Amitriptyline functionally antagonizes cardiac H2 histamine receptors in transgenic mice and human atria.

We have previously shown that histamine (2-(1H-imidazol-4-yl)ethanamine) exerted concentration-dependent positive inotropic effects (PIE) or positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic (H2R-TG) mice that overexpress the human H2 histamine receptor (H2R) in the heart; however, the effects were not seen in their wild-type (WT) littermates. Amitriptyline, which is still a highly prescribed antidepressant drug, was reported to act as antagonist on H2Rs. Here, we wanted to determine whether the histamine effects in H2R-TG were antagonized by amitriptyline. Contractile studies were performed on isolated left and right atrial preparations, isolated perfused hearts from H2R-TG and WT mice and human atrial preparations. Amitriptyline shifted the concentration-dependent PIE of histamine (1 nM-10 µM) to higher concentrations (rightward shift) in left atrial preparations from H2R-TG. Similarly, in isolated perfused hearts from H2R-TG and WT mice, histamine increased the contractile parameters and the phosphorylation state of phospholamban (PLB) at serine 16 in the H2R-TG mice, but not in the WT mice. However, the increases in contractility and PLB phosphorylation were attenuated by the addition of amitriptyline in perfused hearts from H2R-TG. In isolated electrically stimulated human atria, the PIE of histamine that was applied in increasing concentrations from 1 nM to 10 µM was reduced by 10-µM amitriptyline. In summary, we present functional evidence that amitriptyline also acts as an antagonist of contractility at H2Rs in H2R-TG mouse hearts and in the human heart which might in part explain the side effects of amitriptyline.

Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis.

Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.

Role of thalamic ventral posterolateral nucleus histamine H2 and opiate receptors in modulation of formalin-induced muscle pain in rats.

BACKGROUND: Histamine and opiate systems contribute to supraspinal processing of pain. In the present study, we investigated the effects of microinjection of histamine and agonists and antagonists of histamine H2 and opiate receptors into the thalamic ventral posterolateral nucleus on muscle pain in rats. METHODS: The thalamic ventral posterolateral nuclei were bilaterally implanted with two guide cannulas. Muscle pain was induced by intramuscular injection of a diluted formalin solution (2.5%, 50µl) into the belly of gastrocnemius muscle, and pain-related behaviors including paw licking duration and paw flinching number were recorded at five-min blocks for 60min. RESULTS: Formalin produced a biphasic pattern of pain-related behaviors. Ranitidine (a histamine H2 receptor antagonist) alone did not affect pain intensity, whereas it prevented the antinociceptive activities of histamine, dimaprit (a histamine H2 receptor agonist) and morphine (an opiate receptor agonist). Naloxone (an opiate receptor antagonist) alone increased pain, and inhibited histamine-, dimaprit-, and morphine-induced antinociception. Locomotor activity was not changed with these chemicals. CONCLUSIONS: Our results showed an interaction between histamine H2 and opiate receptors at the thalamic ventral posterolateral nucleus in modulation of muscle pain.

[Mechanisms of histamine ameliorating memory impairment induced by pentylenetetrazole-kindling epilepsy in rats].

Objective: To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms. Methods: A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed. Results: Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all P<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all P<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all P<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine. Conclusion: Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.

Cimetidine disrupts the renewal of testicular cells and the steroidogenesis in a hermaphrodite fish.

The importance of histamine in the physiology of the testis in mammals and reptiles has been recently shown. Histamine receptors (Hrs) are well conserved in fish and are functional in several fish species. We report here for the first time that histamine and the mRNA of Hrh1, Hrh2 and Hrh3 are all present in the gonad of the hermaphrodite teleost fish gilthead seabream. Moreover, cimetidine, which acts in vitro as an agonist of Hrh1 and Hrh2 on this species, was intraperitoneally injected in one and two years old gilthead seabream males. After three and five days of cimetidine injection, we found that this compound differently modified the gonadal hrs transcript levels and affects the testicular cell renewal and the gene expression of steroidogenesis-related molecules as well as the serum steroid levels. Our data point to cimetidine as a reproductive disruptor and elucidate a role for histamine in the gonad of this hermaphrodite fish species through Hr signalling.

