Histamine H1- and H2-receptors participate to provide metabolic energy differently.

Histamine participates in a variety of physiological functions. The local effects of histamine have a role to provide metabolic energy for the tissues. The objective of this work is to study the mechanism whereby histamine affects serum glucose and liver glycogen fractions. Six groups of 10 male rats received two injections with histamine, H1-agonist (dipyridylethylamine), H2-agonist (dimaprit), H1-agonist plus H1-antagonist (cetirizine), or H2-agonist plus H2-antagonist (famotidine). Serum glucose and liver glycogen fractions were measured. Histamine caused a significant increase in serum glucose (163.7 ± 5.4 vs. 153.2 ± 3.3 mg/dl, p = 0.023). The effect of histamine was mimicked by selective H1-agonist (164.2 ± 3.5 vs. 152.8 ± 2.9 mg/dl, p = 0.005) but not with H2-agonist (159.3 ± 3.7 vs. 156.3 ± 4.8 mg/dl, p = 0.281). The effect of H1-agonist was abolished in the presence of selective H1-antagonist. Treatment by H1- but not H2-agonist decreased total glycogen by about 35% (30.6 ± 0.5 vs. 47.3 ± 2.8 mg/g wet weight of liver, p = 0.003). The decrease happened wholly in ASG fraction (26.8 ± 1.2 vs. 43.7 ± 3.2 mg/g wet weight of liver, p = 0.004), while AIG did not change significantly (4.2 ± 0.5 vs. 4.5 ± 0.4 mg/g wet weight of liver, p = 0.724). Histamine causes to decrease glycogen in the liver and increased serum glucose. The effects of histamine were mediated via H1-receptors. ASG was metabolically active fraction of liver glycogen in this process. The results confirm the role of histamine in providing metabolic energy of the tissues.

Hypolipemic effects of histamine is due to inhibition of VLDL secretion from the liver: involvement of both H1 and H2-receptors.

The research was performed to study the mechanism whereby histamine affects the profile of plasma lipids. Six groups of ten male rats were received two injections with histamine or its H1- and H2-agonists and antagonists. Histamine caused a significant decrease in the concentrations of triglyceride, total cholesterol, and LDLc, while HDLc had no significant change. The rate of VLDL secretion was 263.6 ± 25.8 mg/h dL in control rats and was inhibited by about 68% in histamine injected rats. These changes have been mimicked by either histamine H1- or H2-agonists. The effects of H1- and H2-agonists were abolished in the presence of cetirizine and famotidine respectively. Histamine causes a significant decrease in serum triglyceride, total, and LDL-cholesterol by both H1 and H2-receptors. The decrease in serum lipids is due to the inhibitory effect of histamine or its agonists on VLDL secretion from the liver.

Histamine H1 receptors regulate anhedonic-like behavior in rats: Involvement of the anterior cingulate and lateral entorhinal cortices.

A decreased H1 receptor activity is observed in the anterior cingulate cortex (aCgCx) of depressed patients. The role of this abnormality in the development of depression-related processes is unstudied. We examined the influence of a decreased brain H1 receptor activity on rat behavior in the sucrose preference test. The H1 receptor deficit was simulated by injection of an H1 antagonist into the aCgCx; also, two aCgCx projection areas, lateral and medial entorhinal cortices were examined. A blockade of H1-receptors in the aCgCx and lateral entorhinal cortex (LEntCx) significantly reduced sucrose preference. These findings suggest the existence of H1 receptor-mediated aCgCx-LEntCx circuitry mechanism regulating anhedonic-like behavior in rats. The presented data suggest that H1 receptor-mediated processes might be a therapeutic target in depressive disorders.

Effects of histamine on human periodontal ligament fibroblasts under simulated orthodontic pressure.

As type-I-allergies show an increasing prevalence in the general populace, orthodontic patients may also be affected by histamine release during treatment. Human periodontal ligament fibroblasts (PDLF) are regulators of orthodontic tooth movement. However, the impact of histamine on PDLF in this regard is unknown. Therefore PDLF were incubated without or with an orthodontic compressive force of 2g/cm2 with and without additional histamine. To assess the role of histamine-1-receptor (H1R) H1R-antagonist cetirizine was used. Expression of histamine receptors and important mediators of orthodontic tooth movement were investigated. PDLF expressed histamine receptors H1R, H2R and H4R, but not H3R. Histamine increased the expression of H1R, H2R and H4R as well as of interleukin-6, cyclooxygenase-2, and prostaglandin-E2 secretion even without pressure application and induced receptor activator of NF-kB ligand (RANKL) protein expression with unchanged osteoprotegerin secretion. These effects were not observed in presence of H1R antagonist cetirizine. By expressing histamine receptors, PDLF seem to be able to respond to fluctuating histamine levels in the periodontal tissue. Increased histamine concentration was associated with enhanced expression of proinflammatory mediators and RANKL, suggesting an inductive effect of histamine on PDLF-mediated osteoclastogenesis and orthodontic tooth movement. Since cetirizine inhibited these effects, they seem to be mainly mediated via histamine receptor H1R.

Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development.

