogene product, are direct substrates for receptor tyrosine kinases (296, 299).

Calcium Channel-Coupled Receptors The increase of Ca 2+ concentration after receptor stimulation, which is coupled to PLC, occurs most commonly in two phases. The first elevation of Ca~ + originates from intracellular stores and is believed to be mediated by IP3 (vide supra). The second component is due to Ca 2+ uptake from extracellular space, although its control by PLC is still unclear. The mechanisms regulating the calcium channel-coupled receptors are not yet elucidated (reviewed in 286). The entry of extracellular Ca 2+ after depletion of rapidly exchanging intracellular Ca 2+ stores may be the first mechanism involved in the control of plasmalemma Ca 2+ channels. Depletion of intracellular Ca 2+ stores appears to induce the activation of plasma membrane Ca 2+ channels via unidentified signal. The same channels may be directly activated by way of membrane receptors, coupled to them through G-proteins. Recently, in pituitary cells and adrenocortical cells~ it was shown that a pertussis toxin-sensitive G-protein is implicated in the mediation of hormone stimulated inward Ca 2+ currents (178). The existence of two different channels controled by the two above mentioned mechanisms, or a third channel, operating under influence of an unknown second messenger, are possible (286).

Molecular Structure of Membrane Receptors The classical techniques of solubilization and purification of membrane proteins have revealed the primary sequences of a series of receptors that are coupled to G proteins: adrenergic, muscarinic and serotoninergic receptors, receptors of substance K and angiotensin (102, 174, 222, 417), and many others. All these receptors share structural analogies with opsin and rhodopsin in the retina. This family of receptors possesses an extracellular domain binding the natural ligand or its analogues, a transmembrane domain of seven segments anchored in the hydrophobic part of the membrane and a cytoplasmic domain, which is in contact with both the transducer and the proteins regulating the desensitization and the internalization of the receptor (457). The transmembrane domain is the most highly conserved region of these receptors coupled to G proteins. The extracellular loops, localized between segments 2, 3 and 4, 5 contain cysteine residues, suggesting the presence of disulfide bonds between these loops (127). The extracellular, N-terminal domain of the protein contains asparagine residues, which link oligosaccharides. The seven serine or threonine residues at the extracellular C-terminal are potential substrates for phosphorylation by specific kinases, which are involved in the process of desensitization. The domain associated with the G proteins is as yet poorly characterized. The

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intracellular loop between segments 5 and 6 of the receptor is in contact with G proteins (222). Various experimental strategies, including gene cloning, sitedirected mutagenesis, low-stringency hybridization polymerase chain reaction (PCR) amplification, and gene tranfer in heterologous systems, such as microinjected Xenopus laevis oocytes, and have been employed to establish the structural differences and analogies between these membrane proteins, ionic channels, membrane transporters and adenylate cyclases in animal species (174, 180, 226, 467). These techniques have been also used to detect new receptor subtypes, as in the case of the adrenergic/33 receptor (118). In brain and peripheral tissues, histamine actions are mediated via cytosolic and cell surface receptors, previously classified as the H~, HIC, H2, H2h and H 3 histamine receptors, according to pharmacological, biochemical characterization and gene cloning. The stimulation of G protein-coupled Ha receptors promotes phospholipase C and A2 activation, Hz receptors induce cAMP formation, while the signal transduction system activated by the recently discovered histamine H 3 receptors was responsive to GTP (9). In platelets, intracellular histamine has been shown to promote platelet aggregation, through binding to a novel intracellular histamine H~c receptor of #M affinity, suggesting intracrine regulation by histamine in this sytem (377). Among the histaminergic receptors, the Ha sub-type has been well characterized using radioactive ligands and photo-activated probes, which allow the specific pharmacological properties of this sub-type to be reproduced by histamine, mepyramine, iodobolpyramine, iodoazidophenpyramine, arylazide histamine, and 7-azidoketanserine (122, 130, 225, 361, 455,466). The binding domain of the H~-receptor lies within a protein possessing disulfide bridges and having an apparent molecular weight of 56 kD in the brain, 50 kD in the thymus (322,361), and 670-800 kD in the liver (130). However, the identity of the Ha-site in liver is disputed (247). A molecular form of 160 kD was observed in the cerebral cortex following radio-inactivation. For the Hz-receptors, a non-specific binding component and the capture of bioamine are observed with histamine, cimetidine, ranitidine, impromidine, tiotidine, and SKF 93479 in purified membranes and in cellular systems (22, 113, 116, 133, 157, 456). These limitations have considerably restricted research progress on the solubilization and identification of Hz-receptors using conventional receptor purification and identification techniques. Cloning and functional characterization of 2 complementary DNAs encoding the histamine H1 and H2 receptors was recently achieved using an electrophysiolocal assay in oocytes after injection of polyadenylated RNAs (470) and by PCR amplification using degenerate oligonucleotides primers based upon homology to other G protein-coupled receptors (138, 139). RECEPTOR-SIGNAL INTEGRATION IN CELLULAR SYSTEMS Cross-Talk and Desensitization

It is now well established that the principal types of signaling pathways, mentioned above, are also interconnected in a complex network of functional