Histamine Receptor 1 and 2 Antagonists Alter Biodistribution of Radioiodine.

UNLABELLED: Nuclear medicine technology assumes responsibility for examination-specific patient preparation procedures. This requires a clear understanding of the possible effects of medications on the outcome of examinations. There is evidence that common over-the-counter drugs, histamine 1 (H1) and histamine 2 (H2) receptor blockers and proton pump inhibitors, may directly or indirectly affect thyroid function. The objective was to determine whether short-term use of these drugs alters biodistribution of radioiodine in a rat model. METHODS: Rats received no drug (controls) or daily subcutaneous injections of H1 blocker (promethazine), H2 blocker (famotidine), or proton pump inhibitor (esomeprazole) commencing 1 d before a single intraperitoneal injection of 0.037 MBq (1 µCi) of (131)I (NaI) and continuing daily until euthanasia at either 1 d or 8 d after (131)I. Organ uptake of (131)I by control and drug-treated rats was compared by γ-well counting. RESULTS: Promethazine significantly increased uptake of (131)I by the thyroid (drug-treated-to-control ratios) both at 1 d (1.32) and 8 d (1.52) after (131)I. Both famotidine and promethazine (respectively) significantly increased salivary gland uptake of (131)I (drug-treated-to-control ratios) at 1 d (1.37, 1.40) and 8 d (4.52, 5.57) after (131)I. Promethazine significantly increased gastric (131)I uptake (drug-treated-to-control ratios) at 1 d (1.47) and 8 d (1.46) after (131)I. Famotidine and promethazine (respectively) significantly decreased uptake of (131)I by the liver (drug-treated-to-control ratios) at 1 d (0.60, 0.71) after (131)I but resulted in a marked increase over control levels (11.21, 9.28) at 8 d. Blood levels of (131)I were not altered by drug treatment. Esomeprazole did not affect radioiodine distribution. CONCLUSION: H1 and H2 blockers alter the biodistribution of radioiodine in the rat. Although the findings remain to be confirmed in humans, these drugs could increase radiation exposure to nontarget tissues, particularly the stomach and salivary tissue, during (131)I therapy and consideration should be given toward avoiding the elective use of these drugs during radioiodine therapy.

Role of the thalamic submedius nucleus histamine H1 and H 2 and opioid receptors in modulation of formalin-induced orofacial pain in rats.

Histamine and opioid systems are involved in supraspinal modulation of pain. In this study, we investigated the effects of separate and combined microinjections of agonists and antagonists of histamine H1 and H2 and opioid receptors into the thalamic submedius (Sm) nucleus on the formalin-induced orofacial pain. Two guide cannulas were implanted into the right and left sides of the Sm in ketamine- and xylazine-anesthetized rats. Orofacial formalin pain was induced by subcutaneous injection of a diluted formalin solution (50 µl, 1.5%) into the vibrissa pad. Face rubbing durations were recorded at 3-min blocks for 45 min. Formalin produced a biphasic pain response (first phase: 0-3 min and second phase: 15-33 min). Separate and combined microinjections of histamine H1 and H2 receptor agonists, 2-pyridylethylamine (2-PEA) and dimaprit, respectively, and opioid receptor agonist, morphine, attenuated the second phase of pain. The analgesic effects induced by 2-PEA, dimaprit, and morphine were blocked by prior microinjections of fexofenadine (a histamine H1 receptor antagonist), famotidine (a histamine H2 receptor antagonist), and naloxone (an opioid receptor antagonist), respectively. Naloxone also prevented 2-PEA- and dimaprit-induced antinociception, and the analgesic effect induced by morphine was inhibited by fexofenadine and famotidine. These results showed the involvement of histamine H1 and H2 and opioid receptors in the Sm modulation of orofacial pain. Opioid receptor might be involved in analgesia induced by activation of histamine H1 and H2 receptors and vice versa.

Flow cytometric analysis with a fluorescently labeled formyl peptide receptor ligand as a new method to study the pharmacological profile of the histamine H2 receptor.

