Regulation of ion transport by histamine in human colon

doi:10.1016/0014-2999(95)00156-F

European Journal of Pharmacology

Volume 279, Issues 2–3, 12 June 1995, Pages 203-209

https://doi.org/10.1016/0014-2999(95)00156-F Get rights and content

Abstract

Histamine, added to the basolateral side of voltage clamped human colon in vitro, induced a rapid onset, transient inward short circuit current which was concentration dependent over the range 0.01–3 mM. This response was largely due to electrogenic chloride secretion since it was virtually abolished by bumetanide or by chloride replacement in the bathing solutions. Responses were unaffected by amiloride or acetazolamide. Neither the histamine H₂ receptor agonist dimaprit (1 mM) nor the histamine H₃ receptor agonist S-(+)-α-methyl histamine (1 mM) altered short circuit current. Responses to histamine were significantly reduced by the histamine H₁ receptor antagonist mepyramine (1–10 μM) but not altered by the histamine H₂ receptor antagonist cimetidine (100 μM) or by the histamine H₃ receptor antagonist thioperamide (1 μM). Short circuit current responses to histamine were not altered by tetrodotoxin (1 μM). Piroxicam (10 μM) and nordihydroguaiaretic acid (100 μM) were without effect when used individually but significantly reduced responses to histamine when used simultaneously. These results indicate that histamine stimulates chloride secretion across human colonic epithelium by a mechanism which is mediated exclusively via histamine H₁ receptors. This action does not involve intrinsic nerves but appears to be dependent upon eicosanoid synthesis.