337

interactions capable of modulating their respective activities. These functional relationships among membrane transducers are directly implicated in the inhibition, potentialisation, and desensitization of cellular activity regulated by cell surface receptors. In the gastric mucosa, these receptor-signal transduction pathways act in an interdependent manner to integrate such cellular activities as proliferation, differentiation and digestive functions in the normal and transformed gastric epithelium (70,151,290,324). Use of 12-O-tetradecanoylphorbol-13-acetate (TPA) in the direct activation of PKC in rat parietal cells showed the reduction of histamine-stimulated cAMP content and aminopyrine accumulation (177). Furthermore, the 1-oleoyl-2-acetyl-glycerol (DG), also inhibited histaminestimulated aminopyrine accumulation (5). Similarly, EGF inhibits histaminestimulated cAMP production (176) and aminopyrine accumulation in rat parietal cells (400). EGF exerts this effect by stimulation of PDE, followed by the diminution of the cellular cAMP content since its activity is abolished in the presence of isobutylmethylxantine (IBMX) (400). Cooperative effects have been suggested between cAMP and gastrin-induced PtdIns breakdown on the acid secretory activity in parietal ceils (353). This was documented by an effect of cholera toxin on rabbit parietal cells. The ADP-ribosylation of the o: subunit of the Gs protein, which leads to a persistent stimulation of adenylate cyclase, induced a pronounced potentialization of gastrin-stimulated aminopyrine uptake

(353). In other tissues (e.g. in heart), the activation of adenylate cyclase by /~-adrenergic agents leads to phosphorylation of voltage-dependent Ca 2+ channels (16). A subsequent effect on Ca 2+ influx has been proposed. Even adenylate cyclase itself may be regulated by PKA; the direct phosphorylation of adenylate cyclase by PKA may be partialJy responsible for the heterologous desensitization of glucagon-stimulated adenylate cyciase activity in hepatocytes (334). In frog erythrocytes, a 130kD protein copurified with adenylate cyclase activity was phosphorylated after treatment with the PKC activator TPA (474). The increase of Ca~+ may also influence adenylate cyclase activity by complexing with calmodulin and activating other pathways which can modulate adenylate cyclase activity (123), or adenylate cyclase may be stimulated directly by Ca2+-calmodulin in some tissues (293). The desensitization of the receptor-transducer systems follows upon a primary exposure of the target tissue either to the natural effector or to a drug. The importance of this phenomenon, designated "tachyphylaxis" or "refractoriness", is to be considered in view of the protection of the tissue from secretory dysfunction after chronic stimulation or drug treatment. This mechanism has been demonstrated for hormones, neuromediators, paracrine agents, and drugs (151). The desensitization 1) is followed by the internalization of the receptor, which "disappears" from the cell surface, 2) is related to the alteration of the receptor which is phosphorylated by a specific kinase or 3) to decoupling of the receptor to transducer, or 4) to a distal regulation by the "second messenger" (67, 151, 160, 182, 335). Vasopressin can short-circuit both the mitogenic activity and the induction of the oncogene c-fos. Glucocorticoids increase the transcription of the

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fl-adrenergic receptor gene, while isoproterenol destabilizes the receptor gene transcript by diminishing the half-life of messenger RNA. Recovery of the cell's sensitivity to the receptor agonist is generally slower and involves either the recycling (towards the membrane) of the internalized receptors or the synthesis of new receptor molecules. For gastric He receptors, we have analyzed the pharmacological, biochemical and functional properties of the desensitization process following brief or long-term exposure of human gastric HGT-1 cells to histamine and its H1 and H2 receptor specific analogues (113, 114, 335). Desensitization process is rapid (half-life of 20 minutes). It is also temperaturedependent and sensitive to histamine dose 20 times lower than that required to activate the H2 receptor. Histamine H2 receptor desensitization manifests itself by a progressive diminution of stimulation. It is maximal for histamine at a concentration of 10-SM (114). This phenomenon is controlled by the action of histamine and cimetidine on the H2 receptors and results from the uncoupling of the Gs subunit to AC or from the persistent activation of Gi (114,335). However, the fate of histamine and its H2 receptors in the parietal cell is, at present unknown. Identical results were obtained when human HGT-1 gastric cells were cultivated in the presence of 10-4M histamine for six days. Chronic treatment of HGT-1 cells by histamine produces a homologous desensitization, since the functional activity of peptidergic receptors activated by glucagon, VIP and GIP, was not affected in this cell line. In heterologous desensitization, the activation of PKC induces the internalization, as well as a considerable reduction, of both the muscarinic receptors and the gastrin receptors in parietal cells purified to 95% (76). Regulation of gastric histamine receptors, PG receptors, and gastrin receptors have been observed in vivo, in relationship with suckling and weaning in the rat (147, 150, 415). We have also observed the down-regulation of the secretin binding sites and its associated heterologous desensitization in rat gastric glands cAMP system (24). The desensitization of the H1 receptor of histamine involves a diminution of the number of binding sites for tritiated mepyramine, a selective antagonist (151,160).

MODELS AND MECHANISMS OF ACID SECRETION

Faced with the complexity of the cell populations composing the gastric mucosa and the parameters regulating acid secretion, cellular preparations and tissue culture allow the direct analysis of histamine H2 receptors and the activation of the H+/K§ proton pump. These methods utilize chemical agents, such as EDTA, and dispersive enzymes, such as pronase, dispase and collagenase, which act on everted gastric pouches or mucosal scrappings. Certain preparations combine the sequential exposure of cells to enzymes and to EDTA, followed by a specific cell type enrichment, either by Percoll gradient separation or centfifugation i n an elutriation rotor (160). Other authors have developed primary cultures of isolated gastric cells or gastric cells in organotypic culture, which produce mucus, pepsin, PG, gastrin or acid (75, 175, 188, 231, 283, 317, 372). However, these cells proliferate poorly, restricting experimentation. T h e