The histamine H2 receptor (H2R) is a Gs protein-coupled receptor. Its activation leads to increases in the second messenger adenosine-3',5'-cyclic monophosphate (cAMP). Presently, several systems are established to characterize the pharmacological profile of the H2R, mostly requiring radioactive material, animal models, or human blood cells. This prompted us to establish a flow cytometric analysis with a fluorescently labeled formyl peptide receptor (FPR) ligand in order to investigate the H2R functionally and pharmacologically. First, we stimulated U937 promonocytes, which mature in a cAMP-dependent fashion upon H2R activation, with histamine (HA) or selective H2R agonists and measured increases in cAMP concentrations by mass spectrometry. Next, indicative for the maturation of U937 promonocytes, we assessed the FPR expression upon incubation with HA or H2R agonists. FPR expression was measured either indirectly by formyl peptide-induced changes in intracellular calcium concentrations ([Ca(2+)]i) or directly with the fluorescein-labeled FPR ligand fNleLFNleYK-Fl. HA and H2R agonists concentration-dependently induced FPR expression, and potencies and efficacies of fMLP-induced increases in [Ca(2+)]i and FPR density correlated linearly. Accordingly, flow cytometric analysis of FPR expression constitutes a simple, inexpensive, sensitive, and reliable method to characterize the H2R pharmacologically. Furthermore, we evaluated FPR expression at the mRNA level. Generally, quantitative real-time polymerase chain reaction confirmed functional data. Additionally, our study supports the concept of functional selectivity of the H2R, since we observed dissociations in the efficacies of HA and H2R agonists in cAMP accumulation and FPR expression.

The role of the central histaminergic receptors in the exercise-induced improvements of the spatial learning and memory in rats.

While it is well known that exercise can improve cognitive performance, the underlying mechanisms are not fully understood. There is now evidence that histamine can modulate learning and memory in different types of behavioral tasks. The present study was designed to examine the possible role of central histamine H1 and H2 receptors in forced treadmill running-induced enhancement of learning and memory in rats. For this purpose the animals received intracerebroventricularly chlorpheniramine (H1 receptor blocker) and cimetidine (H2 receptor blocker) before each day of fifteen consecutive days of exercise. Then their learning and memory were tested on the water maze task using a four-trial-per-day for 4 consecutive days. A probe trial was performed after the last training day. Our data showed that cimetidine reversed the exercise-induced improvement in learning and memory in rats; however, this was not the case regarding chlorpheniramine. Our findings indicate that central histamine H2 receptors play an important role in mediating the beneficial effects of forced exercise on learning and memory.

Profiling of histamine H4 receptor agonists in native human monocytes.

BACKGROUND AND PURPOSE: Since the identification of the histamine H4 receptor, several ligands activating this receptor have been described and more compounds are in development. These ligands are well characterized in pharmacological assays, including radioligand competition binding studies, GTPγS and GTPase assays. In most cases, these experiments are performed in transfected cell lines, expressing unnaturally high levels of target receptors and G-protein signalling components. In this study we investigated the specific properties of H4 receptor ligands in native cells. EXPERIMENTAL APPROACH: Histamine and five different H4 receptor agonists - 4-methylhistamine, UR-PI376, clobenpropit, VUF8430 and ST-1006 - were characterized in freshly isolated human monocytes. The ligands (10 nM-10 µM) were tested as inhibitors of IL-12p70 secretion from human monocytes and the effects of the H2 receptor antagonist ranitidine and the H4 receptor antagonist JNJ7777120 on their action was investigated. KEY RESULTS: Histamine and all the tested agonists reduced IL-12p70 secretion into monocyte supernatants by 40-70%. The potencies varied with pEC50 values ranging from 5.7 to 6.9, depending on the agonist used. All potencies were lower than those determined in the original investigations of the compounds. Pretreatment of monocytes with H2 or H4 receptor antagonists showed that some H4 receptor ligands also had low activity at the H2 receptor. CONCLUSIONS AND IMPLICATIONS: Our study demonstrates discrepancies between the potencies obtained from assays in transfected cell lines and assays in native human cells, indicating the importance of evaluating H4 receptor ligands in native cells.

