Histamine in the control of gastric acid secretion: a topic review

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1 Pharmacological Research 47 (2003) Histamine in the control of gastric acid secretion: a topic review Elisabetta Barocelli, Vigilio Ballabeni Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Università di Parma, Parco Area delle Scienze, 27/A, Parma 43100, Italy Accepted 30 December 2002 Abstract In this paper, the current knowledge about the role of histamine in the control of gastric acid secretion is reviewed. In particular, we focus this topic into three sections considering the recent insights on: histamine receptor subtypes involved in gastric acid secretion, the interplay between neuronal hormonal paracrine pathways and the cerebral histaminergic control of gastric secretion. From the careful perusal of scientific literature, the fundamental role of histamine as local stimulator of gastric acid secretion via H 2 receptors is fairly confirmed while for the H 3 receptor only a minor modulating role is hypothesized. An undisputed function of ECL cells as controllable source of histamine within the so-called gastrin ECL cell parietal cell axis is generally proposed and the intriguing possibility of a remote control of gastric secretion via H 3 receptors is also suggested Elsevier Science Ltd. All rights reserved. Keywords: Secretagogue; Histaminergic system; Gastric acid secretion 1. Introduction Although histamine has been found to be a potent secretagogue of acid secretion since 1920 [1], its physiologic role in the stomach is again a subject of debate as also acetylcholine and gastrin are of prime importance in the stimulation of gastric acid production. In the last decade, a growing number of researches has substantially enriched the knowledge about the mechanisms involved in histamine control of acid secretion with respect to the landscape occurring in the early 90s [2 4]. The new insights about this topic concern the intervention of the histamine H 3 -type receptor, besides the well documented H 2 -subtype [5], in the regulation of gastric acid secretion, the interrelationship between paracrine, neuronal and hormonal regulatory pathways, the involvement of central histaminergic system as remote integrated control of gastric secretory function. In the present paper, we will focus on these new aspects of the experimental research about histamine and gastric acid secretion Histamine receptor subtypes and gastric acid secretion After the discovery of the third histamine receptor subtype [6], its definition as inhibitory auto-hetero-receptor in Corresponding author. Tel.: ; fax: address: barocell@unipr.it (E. Barocelli). the central and in the peripheral neuronal networks [7] and its cloning [8] major attention was devoted by researchers mainly to the re-examination of apparently anomalous effects exerted by histamine. Also for gastric acid secretion, although here histamine plays an undisputed central role through H 2 receptors activation [9], the possible involvement of this modulatory receptor was functionally investigated [10]. The first evidence for a gastric H 3 histamine receptor was provided through in vivo studies performed on fistula cats [11,12] and these findings were confirmed by additional experimental data successively obtained in dogs [13] and rats [14]. In these experiments the peripheral administration of the selective H 3 agonist (R)alpha-methylhistamine partially reduced acid secretory response to indirect stimuli involving vagal or enterochromaffin-like (ECL) cells activation suggesting that this receptor could mediate a not better defined braking action of histamine on one or more steps of acid secretion process. A direct inhibition of the secretory function through H 3 receptors located on the parietal cell itself was suggested by Bado et al. [15] who studied cholinergic stimulation of acid production in isolated rabbit fundic glands. On the contrary, in other papers published in the same period, a substantial ineffectiveness of the H 3 agonists on gastric acid secretion in the vascularly-perfused rat stomach and in the anaesthetized rat was reported [16,17]. On the other hand, data obtained in the isolated mouse stomach supported a stimulant effect of (R)alpha-methylhistamine on acid secretion [18] (Table 1) /03/$ see front matter 2003 Elsevier Science Ltd. All rights reserved. doi: /s (03)