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production of immortal gastric epithelial cell lines by genomic transfection with the oncogenes myc, mutated p53, E1A, SV40 or polyoma virus Jarge T could provide alternative models for studying acid secretion, instead of those involving laboratory animals, normal surviving cells or nonfunctional tumor cells (70, 117, 422). Establishing cell lines derived from sporadic gastric cancers, notably the HGT-1 cell line (230, 337, 396), has greatly improved our knowledge on the expression and pharmacological properties of histaminergic and peptidergic receptors in humans. The study of structure-activity relationships and the short-term and long-term effects of H2 antagonists in clinical experimentation have been developed in our laboratory for HGT-1 cells, in parallel with isolated human gastric glands (112-114, 149, 151, 154). HGT-1 cells are relatively undifferentiated morphologically, but possess a number of peptidergic receptors characteristic of the human gastric epithelium, such as those activated by VIP, gastric inhibitory peptide (GIP), glucagon-related peptides and somatostatins (21, 111, 144, 151, 152, 170, 344, 359, 360). Another approach developed in our laboratory was the establishment of gastric cell lines after genomic transfection of rat gastric glands with recombinant ecotropic retroviruses carrying the immortalizing viral oncogene SV40 large T. After selection we obtained five RGC cell lines possessing poorly differentiated epithelial cells morphology, as detected by phase-contrast microscopy and electron microscopy (71). The next model is represented by the poorly differentiated, human gastric adenocarcinoma cell line MKN-45. This cell line is considered to be derived from the germ cells of the gastric glands and possesses an intracellular canaliculus-like structure, a characteristic feature of parietal cells. Treatment of MKN-45 cells with retinoic acid enhanced cAMP production in response to histamine and increased the number of H2-receptors visualized by (3H) tiotidine binding. It is possible that this effect reflects the differentiation towards more mature gastric epithelial cells (6).

PHARMACOLOGICAL CONTROL OF GASTRIC ACID SECRETION Cimetidine, Ranitidine and Famotidine: The Progress of the Antagonism at H2-geceptors The synthesis by Black of a series of imidazote derivatives including burimamide, the first H2-antagonist, opened the way to a new and efficient treatment of gastroduodenal ulcers (36,189). This work was recognized with the awarding of the Nobel prize in physiology and medicine in 1988. The discovery lies at the origin of the development, by several laboratories, of a series of specific and powerful H2 receptor antagonists possessing prolonged activity and no undesirable side effects. The H2 antagonists have considerable structural variety (38, t13, 135, 149, 287, 392, 425) but possess three elements in common (Fig. 5): 1) an aromatic core, which is either an imidazole (cimetidine), aminomethyl furan (ranitidine, SKF 93479), guanidine thiazote YM-11170, i.e. famotidine or triazole (AH 22216), 2) a flexible chain CH2-S-CH2-CH~ and 3) a cyanoguanidine polar group.

340


.,c

cimetidine

NN~N

ranitidine

s•CH•SCH2CH•CNH2 NSOzNHz

f amotidine

N / C\ HzN NH~

OCH3 H3 C , , , ~ ' ~ CH 3 0 N - - ~ / ~ O C

H3

omeprazole H

Fig. 5. Molecularstructure of three He antagonists and of omeprazole, a specificH § K+-ATPase inhibitor. These drugs possess remarkable specificity of action on membrane receptors. The interaction site of a competitive inhibitor may be located in one or several extracellular loops of the binding site. It may also lie within the intra-membrane of intracellular domains of the receptor (vide infra). In the gastric epithelium, at therapeutic doses, cimetidine, ranitidine, famotidine and the compounds A H 22216 and SKF 93479 have no effect on the /3-adrenergic, acetylcholine, secretin, glucagon, VIP, GIP or PGE2 receptors (113, 143, 153, 158, 272, 287, 291). The criteria used to evaluate the potency of the competitive antagonists (IC~0) includes the antagonist dose resulting in 50% inhibition of induced receptor activity at a defined concentration (S) of histamine. If the Ka is equal to the histamine dose that produces half-maximal receptor stimulation, then, the inhibition constant Ki---ICs0/(1 + S / K a ) allows a direct comparison between the potency of the drugs studied in the different systems. The second criteria is the Schild equation (116), in which antagonism is expressed by the histamine dose ratios (DR) required to produce half-maximal responses in the presence of different antagonist concentrations: log (DR - 1) = n log (antagonist) - log Kb. For a simple competitive antagonism, the Schild plot yields a straight line with a slope of unity. The intercept with the abscissa (DR = 2), is the pA2 value ( - l o g Kb), i.e., the negative log of the receptorantagonist apparent dissociation constant (113,142). The competitive antagonists can thus be classed according to their pA2 (37, 73, 87, 169, 173, 245): tiotidine, famotidine (7.5-7.8)> ranitidine (6.9-7.2)> cimetidine (5.7-6.7). Famotidine is thus 3.5 to 16 times more potent than ranitidine and cimetidine in isolated human gastric glands and in HGT-1 cells (153). These values agree with results obtained in vitro and in vivo for adenylate cyclase stimulation and acid secretion in