Calcium responses of circadian pacemaker neurons of the cockroach Rhyparobia maderae to acetylcholine and histamine.

The accessory medulla (aMe) is the pacemaker that controls circadian activity rhythms in the cockroach Rhyparobia maderae. Not much is known about the classical neurotransmitters of input pathways to the cockroach circadian system. The circadian pacemaker center receives photic input from the compound eye, via unknown excitatory and GABAergic inhibitory entrainment pathways. In addition, neuropeptidergic inputs couple both pacemaker centers. A histamine-immunoreactive centrifugal neuron connects the ventral aMe with projection areas in the lateral protocerebrum and may provide non-photic inputs. To identify neurotransmitters of input pathways to the circadian clock with Fura-2-dependent Ca(2+) imaging, primary cell cultures of the adult aMe were stimulated with acetylcholine (ACh), as the most prominent excitatory, and histamine, as common inhibitory neurotransmitter. In most of aMe neurons, ACh application caused dose-dependent increases in intracellular Ca(2+) levels via ionotropic nicotinic ACh receptors. These ACh-dependent rises in Ca(2+) were mediated by mibefradil-sensitive voltage-activated Ca(2+) channels. In contrast, histamine application decreased intracellular Ca(2+) levels in only a subpopulation of aMe cells via H2-type histamine receptor chloride channels. Thus, our data suggest that ACh is part of the light entrainment pathway while histamine is involved in a non-photic input pathway to the ventral circadian clock of the Madeira cockroach.

Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function.

There is evidence that H2R blockade improves ischemia/reperfusion (I/R) injury, but the underlying cellular mechanisms remain unclear. Histamine is known to increase vascular permeability and induce apoptosis, and these effects are closely associated with endothelial and mitochondrial dysfunction, respectively. Here, we investigated whether activation of the histamine H2 receptor (H2R) exacerbates myocardial I/R injury by increasing mitochondrial and endothelial permeability. Serum histamine levels were measured in patients with coronary heart disease, while the influence of H2R activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells, and myocardial I/R injury in mice. The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls. In neonatal rat cardiomyocytes, histamine dose-dependently reduced viability and induced apoptosis. Mitochondrial permeability and the levels of p-ERK1/2, Bax, p-DAPK2, and caspase 3 were increased by H2R agonists. In cultured human umbilical vein endothelial cells (HUVECs), H2R activation increased p-ERK1/2 and p-moesin levels and also enhanced permeability of HUVEC monolayer. All of these effects were abolished by the H2R blocker famotidine or the ERK inhibitor U0126. After I/R injury or permanent ischemia, the infarct size was reduced by famotidine and increased by an H2R agonist in wild-type mice. In H2R KO mice, the infarct size was smaller; myocardial p-ERK1/2, p-DAPK2, and mitochondrial Bax were downregulated. These findings indicate that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability.

A role for histamine in cardiovascular regulation in late stage embryos of the red-footed tortoise, Chelonoidis carbonaria Spix, 1824.

A chorioallantoic membrane artery in embryos of the red-footed tortoise, Chelonoidis carbonaria was occlusively cannulated for measurement of blood pressure and injection of drugs. Two age groups of embryos in the final 10 % of incubation were categorized by the ratio of embryonic body to yolk mass. All embryos first received cholinergic and ß-adrenergic blockade. This revealed that ß-adrenergic control was established in both groups whereas cholinergic control was only established in the older group immediately prior to hatching. The study then progressed as two series. Series one was conducted in a subset of embryos treated with histamine before or after injection of ranitidine, the antagonist of H2 receptors. Injection of histamine caused an initial phasic hypertension which recovered, followed by a longer lasting hypertensive response accompanied by a tachycardia. Injection of the H2 receptor antagonist ranitidine itself caused a hypotensive tachycardia with subsequent recovery of heart rate. Ranitidine also abolished the cardiac effects of histamine injection while leaving the initial hypertensive response intact. In series, two embryos were injected with histamine after injection of diphenhydramine, the antagonist to H1 receptors. This abolished the whole of the pressor response to histamine injection but left the tachycardic response intact. These data indicate that histamine acts as a non-adrenergic, non-cholinergic factor, regulating the cardiovascular system of developing reptilian embryos and that its overall effects are mediated via both H1 and H2 receptor types.