2 300 E. Barocelli, V. Ballabeni / Pharmacological Research 47 (2003) Table 1 Effects of histamine H 3 receptor activation on gastric acid secretion Species Technique Stimulation/inhibition Reference Conscious cat Gastric fistula [11,12] Conscious dog Gastric fistula [13] Rabbit Isolated fundic gastric glands [15] Anaesthetized rat Lumen flushed stomach [14] Anaesthetized rat Lumen perfused stomach No effect [17] Rat Vascularly perfused stomach No effect [16] Mouse Isolated whole stomach + [18] Inhibition and stimulation are denoted by and + symbols, respectively. These different findings in favor of an inhibitory or stimulatory effect of histamine on acid secretion via H 3 receptors, are probably due to the use of different species as well as the employment of experimental techniques differing for the stimulants and the biological substrates. In an effort to clarify the role of the H 3 receptor in the control of acid response to various secretagogues we recently considered the effects on pentagastrin, bethanechol and vagal stimulation in anaesthetized rats. This enabled us to demonstrate that this receptor subtype tonically contributes to extinguish H + secretion in rat stomach only when low acid secretion occurs thus playing a minor role within the multiple regulation of the acid secretory function [19]. As concerns the gastric localization of the H 3 receptors, the early Korte s binding work [20] with [ 3 H]-N-alphamethylhistamine and the subsequent research performed by Yanai et al. [21] with the tritiated S-methylthioperamide provided the direct evidence for the presence of this receptor in guinea-pig and rat stomach. Successively, evidence for the existence of H 3 receptors in human gastric mucosa was provided considering [ 3 H]-N-alpha-methylhistamine specific binding in antral and fundic biopsy specimens [22] and in human gastric tumoral cells HGT-1 [23]. Several studies furnished functional evidence for a heterogeneous distribution of the histamine H 3 receptors in the distinct elements of gastric wall on the basis of their involvement in the release of the mediators controlling acid secretory response. In gastric purified ECL cells prepared from rats, selective H 3 stimulants cause a decrease of histamine release [24,25]. This finding is consistent with the observation that (R)alpha-metylhistamine inhibits histamine synthesis in rabbit ECL cells [26] and basal histamine secretion in isolated rabbit gastric glands [27]. Also the intravenous administration of H 3 agonist in dogs reduces pentagastrin-induced histamine concentrations in plasma [28]. All these data support the hypothesis that, through the activation of H 3 receptors located on gastric ECL cells, histamine can downregulate its own synthesis and secretion in the stomach. Discordant results derive from the experiments performed on rat purified ECL cells by Lindstrom et al. who failed to confirm any significant involvement of histamine H 3 autoreceptors in the control of gastric histamine release [29]. The feed-back inhibition of histamine previously demonstrated by the same authors in vivo [30] was concluded to be an indirect action of histamine on adjacent non-ecl cells rather than a direct involvement of ECL cells. According to this view, an inhibitory paracrine pathway linking somatostatin and histamine cells was proposed by Vuyyuru et al. [31] which in antral mucosal segments obtained from rat, dog and human stomach, demonstrated that gastric histamine predominantly inhibits somatostatin release through H 3 receptor activation. A similar reciprocal inhibition between fundic ECL cells and somatostatin cells was proved in isolated mouse stomach where histamine, via H 3 receptors, inhibited somatostatin and thus stimulated histamine and acid secretion [18]. These findings lead the authors to conclude that in semplified preparations, as ECL cells, it prevails an H 3 dependent autocrine way inhibiting histamine release. On the other hand, in the intact stomach, an H 3 paracrine effect exerted on somatostatin cells yielding uncontrolled histamine release, appears to be dominant. The picture results still more complex when the neural control of gastric secretory function is considered. In isolated vascularly perfused rat stomach, Yokotani et al. [32] provided evidence for the presence of an histamine H 3 heteroreceptor mediating inhibition of acetylcholine release from vagus nerve terminals (Table 2). Recently, we corroborated this finding in functional studies on anaesthetized rats since the H 3 agonist (R)alpha-methylhistamine inhibited acid secretory response to direct vagal stimulation without affecting protons production induced by exogenous cholinomimetics [19]. The experimental data from the same investigation suggested the presence of H 3 receptors also on ECL cells, where H 3 receptors are tonically activated and inhibit acid secretion stimulated by low-dose of pentagastrin. Although the bulk of literature data is indicative of the multiple location of histamine H 3 receptors in different elements of the gastric wall with opposite effects on acid secretion, for the H 3 receptors a predominant inhibitory role is generally recognized. The difficulty in drawing consistent conclusions about the meaning of histamine H 3 receptor in the control of gastric secretion depends on the conditions of acid stimulation which varies according to the different species/techniques/preparations used; however, in our opinion, H 3 receptors seem to have an ancillary role in the regulation of the acid secretory function. To date, H 3 agonists/antagonists did not find any indications for the treatments of gastric disorders while histamine

