Identification of histamine receptors and effects of histamine on murine and simian colonic excitability

Abstract

Background Inflammatory responses can include recruitment of cells of hematopoietic origin to the tunica muscularis. These cells can secrete a variety of factors which can reset the gain of smooth muscle cells (SMC) and influence motor patterns. Histamine, a major mediator in inflammation, is released by mast cells and exerts diverse effects in SMC by binding to histamine (H) receptors. The profiles of H receptor expression in animal models used to study inflammatory diseases are unknown. Methods H receptor expression and electro-mechanical responses to histamine were tested in simian and murine colonic smooth muscle using qualitative and quantitative PCR, isometric force measurements, microelectrode recordings and patch clamp techniques. Key results H1, H2 and H4 receptor transcripts were expressed at similar levels in simian colonic tissue whereas only the H2 receptor transcript was detected in murine colonic tissue. Stimulation of simian colonic muscles with histamine caused depolarization and contraction in the presence of TTX. Histamine activated non-selective cation channels in simian SMC. In contrast, histamine caused hyperpolarization and inhibited contractions of murine colon. The hyperpolarization was inhibited by the KATP channel blocker, glibenclamide. Histamine-activated K+ currents were inhibited by glibenclamide in murine colonic SMC. Conclusions & Inferences H receptor expression in simian SMC was similar to that reported in humans. However, H receptor profile and responses to histamine were considerably different in mice. Thus, monkey colon may be a more suitable model to study how inflammatory mediators affect the gain of smooth muscle excitability.

Effects of Histamine on Cultured Interstitial Cells of Cajal in Murine Small Intestine

“…To identify the receptor subtypes of histamine involved in cultured ICCs, cells were treated with various histamine receptor agonists. 2-Pyridylethylamine (2-PEA) (a selective H1-agonist) [26], Dimaprit (a selective H2-agonist) [24], R-alpha-methylhistamine (R-alpha-MeHa) (a selective H3-agonist) [24], and 4-methylhistamine (4-MH) (a selective H4-agonist) [27] were all administered at a concentration of 50µM. 2-PEA depolarized pacemaker potentials, but others histamine receptor agonists had no effects on pacemaker potentials (n=5, respectively; Fig.…”

“…Bolton et al [38] showed that histamine depolarized longitudinal smooth muscle cells and increased action potential discharge in guinea-pig ileum. Recently, Kim et al [24] investigated that H1, H2 and H4 receptor transcripts were expressed at similar levels in simian colonic tissue whereas only the H2 receptor transcript was detected in murine colonic tissue. Stimulation of simian colonic muscles with histamine caused depolarization and contraction in the presence of TTX.…”

“…Histamine-activated K + currents were inhibited by glibenclamide in murine colonic smooth muscle cells. Therefore, they suggested that since histamine receptor expression in simian colon is closer to that reported in human, they suggested that it is a more suitable model to predict the effects of the inflammatory mediator, histamine, on colonic motility in humans [24]. However, previous studies on the effects of histamine on GI motility studies were usually performed on smooth muscles, and no investigation has been conducted on the effects of histamine on ICCs, the pacemaker cells in the GI tract.…”

“…Kim et al [24] suggested that only the H2 receptor transcript was detected in murine colonic tissue. These results are different from our this study.…”

“…Oishi et al [23] studied the effect of histamine receptor ligands on the intestinal transit of a charcoal meal in mice, but did not observe any H receptor mediated effect in response to the histamine-receptor agonist. Recently, Kim et al [24] investigated the expression of histamine receptors and responses to histamine in colonic contractility in mouse and monkey and they suggested that histamine receptor expression in simian colon is closer to that reported in human. However, the effects of histamine on mouse small intestinal ICCs have not been previously investigated, and thus, we conducted this study to investigate the effects of histamine in mouse small intestinal ICCs.…”