Modulation of neutrophil oxidative burst via histamine receptors.

Histamine has the ability to influence the activity of immune cells including neutrophils and plays a pivotal role in inflammatory processes, which are a complex network of cellular and humoral events. One of the main functions manifested by activated neutrophils is oxidative burst, which is linked to the production of reactive oxygen species; therefore, the effects of histamine receptor agonists and antagonists on the oxidative burst of neutrophils is reviewed. A role for the well-characterized histamine H1 and H2 receptors in this process is discussed and compared to that of the recently discovered H4 receptor.

Histamine promotes rat motor performances by activation of H(2) receptors in the cerebellar fastigial nucleus.

The cerebellar fastigial nucleus (FN), together with the interpositus nucleus (IN), constitutes the two final output nuclei of the spinocerebellum and plays an important role in body and limb movements. Previous studies have revealed a direct histaminergic projection from the hypothalamus to the cerebellar nuclei and an excitatory effect of histamine on the IN neurons. However, role of hypothalamic histaminergic projection in the FN has been still little known. Here we show that histamine elicited the FN neurons of rats a concentration-dependent excitatory response in vitro. The histamine-induced excitation on FN neurons was mediated by postsynaptic histamine H2 rather than H1 receptors. In behavioral tests, microinjection of histamine into bilateral FNs remarkably improved motor performances of rats on both accelerating rota-rod and balance beam. Selective H2 receptor antagonist ranitidine considerably declined those motor performances and selective H2 receptor agonist dimaprit mimicked the facilitation effect of histamine on the movements. But selective H1 receptor antagonist triprolidine and agonist 2-pyridylethylamine had no effect. Furthermore, microinjection of histamine into bilateral FNs narrowed stride width of footprint but did not influence wire suspension, whereas microinjection of histamine into bilateral INs increased stride length and promoted suspension. These results demonstrate that histamine enhances rat motor balance and coordination through modulation of both proximal and distal muscles by activation of histamine H2 receptors in the cerebellar FN and IN, and suggest that the hypothalamocerebellar histaminergic projections may modulate the final outputs of the spinocerebellum and participate in the cerebellum-mediated motor control.

[Effects of histamine on contractile activity of lymphatic node capsules. The NO role].

Effects of histamine (10(-9)--5 x 10(-5) M) on the phase and tonic contractile activity of capsular smooth muscles of isolated bovine mesentery lymph node were investigated. Dual dose-depended effect of histamine was found. Low concentrations of histamine less than 10(-7) M caused a decrease of contractile activity, whereas higher concentrations of histamine (more than 5 x 10(-7) M) resulted in increase of the phase and tonic contractions. Both H1- and H2-receptors of smooth muscle cells are involved in the response. Much of the relaxing histamine-induced response is produced by the stimulation of the endothelial cells. We believe that activating effect of histamine is due to the excitation of H1-receptors located on the membrane of myocytes, whereas its inhibitory effect occurs in two ways: 1) via excitation of H2-receptors located on the membrane of myocytes; 2) via stimulation of the NO production by the endothelial cells of lymph node sinus.

Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats.