3 E. Barocelli, V. Ballabeni / Pharmacological Research 47 (2003) Table 2 Effects of histamine H 3 receptor activation on the release of mediators of gastric acid secretion Species Evoked release of mediator Preparation Reference Rat Histamine Gastric purified ECL [24,25] Rabbit Basal histamine Isolated gastric glands [27] Dog Histamine Plasma in vivo [28] Rat Histamine Stomach endocrine cells [30] Rat, dog, human Histamine gastrin somatostatin Antral mucosal segments [31] Mouse Histamine somatostation Isolated stomach luminal effluent [18] Rat Acetylcholine Isolated stomach vascular perfusate [32] Increase and reduction of mediator release are denoted by and symbols, respectively. H 2 receptor blockers still remain a common therapeutic tool for acid related diseases. An innovative exciting role for the H 2 antagonists has been proposed in the inhibition of cell growth and differentiation, since H 2 receptors were proved to be expressed in several human neoplastic cell lines [33]. Indeed, more recently various clinical trials indicate that cimetidine treatment, as an adjunct to curative operation, can improve survival in patients with gastrointestinal cancer [34,35]. These data confirm that histamine, in addition to a broader range of biological actions, exerts also growth-promoting effects via H 2 receptors opening new fields for the therapeutic application of H 2 -blockers actually overtaken by proton pump inhibitors as antisecretory drugs. In the stomach of many Helicobacter pylori-infected subjects an increased content of N-alpha-methylhistamine was detected and it was attributed to the bacteria metabolism [22,36]. This histamine metabolite, besides other inflammatory mediators, seems to be correlated with local changes as reduction of the antral somatostatin release [22] and the inhibition of acid secretion [37] through the activation of histamine H 3 gastric receptors. However, the involvement of histamine H 2 receptors in the effects of N-alpha-methylhistamine cannot be ruled out considering the finding that this amine is a dual H 2 /H 3 agonist [38]. In chronic infection of the gastric mucosa, as occurs with H. pylori colonization, a significant correlation between H. pylori-positivity of patients and the presence of mast cells in the inflamed gastric mucosa has been demonstrated [39]. Experimentally, in rats infected with H. pylori protein extracts, the disturbance of gastric mucosal microcirculation was partly associated with histamine hypothetically released from mast cells. The protective effect exerted not only by ketotifen but also by pyrilamine pretreatment indicated the activation of vascular H 1 receptors [40]. Onthe whole, histamine seems to be the common transmitter of two distinct regulatory systems in the gastric mucosa: the ECL cells involved in the control of acid secretion and the mast cells mainly associated to the regulation of gastric mucosal blood flow [41,42]. Whereas, the histamine receptor subtypes H 1,H 2 and H 3 have been proved to be differently involved in the gastric responses to this multifunctional mediator, to date no evidence for a role of histamine H 4 receptor has been provided. Indeed this receptor subtype recently identified shows highest expression in bone marrow and leukocytes with moderate levels in other organs [43] and on the basis of the present biological knowledge it seems to play a significant role only in the immune system [44] Interplay between neuronal, hormonal and paracrine stimuli Histamine, gastrin and acetylcholine are known to be critically involved in the stimulation of gastric acid secretion but their mutual intercorrelation remains to be clarified. The crucial importance of the local hormone gastrin was conclusively confirmed by studies performed on gastrin-deficient mice. In these knockout animals, the total lack of gastric acid response to histamine, carbachol or gastrin was associated to a reduction of parietal cells number and histidine decarboxilase expression in ECL cells. The significance of gastrin for the maintenance of the normal acid-secretory machinery was corroborated by the partial restoration of gastric acid secretion obtained when gastrin replacement was allowed [45]. It is noteworthy that gastrin seems to play this key role in gastric acid secretion primarily operating as trophic factor for both parietal and ECL cells. Indeed, the secretory response to this peptide requires the mediation of endogenous histamine as evidenced by the failure to induce gastrin-dependent acid response in H 2 receptor or l-histidine decarboxylase-deficient mice [46,47]. The responsiveness of these mutants to carbachol strengthens the concept that histamine release is essential for gastric acid secretion evoked by gastrin but not by choline esters which seem stimulate acid production acting directly on parietal cells. Investigations both in vitro and in vivo, through microdialysis technique in conscious rats, have confirmed that acetylcholine did not significantly affect histamine secretion from ECL cells [48,49]. From studies on preparations of pure, well-functioning ECL cells, it has been demonstrated that they actively produce and secrete histamine under the direct control of various gastrointestinal hormones and neural mediators [24,50,51]. Indeed, besides the stimulation exerted by gastrin and CCK-8s via CCK B -receptors, adrenergic agonists have been shown to stimulate ECL cell histamine mobilization through 2 -receptors [52]. Peptides from the enteric neurons such as pituitary adenylate