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Localized elevation of H1R and H2R expression in the gut has been previously demonstrated in human inflammatory gastrointestinal conditions, including food allergy (Sander et al., 2006). H1R has been shown to influence vasodilation, contractility, transepithelial permeability (Keely et al., 1995; Togias, 2003), and communication with the enteric nervous system (Bell et al., 2015). Furthermore, these histamine receptors have been implicated in immunoregulatory roles by influencing both Th1- and Th2-type helper T lymphocyte responses (Bell et al., 2015; Jutel et al., 2001).
Central histaminergic H3 receptor (H3R) has been extensively investigated as a potential therapeutic target for various neurological and neurodegenerative disorders. Despite promising results in preclinical rodent models, clinical trials have not provided conclusive evidence for the benefit of H3R antagonists to alleviate cognitive and behavioral symptoms of these disorders. Inconsistent pharmacological efficacies may arise from aberrant changes in H3R over time during disease development. Because H3R is involved in feedback inhibition of histamine synthesis and secretion, the expression of the autoreceptor may also be reciprocally regulated by altered histamine levels in a pathological condition. Thus, we investigated H3R expression in a mouse model of cow’s milk allergy, a condition associated with increased histamine levels. Mice were sensitized to bovine whey proteins (WP) over 5 weeks and H3R protein and transcript levels were examined in the brain. Substantially increased H3R immunoreactivity was observed in various brain regions of WP-sensitized mice compared to sham mice. Elevated H3R expression was also found in the thalamic/hypothalamic region. The expression of histaminergic H1, but not H2, receptor subtype was also increased in this and the midbrain regions. Unlike the brain, all three histaminergic receptors were increased in the small intestine. These results indicated that the central histaminergic receptors were altered in WP-sensitized mice in a subtype- and region-specific manner, which likely contributed to behavioral changes we observed in these mice. Our study also suggests that altered levels of H3R could be considered during a pharmacological intervention of a neurological disease.
Prostaglandin D<inf>2</inf> regulates human colonic ion transport via the DP<inf>1</inf> receptor
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Prostaglandin D₂ is released by mast cells and is important in allergies. Its role in gastrointestinal function is not clearly defined. This study aimed to determine the effect of exogenous PGD₂ on ion transport in ex vivo normal human colonic mucosa.
Mucosal sheets were mounted in Ussing chambers and voltage clamped to zero electric potential. Ion transport was quantified as changes in short-circuit current. In separate experiments epithelial monolayers or colonic crypts, isolated by calcium chelation, were treated with PGD₂ and cAMP levels determined by ELISA or calcium levels were determined by fluorimetry.
PGD₂ caused a sustained, concentration-dependent rise in short-circuit current by increasing chloride secretion (EC₅₀ = 376 nM). This effect of PGD₂ is mediated by the DP₁ receptor, as the selective DP₁ receptor antagonist BW A686C inhibited PGD₂-induced but not PGE₂-induced rise in short-circuit current. PGD₂ also increased intracellular cAMP in isolated colonic crypts with no measurable influence on cytosolic calcium. PGD₂ induces chloride secretion in isolated human colonic mucosa in a concentration-dependent manner with concomitant elevation of cytoplasmic cAMP in epithelial cells.
The involvement of DP₂ receptor subtypes has not previously been considered in regulation of ion transport in human intestine. Since inflammatory stimuli may induce production of eicosanoids, selective regulation of these pathways may be pivotal in determining therapeutic strategies and in understanding disease.
Zinc sulphate attenuates chloride secretion in Human colonic mucosae in vitro
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We examined chloride secretion stimulated pharmacologically by two separate transduction pathways (Kunzelmann, 2002). Forskolin and PGE2 elevate intracellular cAMP to cause Cl− secretion, and carbachol and histamine elevate intracellular Ca2+ to stimulated epithelial Cl− secretion (Keely et al., 1995; Chough et al., 1993). The presence of zinc in the basolateral (but not apical) compartment significantly attenuated the stimulated transepithelial Cl− secretion induced by both cAMP- and Ca2+-mediated secretagogues.
Zinc's usefulness in the treatment of diarrhoea is well established as an addition to oral rehydration. Mechanisms of action of zinc have been explored in intestinal epithelia from rodents and in cell lines. The aim was to examine how zinc alters ion transport and signal transduction in human colon in vitro. Voltage clamped colonic sheets obtained at the time of surgical resection were used to quantify ion transport responses to established secretagogues. Nystatin permeabilisation was used to study basolaterally-sited ion channels. Direct actions of zinc were determined using preparations of colonic crypts isolated from human mucosal sheets. Electrophysiological measurements revealed zinc to be an inhibitor of electrogenic ion transport stimulated by forskolin, PGE₂, histamine and carbachol in isolated human colonic epithelium. Basolateral addition of zinc sulphate had no direct effect on the epithelium. To further outline the mechanism of action, levels of secondary intracellular messengers (3’, 5’-cyclic adenosine monophosphate; cAMP) were determined in isolated colonic crypts, and were found to be reduced by zinc sulphate. Finally, indirect evidence from nystatin-permeabilised mucosae further suggested that zinc inhibits basolateral K⁺ channels, which are critical for transepithelial Cl⁻ secretion linked to water flux. Anti-secretory, and therefore anti-diarrhoeal, actions of exogenous zinc are due, at least in part, to direct basolateral epithelial K⁺ channel inhibition.
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The pathophysiological relevance of histamine has been frequently shown in allergic and non-allergic diseases including gastrointestinal diseases such as IBD and IBS [18,38,64,74–78]. In the human intestine histamine influences a variety of gut functions including fluid and ion transport [79–81] which is partly nerve mediated [79]. Histamine directly excites human submucous neurons [82].
This paper summarizes the current knowledge on the interactions between intestinal mast cells, enteric neurons and visceral afferents which are part of the gut brain axis. The focus of this review is on the relevance of the mast cell–nerve axis in the human intestine. Similarities and important differences in the organization of the mast cell–nerve axis between human and rodents are discussed. Functionally important human mast cell mediators with neural actions in the human ENS are histamine (H1-4 receptors), proteases (PAR1 receptors), several cytokines and chemokines and probably also serotonin (5-HT₃ receptors). On the other hand, mediator release from human intestinal mast cells is modulated by neuropeptides released from enteric and visceral afferent nerves. This article is part of a Special Issue entitled: Mast Cells in Inflammation.
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The involvement of histamine receptors in histamines’ effect on permeability of different tissues has been widely demonstrated. H1 receptors seem to play the most important role; in airway epithelia (Flynn et al., 2009; Chan et al., 1987), in vascular epithelia (Flynn et al., 2009), in nostrils (Yang et al., 2003), in Fallopian tubes and ovaries (Downing et al., 1999, 2002) and in human colon (Keely et al., 1995). Nevertheless, H2 receptors may also play a part, as for example in the lung (Braude et al., 1984), in porcine proximal colon (Ahrens et al., 2003) and in rat pleura (Lo et al., 1985).
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Regular paperRegulation of ion transport by histamine in human colon

Abstract

Prostaglandins

Gastroenterology

Gastroenterology

Biochim. Biophys. Acta

Gastroenterology

Gastroenterology

Biol. Chem.

Comp. Gen. Pharmacol.

Life Sci.

Gastroenterology

Neuroscience

Neuroscience

Submucosal plexus and electrolyte transport across rat colonic mucosa

J. Physiol.

Highly potent and selective ligands for histamine H3 receptors

Nature

Systemic mastocytosis

New Engl. J. Med.

Mechanisms of chloride secretion in a colonic epithelial cell line

Fibroblasts modulate intestinal secretory responses to inflammatory mediators

J. Clin. Invest.

Cimetidine — a nonthiourea H2-receptor antagonist

J. Int. Med. Res.

Immunological regulation of epithelial function

Am. J. Physiol.

Effects of neuronal stimulation on mucosal transport in guinea pig ileum

Am. J. Physiol.

Histamine action on guinea pig ileal mucosa

Am. J. Physiol.

Basolateral K conductance: role in regulation of NaCl absorption and secretion

Am. J. Physiol.

Regular paper
Regulation of ion transport by histamine in human colon

Highly potent and selective ligands for histamine H₃ receptors

Cimetidine — a nonthiourea H₂-receptor antagonist