Pharmacological Research 47 (2003) 299–304 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 H2 receptors is fairly confirmed while for the H3 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 H3 receptors is also suggested. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Secretagogue; Histaminergic system; Gastric acid secretion 1. Introduction the central and in the peripheral neuronal networks [7] and its cloning [8] major attention was devoted by researchers Although histamine has been found to be a potent secret- mainly to the re-examination of apparently anomalous ef- agogue of acid secretion since 1920 [1], its physiologic role fects exerted by histamine. Also for gastric acid secretion, in the stomach is again a subject of debate as also acetyl- although here histamine plays an undisputed central role choline and gastrin are of prime importance in the stimula- through H2 receptors activation [9], the possible involvement tion of gastric acid production. In the last decade, a growing of this modulatory receptor was functionally investigated number of researches has substantially enriched the knowl- [10]. The first evidence for a gastric H3 histamine receptor edge about the mechanisms involved in histamine control of was provided through in vivo studies performed on fistula acid secretion with respect to the landscape occurring in the cats [11,12] and these findings were confirmed by additional early ’90s [2–4]. experimental data successively obtained in dogs [13] and The new insights about this topic concern the interven- rats [14]. In these experiments the peripheral administra- tion of the histamine H3-type receptor, besides the well doc- tion of the selective H3 agonist (R)alpha-methylhistamine umented H2-subtype [5], in the regulation of gastric acid partially reduced acid secretory response to indirect stim- secretion, the interrelationship between paracrine, neuronal uli involving vagal or enterochromaffin-like (ECL) cells and hormonal regulatory pathways, the involvement of cen- activation suggesting that this receptor could mediate a tral histaminergic system as remote integrated control of not better defined braking action of histamine on one or gastric secretory function. In the present paper, we will fo- more steps of acid secretion process. A direct inhibition cus on these new aspects of the experimental research about of the secretory function through H3 receptors located on histamine and gastric acid secretion. the parietal cell itself was suggested by Bado et al. [15] who studied cholinergic stimulation of acid production in 1.1. Histamine receptor subtypes and gastric isolated rabbit fundic glands. On the contrary, in other acid secretion papers published in the same period, a substantial ineffec- tiveness of the H agonists on gastric acid secretion in the After the discovery of the third histamine receptor sub- 3 vascularly-perfused rat stomach and in the anaesthetized type [6], its definition as inhibitory auto-hetero-receptor in rat was reported [16,17]. On the other hand, data obtained ∗ in the isolated mouse stomach supported a stimulant ef- Corresponding author. Tel.: +39-0521-905-090; fax: +39-0521-905-091. fect of (R)alpha-methylhistamine on acid secretion [18] E-mail address: [email protected] (E. Barocelli). (Table 1). 1043-6618/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1043-6618(03)00009-4 300 E. Barocelli, V. Ballabeni / Pharmacological Research 47 (2003) 299–304 Table 1 Effects of histamine H3 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 stim- was concluded to be an indirect action of histamine on adja- ulatory effect of histamine on acid secretion via H3 recep- cent non-ECL cells rather than a direct involvement of ECL tors, are probably due to the use of different species as well cells. According to this view, an inhibitory paracrine path- as the employment of experimental techniques differing for way linking somatostatin and histamine cells was proposed the stimulants and the biological substrates. In an effort to by Vuyyuru et al. [31] which in antral mucosal segments clarify the role of the H3 receptor in the control of acid re- obtained from rat, dog and human stomach, demonstrated sponse to various secretagogues we recently considered the that gastric histamine predominantly inhibits somatostatin effects on pentagastrin, bethanechol and vagal stimulation in release through H3 receptor activation. A similar reciprocal anaesthetized rats. This enabled us to demonstrate that this inhibition between fundic ECL cells and somatostatin cells receptor subtype tonically contributes to extinguish H+ se- was proved in isolated mouse stomach where histamine, cretion in rat stomach only when low acid secretion occurs via H3 receptors, inhibited somatostatin and thus stimulated thus playing a minor role within the multiple regulation of histamine and acid secretion [18]. These findings lead the the acid secretory function [19]. authors to conclude that in semplified preparations, as ECL As concerns the gastric localization of the H3 receptors, cells, it prevails an H3 dependent autocrine way inhibiting the early Korte’s binding work [20] with [3H]-N-alpha- histamine release. On the other hand, in the intact stomach, methylhistamine and the subsequent research performed by an H3 paracrine effect exerted on somatostatin cells yielding Yanai et al. [21] with the tritiated S-methylthioperamide uncontrolled histamine release, appears to be dominant. provided the direct evidence for the presence of this recep- The picture results still more complex when the neural tor in guinea-pig and rat stomach. Successively, evidence control of gastric secretory function is considered. In iso- for the existence of H3 receptors in human gastric mucosa lated vascularly perfused rat stomach, Yokotani et al. [32] 3 was provided considering [ H]-N-alpha-methylhistamine provided evidence for the presence of an histamine H3 het- specific binding in antral and fundic biopsy specimens [22] eroreceptor mediating inhibition of acetylcholine release and in human gastric tumoral cells HGT-1 [23]. Several from vagus nerve terminals (Table 2). Recently, we corrob- studies furnished functional evidence for a heterogeneous orated this finding in functional studies on anaesthetized distribution of the histamine H3 receptors in the distinct rats since the H3 agonist (R)alpha-methylhistamine inhib- elements of gastric wall on the basis of their involvement ited acid secretory response to direct vagal stimulation in the release of the mediators controlling acid secretory without affecting protons production induced by exogenous response. In gastric purified ECL cells prepared from rats, cholinomimetics [19]. The experimental data from the same selective H3 stimulants cause a decrease of histamine investigation suggested the presence of H3 receptors also on release [24,25]. This finding is consistent with the ob- ECL cells, where H3 receptors are tonically activated and in- servation that (R)alpha-metylhistamine inhibits histamine hibit acid secretion stimulated by low-dose of pentagastrin. synthesis in rabbit ECL cells [26] and basal histamine Although the bulk of literature data is indicative of the secretion in isolated rabbit gastric glands [27]. Also the multiple location of histamine H3 receptors in different el- intravenous administration of H3 agonist in dogs reduces ements of the gastric wall with opposite effects on acid se- pentagastrin-induced histamine concentrations in plasma cretion, for the H3 receptors a predominant inhibitory role [28]. All these data support the hypothesis that, through is generally recognized. The difficulty in drawing consistent the activation of H3 receptors located on gastric ECL cells, conclusions about the meaning of histamine H3 receptor in histamine can downregulate its own synthesis and secretion the control of gastric secretion depends on the conditions in the stomach. Discordant results derive from the exper- of acid stimulation which varies according to the different iments performed on rat