4 302 E. Barocelli, V. Ballabeni / Pharmacological Research 47 (2003) cyclase activating peptide (PACAP) and vasoactive intestinal peptide (VIP) stimulate ECL cells via PAC 1 and VPAC 2 receptors respectively, while contradictory results are provided in favour of the presence of muscarinic receptors on ECL cells [24,52]. Studies performed on highly purified and cultured ECL cells by different laboratories showed that several regulatory peptides and inflammatory mediators affect ECL activity as inhibitors. Somatostatin, from paracrine D cells neighboring ECL cells, was proved to totally inhibit gastrin- and PACAP-induced histamine secretion from isolated/cultured ECL cells acting at somatostatin receptors subtype 2 [52,53]. Also, using isolated mouse stomach, somatostatin was demonstrated to inhibit gastric acid secretion blocking primarily histamine release from ECL cells rather than directly inhibiting parietal cells [54]. The neuropeptide galanin, present in the myenteric/submucosal plexus, inhibits the aforementioned histamine release, although with a minor efficacy, interacting predominantly at GAL 1 receptor site [55]. Thus, ECL cells play a pivotal role as interface between parietal cells and various adjacent endocrine/neuronal elements. An additional control of histamine secretion from ECL cells is indirectly performed by some neuropeptides (CGRP, Met-enkephalin, PYY) and endothelin which proved to be ineffective on isolated ECL cells but modified microdializate histamine concentration in gastric mucosa of conscious rats [49]. Possible targets for these mediators were suggested to be somatostatin D cells or gastric microvasculature [49]. When inflammatory events occur in gastric mucosa, further tissutal factors come into play. IL-1 and TNF- high mucosal concentrations increase local PGE 2 production which has been claimed to impair histamine secretion from ECL cells through EP 3 receptors [56]. Within this picture, the so called gastrin-ecl cell-parietal cell axis truly has ECL cell as its fulcrum. Indeed, this paracrine cell is essential for gastrin-mediated secretory responses, it is the predominant source of gastric histamine, which represents the primary mediator for parietal cell activation, and it is the site of integration of several regulators acting in concert (directly and/or indirectly) to coordinate gastric acid secretion in vivo. From this point of view, it is possible to overtake the mere mechanistic schemes proposed in the transmission and permission theories [57,58] in favour of a more articulate vision of secretory process where distinct and orchestrate roles are played by gastrin, histamine and acetylcholine (Fig. 1). Fig. 1. Cartoon showing acetylcholine, histamine, somatostatin and gastrin interconnections in the regulatory pathways of gastric acid secretion. Proposed locations of peripheral inhibitory histamine H 3 receptors based on the literature reviewed in the text are sketched. Acetylcholine (M), histamine (H), somatostatin (SST), gastrin (CCK) receptors are indicated; inhibitory signal; + stimulatory signal.

5 E. Barocelli, V. Ballabeni / Pharmacological Research 47 (2003) Central histaminergic control of gastric secretory function Notwithstanding the growing knowledge of brain gut interactions [59 61] and the recognition of histamine as neurotransmitter widely distributed in CNS [62], the role of this amine in the central control of gastric acid secretion has been scarcely investigated. Early on, the intracerebroventricular injection of H 1 and H 2 antagonists did not seem to influence acid secretion in pylorus ligated rats [63]. Successively, apparently conflicting results were reported indicating a stimulatory effect of centrally administered histamine on basal gastric secretion [64] or an inhibitory effect of the amine on pentagastrin-induced secretory response in anaesthetized rats [65]. The different range of doses used in these investigations as well as the distinct secretory condition could explain these non-consistent findings. A central inhibitory role of histamine on acid secretion is corroborated and enriched by our data obtained in pylorus-ligated rats which provide evidence for an H 3 dependent reduction of acid response exerted by the H 3 selective agonist (R)alpha-methylhistamine [66]. More recently, also for the poorly selective agonist N-alpha-methylhistamine a dose-dependent attenuation of gastric acid output was detected after intraventricular injection of microgram/kilogram doses in rats [67]. Based on these findings, it is likely that the activation of central histamine H 3 receptors generates a vagal descending inhibitory signal able to decrease gastric acid production possibly through the mediation of somatostatin [65]. 2. Concluding remarks On the basis of the scientific contributions herein reported, the physiological relevance of histamine as local stimulator of gastric acid secretion (via H 2 receptors) is clearly confirmed. 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