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humans, rat, and dogs (34, 163, 197, 328, 378, 381,407, 4.25). For example, acid secretion is 50% inhibited when the plasma concentration is 20-30 ng/ml for famotidine and 100 and 500 ng/ml for ranitidine and cimetidine, respectively (49, 327, 392). In the treatment of Zollinger-Ellison syndrome, acid secretion is blocked by a dose of famotidine of 60 mg administered every six hours. The same effect is obtained with ranitidine only at a dose of 500 mg or with cimetidine at a dose of 1.9 g (197). The H2 antagonists are capable of interacting with H1 and H 3 receptors, but do so only at very high doses that exceed the concentrations measured in the peripheral blood of patients treated for gastroduodenal ulcers. Likewise, the histamine H2 receptors in human gastric glands are selective vis-a-vis the H~, H2, and H3 agonists and antagonists (149,153). Famotidine is 330 and 6,7000 times more potent on the H2 receptors than is triprolidine or thioperamide, antagonists of H1 and H3 receptors, respectively: H2> H~ > H3 (153). In accordance with the observations of Green and Maayani on the central nervous system (164), the anti-depressants amitriptyline and imipramine block the activity of the H2 receptor in gastric mucosa of guinea pig (22, 23,439). This action does not seem to occur with acid secretion in vivo, during the treatment of depression (40). However, another tricyclic antidepressant, trimipramine, has been found to promote ulcer healing in certain patients unresponsive to cimetidine and anti-acid treatments (271,350). The pharmacokinetics and drug metabolism (163, 285, 342, 392), as well as the specificity and the reversibility of the interaction between the H2 antagonist and the receptor-transducer system, influences the effectiveness and handling of peptic ulcers. These parameters determine the dose and the timing of daily intake of medication. For example, cimetidine, which has a specific action on the H2 receptor, does not desensitize its H2 antagonism and does not produce a rebound effect when the treatment of cultured human gastric HGT-I cells by cimetidine is interrupted (115). When HGT-1 cells are exposed to 10-5M cimetidine for 6 days, the activity of the He receptor is not altered after the antagonist is eliminated from the incubation medium by successive washes. Under the same conditions, cimetidine does not modify its own Ha receptor antagonism, which confirms that desensitization occurs subsequently to receptor activation (115). The gastric cells are not sensitized to histamine following a prolonged blockade by cimetidine (113, 114, 212, 275). The hypersecretion of acid, observed by several authors following the cessation of treatment by H2-receptor antagonists is thus open to question. There is no pharmacological evidence, from experimental protocols using isolated gastric cells which support a secretory rebound with H2 antagonists (212, 275). Cimetidine protects the H2 receptor against the desensitization induced by histamine (115). This protective effect occurs at elevated. concentrations of cimetidine (10 .5 to 10 -4 M). Those concentrations are in the range of values measured from peripheral blood (4 to 8 x 10-6 M) during the first eight hours following a standard administration of cimetidine (39). The interaction between cimetidine and the H2 receptor is thus rapidly reversible and the same situation is observed in vivo (189). Compound SKF 93479 produces, to the contrary, a complete loss of H2 receptor activity without affecting the peptidergic receptors in the human gastric HGT-1 cells (115). This drug has a very slow

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dissociation rate (about 45 rain). It is 50 times more potent if there is a 120 rain pre-incubation with the HGT-1 cells, as compared to simultaneous addition with histamine (113). The compound, SKF 93479, belongs to a class of H2 antagonists which includes loxtidine (a derivative of phenoxytriazole), ranitidine (furan), famotidine (thiazole), AH 22216 (triazole) and L-643, 441 (thiadiazole). These antagonists have a prolonged, partially irreversible activity (38, 50, 101, 113, 153, 287, 328, 437). This apparent effect of famotidine on the H2 receptor in human gastric HGT-1 cells is in accordance with Schild's representation, which yields a slope of n =0.64, different from unity, thus indicating a non-competititve antagonism (153). These results are equally compatible with the prolonged in vivo action of famotidine, both in animals and man (88, 161, 197, 294, 328, 397, 407, 425). In dogs with a gastric fistula, acid secretion is suppressed by 100%, 59% or 18% by the oral administration of 2mg/kg famotidine at 4, 24 and 48 hours preceeding the histamine test (328). In comparison, ranitidine, at a concentration of 15 mg/kg, exerts an inhibitory effect of 87% at four hours but only a marginal reduction of 9% when administered 24 hours before histamine. There is, however, some controversy concerning the relative irreversibility and the non-competitive inhibition by famotidine on the H2 receptor in gastric ceils isolated from animals. In particular, famotidine exerts a reversible antagonism in the rabbit and the unweaned rat (34,401) and a partially reversible antagonism in parietal cells isolated from the adult guinea pig (169). A linear Schild plot representation, with a pA2 of 7.5 for acid secretion, has been reported in mice (6.03 and 5.35 for ranitidine and cimetidine, respectively) and a pA2 of 7.65 for gastric adenylate cyclase was measured in guinea-pig (6.33 for cimetidine) (37, 173). The histaminergic inhibition by famotidine is constant as a function of time in the mouse and the rabbit (37,401). These differences may be attributed to the diversity of tests used to evaluate the activity of H2 receptor and acid secretion in vivo and in vitro (89). The H2 receptor as well as the H + pump (vide infra) possess functional and pharmacological properties that differ with respect to their post-natal development in animal species: man, guinea pig or rabbit (1, 14, 149, 245). In respect to the maturation of the gastric epithelium during ontogenesis, and nutritional factors, such as milk, which can modify the activity of the H2 receptor (112, 147, 150, 151, 160). Lastly, the use of dispersive enzymes and prolonged incubation periods (3 to 5 hours) at 37~ necessary to isolate gastric cells or purified membranes (vide supra). These techniques may also result in a degradation or a desensitization of histaminergic and peptidergic receptors (113, 115, 366). Finally, certain Hz antagonists indirectly control the activity of the histaminergic receptor by inhibiting the degradation of histamine both in vivo and in vitro (430). Pharmacological Control of the Gastric H+/K+-ATPase