The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra-hippocampal microinjections of histamine, pyrilamine (an antagonist of histamine H(1) receptors), ranitidine (an antagonist of histamine H(2) receptors), morphine (an opioid receptor agonist) and naloxone (an opioid receptor antagonist) in separate and combined treatments. Orofacial pain was induced by subcutaneous (sc) injection of formalin (50 µl, 1%) in the upper lip region and the time spent face rubbing was recorded in 3 min blocks for 45 min. Formalin (sc) produced a marked biphasic (first phase: 0-3 min, second phase: 15-33 min) pain response. Histamine and morphine suppressed both phases of pain. Histamine increased morphine-induced antinociception. Pyrilamine and ranitidine had no effects when used alone, whereas pretreatments with pyrilamine and ranitidine prevented histamine- and morphine-induced antinociceptive effects. Naloxone alone non-significantly increased pain intensity and inhibited the antinociceptive effects of morphine and histamine. The results of the present study indicate that at the level of the hippocampus, histamine through its H(1) and H(2) receptors, mediates orofacial region pain. Moreover, morphine via a naloxone-reversible mechanism produces analgesia. In addition, both histamine H(1) and H(2) receptors, as well as opioid receptors may be involved in the interaction between histamine and morphine in producing analgesia.

Histamine inhibits adhesion molecule expression in human monocytes, induced by advanced glycation end products, during the mixed lymphocyte reaction.

BACKGROUND AND PURPOSE: Post-transplant diabetes mellitus is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor on monocytes/macrophages plays important roles in the genesis of diabetic complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T-cells, reducing allograft survival. Out of four distinct AGE subtypes (AGE-2, AGE-3, AGE-4 and AGE-5), only AGE-2 and AGE-3 induced expression of intercellular adhesion molecules (ICAMs), output of cytokines and proliferation of lymphocytes, during the mixed lymphocyte reaction (MLR). Here we have assessed the role of histamine in the actions of AGEs during the MLR. EXPERIMENTAL APPROACH: Human peripheral blood cells were used in these experiments. Flow cytometry was used to examine the expression of the ICAM-1, B7.1, B7.2 and CD40. Production of the cytokine interferon-gamma, and levels of cAMP were determined by elisa. Lymphocyte proliferation was determined by [(3)H]-thymidine uptake. KEY RESULTS: Histamine concentration dependently inhibited the action of AGE-2 and AGE-3. The actions of histamine were antagonized by an H(2)-receptor antagonist, famotidine, and mimicked by H(2)/H(4)-receptor agonists, dimaprit and 4-methylhistamine. The effects of histamine were reversed by a protein kinase A (PKA) inhibitor, H89, and mimicked by dibutyryl cAMP and an adenylate cyclase activator, forskolin. CONCLUSIONS AND IMPLICATIONS: Histamine down-regulated AGE-2- and AGE-3-induced expression of adhesion molecules, cytokine production and lymphocyte proliferation via histamine H(2) receptors and the cAMP/PKA pathway.

Involvement of histamine and histamine H2 receptors in nicotinamide-induced differentiation of human amniotic epithelial cells into insulin-producing cells.

OBJECTIVE AND DESIGN: Human amniotic epithelial cells (HAEC) resemble stem cells in their ability to differentiate into all three germ layers: endoderm, mesoderm, and ectoderm. Histamine receptors are expressed on HAEC. We examined the influence of histamine, and H(1) and H(2) antagonists on the generation of pancreatic islet beta-like cells from HAEC. MATERIALS AND METHODS: HAEC were isolated after term pregnancies (N = 12) and cultured for 14 days with nicotinamide (10 mM) in normoxia. Altogether, 72 cultures were established. Histamine (100 microM) effects were investigated with mepyramine (10 microM) or cimetidine (10 microM). After 7 and 14 days, the mean concentration of C-peptide (MCCP) in the culture medium was measured immunoenzymatically as a marker of pancreatic differentiation. RESULTS: MCCP was approximately threefold higher on day 14, compared to day 7. Histamine significantly increased MCCP, and more evident differences were observed after 7 days of culture than after 14 days. The mean percent increase +/-SEM in MCCP amounted to 142.19 +/- 21.7 and 79.03 +/- 12.35 compared to the controls on day 7 and 14, respectively. H(2) blockade significantly reduced histamine-related increase in MCCP, both on day 7 and 14 by 88.7 +/- 14.3 and 39.2 +/- 12.4%, respectively. H(1) receptor antagonist did not affect MCPP. CONCLUSION: Nicotinamide-induced pancreatic differentiation of HAEC into beta-like cells may be augmented, probably at its earlier stage, by histamine acting via H(2) receptors.