The H+/K+-ATPase (EC 3.6.1.36) is a membrane-associated and ouabaininsensitive enzyme that provides the driving force for HCI secretion into the gastric lumen, resulting a pH difference greater than 6units between the cytoplasm and the gastric lumen. The parietal cells undergo extensive mot-

Pharmacological Controm of Gastric Acid Secretion

343

phological transformation which results in H + secretion. These changes include an extensive reduction in the tubulovesicular system in the cytoplasm together with the appearance of intracellular secretory canaliculi (265). Several agents including histamine, gastrin, and carbachol induce the fusion of the vesicles with the luminal membrane or expansion of the apical plasma membrane. Each secretagogue induced rapid increases in steady-state levels of mRNAs encoding carbonic anhydrase II and H+/K+-ATPase in isolated canine gastric parietal cells (58). The H+/K+-ATPase catalyzes the electroneutral exchange of cytoplasmic H + and external K +, coupled with ATP hydrolysis. The proton pump is composed of 2 subunits, the 114kD catalytic ~ subunit concerned with ion translocation, and the/3 subunit is a 60-80 kD glycoprotein with a 35 kD protein core appearing to have no transport function. The enzyme is composed of 1034 residues. The Asp-386 residue (phosphorylation site), the Lys-497 residue (pyridoxal 5'-phosphate-binding site) and the Lys-518 residue (fluoresceinisothiocyanate-binding site) are located near the catalytic ATP-binding site. Omeprazole binds the cysteine residue of the el subunit. Both subunits span the plasma membrane, the a; subunit probably 8 times and the /3 subunit only once. The proton pump belongs to the family of P-type ATPases, which include Na+/K +ATPase and Ca2+-ATPase that forms the aspartyl phosphate intermediate during ATP hydrolysis. The recently cloned H+/K+-ATPase/3 subunits from the human, mouse, rat and bovine stomach show a number of structural similarities with the Na+/K+-ATPase/3 subnit. Both contain a large extracytosolic domain containing 3 pairs of disulfide-linked cysteine residues (61, 62, 260, 336, 402). The ol and/3 subunits of the Na+/K+-ATPase are both required for ATPase activity and for binding the inhibitor ouabain. Moreover, the H+/K+-ATPase/3 isoform can act as a substitute for the Na+/K+-ATPase /3 subunit. It can assemble to the oc Na+/K+-ATPase subunit and support the structural maturation, intracellular transport, and functional activity of the crNaK//3HK hybrid chimera, including Na+/K+-pump transport capabilities in Xenopus oocytes (196). Both pumps are expressed in parietal cells but at opposite poles of the cell. Kinetic enzyme studies have defined a complex succession of catalytic and transport reactions, involving K+/K + exchange, and enzyme phosphorylation in the presence of M g 2+ (249, 250, 336, 419). The results using isolated vesicles from the apical membrane of the oxyntic cells and permeabilized gastric glands suggest that the H+/K +ATPase exist in 2 functionally different compartments (184, 465). Stimulation promotes the recruitment of the enzyme from an inactive, K+-restricted, to an active, K+-permeable compartment. This electroneutral exchange of extracellular K + and intracellular H + generates an extremely high transmembrane pH gradient. Northern and Western blot analysis has shown that the H+/K+-ATPase and/3 subunits are expressed in the stomach of a variety of animal species, and specifically localized in the tubulovesicular network of the parietal cell (61,402). Both the ol and /3 subunits have been reported as major autoantigens in autoimmune gastritis associated with the pernicious anemia (54, 213, 273, 435). Pernicious anamia is the final stage of autoimmune gastritis and the resultant gastric lesions shows severe mucosal atrophy with ensuring failure of intrinsic factor secretion by the parietal cell. The nucleotide sequences of the 0~subunit of

344


human, rat, and pig H+/K+-ATPase have been reported (262). The mouse /3 subunit gene is split into 7 exons, the intracellular amino-terminal and putative transmembrane domains are encoded by individual exons, the extracellular domain is encoded by 5 exons (62). The genes encoding the H+/K+-ATPase ol and /3 subunits appear to be expressed exclusively in parietal cells. The availability of cosmid clones containing 28 kb of sequences flanking the 5' end of the H+/K+-ATPase/3 subunit gene should allow others to study factors involved in the tissue-specific expression of this gene in parietal cells and the response elements involved in transcription (62). The upstream region of the rat H+/K+-ATPase /3 subunit gene contains repeat sequences and palindromes, potential binding sites for RNA polymerase II and E4TF1, and CACCC box sequences (263). The stomach, but not other tissues, has nuclear proteins capable of binding to the regions upstream of the potential RNA polymerase II binding sites (TATA box). Sequence analysis of the human H+/K+-ATPase ~ subunit promoter revealed the presence of sequence motifs that were also present in the promoter region of the human and rat pepsinogen genes (179, 203, 214, 262, 323). The 3 tandem GATAGC sequences in the rat gene may be important for controlled expression of the H+/K+-ATPase /3 subunit gene in gastric parietal cells (263). These observations suggest the potential role for stomach-specific transcriptional response elements. Further characterization and isolation of these cis-acting elements should allow the construction of efficient vectors containing fusion genes for appropriate regional, temproal and cell-specific expression in gastric epithelia of transgenic animals. Maturative changes, biochemical, and genetic aspects of the H+/K+-ATPase ontogeny have been studied during fetal and postnatal development in various animal species (82, 186, 274, 340). The H+/K+-ATPase can be directly blocked by a number of benzimidazolie derivatives, including omeprazole (Fig. 5) and picoprazole (59, 160, 249, 452-454). Consequently there exists different drugs that can control acid secretion by acting either on the basal pole of the parietal cell (cholinergic, gastrinic and H2 receptor antagonists) or the apical pole (omeprazole, trifluoperazine, verapamil and trimethoxybenzoate). Other molecules possessing a tertiary amine functional group inhibit the K + site of proton ATPase: trifluoperazine, an inhibitor of calmodulin, verapamil and diethylaminooctyl trimethoxybenzoate (160, 200, 307). Other compounds also inhibit gastric acid secretion as non-competitive inhibitors of the H+/K+-ATPase (339, 341), polyamines and fenoctimine (a substituted piperidine), or as competitive inhibitors of the H+/K+-ATPase, sofalcone (an isoprenyl chacone competitive at the ATP site), SCH28080 (a competitor of the K + site of the enzyme), the sulfoxide reagent Ro 18-5364 and the substituted benzimidazole AG-1749 containing a trifluoroethoxy group (27,300, 305,403). Bafilomycin, on the other hand, was much more effective in inhibiting proton transport mediated by the H+-ATPases in the kidney and bone (ICs0=2nM) than in inhibiting the H+/K+-ATPase in gastric membrane vesicles, ICs0 = 50 #M (282). Omeprazole consists of a benzimidazole core and of a pyridine core substituted with methyl and oxymethyl groups and irreversibly inhibits the proton pump Fig. 5. When acid secretion is stimulated, the half-life of omeprazole is 3 min; when secretion is


345

inhibited, the half-life increases to 73 rain. Omeprazole is a prodrug. It is activated by acid and converted in the intravesicular space and in secretory channels to its active form, a sulphenamide that interacts with the luminally accessible SH-groups of the enzyme (128, 218, 258, 298, 452-454). The compound fi-Mercaptoethanol prevented binding of the inhibitor and inhibition of the enzyme. Omeprazole was also shown to interact with the Na+/K+-ATPase from dog kidney (218), at a lower affinity (ECso = 19-186/~m) than the H+/K+-ATPase (ECso = 5.2-36 ~m). Omeprazole is a potent, long-lasting inhibitor of gastric acid secretion in animals and humans with gastric and duodenal ulcers, gastroesophageal reflux disease, and Zollinger-Ellison syndrome (129, t92, 235,448). Basal H + secretion was inhibited by 50%, 3 h after a single 60 mg dose of omeprazole, and by 78%, 4 h after administration of the drug (284). Omeprazole is absorbed from small intestine and its half-life in plasma is about 60 min. The duration of action following a single dose of omeprazole exceeds 24 h because of the stable complex between the enzyme and inhibitor. Side Effects of Antiacid Drugs The control of gastric acid secretion can be achieved by the pharmacological control of histamine H2 receptors, cholinergic receptors, H+/K+-ATPase, and combined with the introduction of other possible therapeutic agents, such as PG or new drugs with antiulcer and antisecretory activities (93). With the exception of ranitidine and famotidine, most of the anti-secretory agents that possess a prolonged or irreversible action have been withdrawn from preclinical experimentation (clinical trials) following the demonstration of their toxic effects, including the appearance of gastric cancers in the rat for compound SKF 93479, tiotidine and loxtidine. The toxic and secondary effects of the H 2 antagonists presently prescribed for peptic ulcer and the Zollinger-Ellison syndrome treatment (376) are compared with the toxicity of omeprazole and the prostaglandin analogues (enprostil and misoprostol, for example)~ This comparison is presented in Table 1. These effects are variable and depend on whether the administration is an oral or parenteral route. The administration of loxtidine, tiotidine, as well as of the H+/K+-ATPase inhibitors omeprazole and the substituted benzimidazole analogue BY308, induce achlorhydria and hypergastrinemia followed by neoplastic transformation and hyperplasia of the enterochromaffin cells into rat oxyntic mucosa (50, 92, 106, 108,234, 242,278,333,367, 434). There exists also the evidence that omeprazole may have a possible genotoxic effect on gastric mucosal cells. Its administration caused a significant increase in the uptake of radiolabelled thymidine into DNA in gastric mucosal cells, while the effect of loxtidine was negative. This effect of omeprazole can not be explained on the basis of increased gastrin levels which is identical after loxtidine and omeprazole treatment (53). A potential role for the anti-secretory drugs on carcinogenic N-nitrosylated compounds produced by the bacterial flora, was demonstrated in the rat. The same situation has been observed only in 39 treated patients and three controls out of 9,504 patients taking cimetidine and 8,994 matched controls (278). It is therefore, difficult


346 T a b l e 1.

TISSUES

Toxic and side-effects produced by antiacid drugs during the treatment of gastric ulcers and the ZoUinger-EUison syndrome CIM

STOMACH Cancers/carcinomas Hypergastrinemia + Proliferation, hyperplasia Mucosa ECL Somatostatin P+ Serotonine Gastrin P Endogenous PG INTESTINE Trophic effects + Constipation, diarrhea + LIVER Cytochrome P450 ++ CARDIO-VASCULAR SYSTEM Inotropic effects, hypotension +/Endocrine system Anti-androgene + PRL, LH, FSH, TSH, PTH, + T4, E BLOOD, HEMATOPOIESIS Cytopenia + Coagulation + CENTRAL NERVOUS SYSTEM Confusion, headache, attention +

RA

FA

OME

+

-

rat: + ++

+

P P+ P+/P+

+

+ +

+

PG

p+/H + p+/H + p+/+ p+/H +

+ p+/H + p+ p-

++

+

++

+/+/-

+/-

+/-

+/-

+ +

+/-?

+

--?

cimetidine; RA: ranitidine; FA: famotidine; OME: omeprazole; PG: prostaglandins. (+1) and ( - ) : presence and absence of adverse effects; P+ and H+: stimulation of cell proliferation (P) and induction of hyperplasia (H) CIM:

to conceive that these antisecretory agents would have a significant carcinogenic effect in man. In agreement, omeprazole does not alter the morphological characteristics of the endocrine cells in the oxyntic mucosa of patients given omeprazole for duodenal ulcer of Zollinger-Ellison syndrome (86, 280). Patients with Zollinger-Ellison syndrome given omeprazole for up to 3 years developed no significant changes in percentage of enterochromaffin ECL cells, no carcinoid tumors, and no changes in gastrin serum concentrations. The increase in serum gastrin levels observed in duodenal ulcer patients during drug therapy has a very low trophic effect, if any, on human gastric ECL cells. ECL cells are currently regarded as a major source of histamine in the human oxyntic mucosa. The rat oncogenicity studies are an inadequate risk model for human due to the sharp differences observed (32). Certain antisecretory agents, including cimetidine and omeprazole, interfere with the metabolism of certain drugs by cytochrome P450, a constituent of the microsomal oxidative system in the liver (20, 96, 134, 233,251). The presence of an imidazole core in cimetidine, a benzimidazole moiety in omeprazole and a furan ring in ranitidine enables these drugs to fix to the heme iron of cytochromone P450 (96). Famotidine, which possesses a thiazole ring, is


347

prescribed at weaker therapeutic doses and does not interfere with the oxidative metabolism of the drugs. It appears to be established that treatment with cimetidine or ranitidine can affect cardiac rhythm and blood pressure whereas other secondary effects are generally minor (267, 429). It is still controversial whether famotidine has the same side-effects. Hematological, anti-androgen (impotence, gynecomastia) and endocrine effects have been described, especially for cimetidine (210). At therapeutic doses, this antagonist inhibits the binding of dihydrotestosterone to androgen receptors and increases the concentration of circulating testosterone in marl. Ranitidine and famotidine do not produce this non-specific effect on the androgen receptors (81, 131, 252, 326). Cimetidine crosses the placental barrier by passive transport, is concentrated in milk and produces a sexual dysfunction in the adult rat (4,379). This antagonist should thus be used with caution in women who are pregnant or nursing. The adverse effects of H2 antagonists on the brain, the cardiovascular system, and hematopoiesis are due to the presence of histaminergic receptors in the cerebral structures, the cardiac muscle, the endothelial cells in brain and peripheral tissue, in both stem cells and mature blood cell (31, 89, 97, 160, 208, 211, 220, 232). These cells, whether normal or leukemic, possess H2-type receptors, coupled to AC (totipotent CFUs stem cells, granulocytes, lymphocytes, monocytes) or posses H2h-type receptors, coupled to guanylate cyclase as in the case of the blood platelets (56, 142, 146, 156, 157, 159, 160). The H2 receptors induce the transition from Go to S of the cell cycle in the precursors FU gm and stimulate the proliferation and differentiation of granulocytes (t5, 215, 306). Histamine, via the H2 receptors inhibits the secretion of free radicals by the monocytes/macrophages lignages, as well as chemotaxis, phagocytosis and the secretion of lysosomal enzymes (52, 146). Thus, cimetidine, ranitidine, and the other antagonists at histamine H2 receptors are likely to affect allergic, immune and inflammatory reactions, whereas they would probably have an inhibitory effect on hematopoiesis. On the other hand, the undesirable effects observed during the treatment of peptic ulcers may be beneficial in certain pathological situations in which the histaminergic receptors are implicated (52).

CONCLUSIONS The recent progress in the pharmacology of drugs directed against peptic ulcers shows that this major pathology can now be managed by a series of compounds that control either the activity of membrane receptors activated by histamine (H2 receptors), gastrin and acetylcholine, or, alternatively, the functioning of the gastric H+/K+-ATPase. The antagonism at H2 receptors has been substantiated through the development of new, powerful, selective drugs having prolonged activity and ability to regulate acid secretion without blocking it irreversibly. These characteristics are at the origin of the reduction of certain secondary effects observed during treatment with omeprazole and cimetidine: hypergastrinemia, hyperplasia of the gastric epithelial cells and rearrangement of the relative density of gastrin- and somatostatin-secreting cells, interference with

348


the liver cytochrome P450, action on cardiac rhythm and hematologic and anti-androgen effects. The success in molecular cloning of the genes encoding the histamine H1 and H2 receptors (138, 139, 362, 470) might be very helpful in ulcer therapy based on the control of gastric acid secretion by H2 receptor antagonists and cloning of the H 3 receptor gene. The evidence that the 4.5 kb DNA sequence cloned is that of the H2 receptor gene was based on the following data. Histamine increased in a dose-dependent manner cellular cAMP content in L cells permanently transfected with the H2 receptor gene. The H2-selective antagonist cimetidine shifted the histamine dose-response curve to the right. The H2 receptor-selective ligand (3H)tiotidine binding was inhibited by cimetidine. Expression of H2 receptor gene by Northern blot analysis was found in parietal cells of the fundic mucosa but not in chief cells, liver, ileum, heart, or adrenal glands (139). These elegant studies by Gantz et al. should provide essential information regarding the expression of the histamine H2 receptor gene using polyadenylated RNAs or PCR in tissues suspected to express the H2 receptor gene and those that accumulate the messenger at low levels. The comparison of the aligned sequences and conformations of the human~ canine and rat histamine H2 receptors should elucidate the molecular domains and the amino acid sequences of the H2 receptor structure serving as flexible elements responsible for the conformational variants that are involved in the acquisition of active/inactive forms of the transmembrane binding receptor and its coupling to the corresponding Gs protein complex. In addition these analyses should also identify the molecular domains of the H2 receptor that are essential for its three dimensional architecture. Molecular rearrangements between the receptor and the ligand may therefore play a crucial role in the acquisition of the activated forms of the receptor binding domain and the resulting coupling of the transmembrane protein to the G protein. In order to improve our actual knowledge on the tripartite interaction among histamine, the antagonist and the H2 receptor, the search for better H2 antagonists should be coordinated in view of the molecular modelling of the H2 histaminergic receptor structure, and the design of test compounds with potentially specific biological activity (436). Previous investigations on structureactivity of agonists and antagonists at H2 receptors (116) may be considered together with site-directed mutagenesis of the H2 receptor gene and analysis of the histamine conformers in biological fluids (449). In this connection, it should be stressed that deletions and mutations in the receptor structure, its putative ligand recognition domains and c~s protein interaction domains may influence the functional targeting of the proreceptor in the plasma membrane after gene transfer, to translocate aberrant forms of the binding site that are not able to undergo the activated receptor conformations after ligand interaction. These limitations are extended by the possibility that the active sites necessary to induce these receptor/ligand conformational changes are not necessarily located in adjacent aminoacids. Similar ligand structures in peptide hormones- and histamine-may therefore activate very different membrane receptors by their aminoacid sequence and molecular architecture. We have presented here a brief overview of the complexity and of the diversity of the regulatory networks implicated in acid secretion and the


349

p r e s e r v a t i o n o f t h e g a s t r o - d u o d e n a l m u c o s a . This s t a t u s q u o is i n t e g r a t e d in t h e i m m e d i a t e r e s p o n s e o f t h e c e l l u l a r m a c h i n e r y to t h e s i g n a l i n g s y s t e m s , a n d in t h e m e m o r i z a t i o n of this signal b y a d a p t a t i o n to a n o t h e r s t i m u l u s , a n d finally, in a late r e s p o n s e which i n v o l v e s a g e n e t i c e x p r e s s i o n , t h e r e n e w a l a n d t h e f u n c t i o n a l d i f f e r e n t i a t i o n o f t h e cells o f t h e g a s t r i c e p i t h e l i u m . F u r t h e r i d e n t i f i c a t i o n o f t h e e x t e r n a l a n d n u c l e a r factors with p o s i t i v e o r n e g a t i v e i n f l u e n c e o n t h e p r o m o t e r / e n h a n c e r r e s p o n s e e l e m e n t s o f t h e g e n e s e n c o d i n g t h e H2 r e c e p t o r o r the H + / K + - A T P a s e s u b u n i t s will p r o v i d e n e w insights in t h e p h y s i o l o g i c a l , m o l e c u l a r a n d p h a r m a c o l o g i c a l c o n t r o l o f gastric s e c r e t i o n . I m p r o v i n g o u r k n o w l e d g e o f h i s t a m i n e s e c r e t i o n a n d t h e m e c h a n i s m s of gastric s e c r e t i o n b y p h y s i o l o g i c a l r e g u l a t o r s , as well as s t u d y i n g t h e r e p a i r s y s t e m s o f t h e gastric m u c o s a , s h o u l d l e a d to a r e f i n e m e n t in t h e use o f m e d i c a t i o n for t h e t r e a t m e n t o f p e p t i c ulcers.

ACKNOWLEDGEMENTS A i d e d by a G r a n t f r o m M e r c k S h a r p a n d D o h m e C h i b r e t to C. G . (1992)

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Cellular site of gastric acid secretion.

Ferulic acid: pharmacological and toxicological aspects.

Aspects of basal gastric secretion in man.

Pathogenesis of leptospirosis: cellular and molecular aspects.

Pharmacological agents of gastric acid secretion: receptor antagonists and pump inhibitors.

Fat and gastric acid secretion.

Regulation of gastric acid secretion.

Circadian differences in pharmacological blockade of meal-stimulated gastric acid secretion.

Editorial: Antihistamines and gastric acid secretion.

Cellular and molecular biological aspects of human bronchogenic carcinogenesis.

Molecular and cellular aspects of calcium channel antagonism.

Cellular and molecular aspects of adipose tissue development.

Aspects of the effect of metiamide on pentagastrin-stimulated and basal gastric secretion of acid and pepsin in man.

Pharmacological control of corticosterone secretion in the intact rat [proceedings].

Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects.

Vagal and sympathetic control of gastric and duodenal bicarbonate secretion.

Letter: Acid secretion by gastric mucous membrane.

Acid secretion by isolated canine gastric mucosa.

Current concepts on physiological control of gastric acid secretion. Clinical applications.

[Central neurotransmitters and regulation of gastric acid secretion].

Role of human epidermal growth factor receptor 2 in gastric cancer: biological and pharmacological aspects.

Ontogeny of gastric function in the pig: acid secretion and the synthesis and secretion of gastrin.

Gastric acid secretion and acute gastroduodenal disease after burns.

Gastric acid secretion and gastrin release in the baboon.