A reduction in the synthesis of the neuromodulator histamine has been associated with Tourette's syndrome and obsessive-compulsive disorder. Symptoms of these disorders are thought to arise from a dysfunction or aberrant development ofcorticostriatal circuits. Here, we investigated how histamine affects developing corticostriatal circuits, both acutely and longer-term, during the first postnatal weeks, using patch-clamp and field recordings in mouse brain slices (C57Bl/6, male and female). Immunohistochemistry for histamine-containing axons reveals striatal histaminergic innervation by the second postnatal week, and qRT-PCR shows transcripts for H1, H2, and H3 histamine receptors in striatum from the first postnatal week onwards, with pronounced developmental increases in H3 receptor expression. Whole-cell patch-clamp recordings of striatal spiny projection neurons and histamine superfusion demonstrates expression of functional histamine receptors from the first postnatal week onwards, with histamine having diverse effects on their electrical properties, including depolarization of the membrane potential while simultaneously decreasing action potential output. Striatal field recordings and electrical stimulation of corticostriatal afferents revealed that histamine, acting at H3 receptors, negatively modulates corticostriatal synaptic transmission from the first postnatal week onwards. Last, we investigated effects of histamine on longer-term changes at developing corticostriatal synapses and show that histamine facilitates NMDA receptor-dependent LTP via H3 receptors during the second postnatal week, but inhibits synaptic plasticity at later developmental stages. Together, these results show that histamine acutely modulates developing striatal neurons and synapses and controls longer-term changes in developing corticostriatal circuits, thus providing insight into the possible etiology underlying neurodevelopmental disorders resulting from histamine dysregulation.SIGNIFICANCE STATEMENT Monogenic causes of neurologic disorders, although rare, can provide opportunities to both study and understand the brain. For example, a nonsense mutation in the coding gene for the histamine-synthesizing enzyme has been associated with Tourette's syndrome and obsessive-compulsive disorder, and dysfunction of corticostriatal circuits. Nevertheless, the etiology of these neurodevelopmental disorders and histamine's role in the development of corticostriatal circuits have remained understudied. Here we show that histamine is an active neuromodulator during the earliest periods of postnatal life and acts at developing striatal neurons and synapses. Crucially, we show that histamine permits NMDA receptor-dependent corticostriatal synaptic plasticity during an early critical period of postnatal development, which suggests that genetic or environmental perturbations of histamine levels can impact striatal development.

Helix 8 is the essential structural motif of mechanosensitive GPCRs.

G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H1 receptors (H1Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H1Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology.

Store-operated calcium entry (SOCE) contributes to phosphorylation of p38 MAPK and suppression of TNF-α signalling in the intestinal epithelial cells.

Calcium influx via store-operated calcium entry (SOCE) has an important role for regulation of vast majority of cellular physiological events. MAPK signalling is also another pivotal modulator of many cellular functions. However, the relationship between SOCE and MAPK is not well understood. In this study, we elucidated the involvement of SOCE in Gαq/11 protein-mediated activation of p38 MAPK in an intestinal epithelial cell line HT-29/B6. In this cell line, we previously showed that the stimulation of M3 muscarinic acetylcholine receptor (M3-mAChR) but not histamine H1 receptor (H1R) led to phosphorylation of p38 MAPK which suppressed tumor necrosis factor-α (TNF-α)-induced NF-κB signalling through ADAM17 protease-mediated shedding of TNF receptor-1 (TNFR1). First, we found that stimulation of M3-mAChR and protease-activated receptor-2 (PAR-2) but not H1R induced persistent upregulation of cytosolic Ca2+ concentration through SOCE. Activation of M3-mAChR or PAR-2 also suppressed TNF-α-induced NF-κB phosphorylation, which was dependent on the p38 MAPK activity. Time course experiments revealed that M3-mAChR stimulation evoked intracellular Ca2+-dependent early phase p38 MAPK phosphorylation and extracellular Ca2+-dependent later phase p38 MAPK phosphorylation. This later phase p38 MAPK phosphorylation, evoked by M3-mAChRs or PAR-2, was abolished by inhibition of SOCE. Thapsigargin or ionomycin also phosphorylate p38 MAPK by Ca2+ influx through SOCE, leading to suppression of TNF-α-induced NF-κB phosphorylation. Finally, we showed that p38 MAPK was essential for thapsigargin-induced cleavage of TNFR1 and suppression of TNF-α-induced NF-κB phosphorylation. In conclusion, SOCE is important for p38 MAPK phosphorylation and is involved in TNF-α signalling suppression.

Role of histamine H1 receptor in caffeine induced locomotor sensitization.

The present study elucidated the role of histamine H1 receptor in the caffeine induced locomotor sensitization. Intermittent administration of caffeine (15 mg/kg, i.p.) on alternate days (induction phase) i.e. 1st, 3rd, 5th, 7th, 9th, 11th and 13th resulted in the development of locomotor sensitization. In addition, challenge with sub-stimulant dose of caffeine (10 mg/kg, i.p.) directly on 17th day to induction group animals resulted in expression to locomotor sensitization to caffeine. I.c.v. injection of histaminergic agents concomitantly with caffeine during induction phase i.e. histamine H1 receptor agonist, FMPH (6.5 µg/mouse) significantly potentiated while H1 receptor antagonist, cetirizine (0.1 µg/mouse) attenuated the locomotor sensitization induced by caffeine (15 mg/kg, i.p.). In addition, challenge with caffeine (10 mg/kg, i.p.) on the expression day (17th) to the induction group mice on FMPH + caffeine treatment showed enhanced, while those on cetirizine + caffeine treatment exhibited lesser expression to locomotor sensitization. Therefore, a possible contributory role of the central histaminergic system via H1 receptor stimulation or up-regulation in the caffeine-induced locomotor sensitizing effect is proposed.

Histaminergic H1 and H2 Receptors Mediate the Effects of Propofol on the Noradrenalin-Inhibited Neurons in Rat Ventrolateral Preoptic Nucleus.

The ventrolateral preoptic nucleus is a sleep-promoting nucleus located in the basal forebrain. A commonly used intravenous anesthetic, propofol, had been reported to induce sleep spindles and augment the firing rate of neurons in ventrolateral preoptic nucleus, but the underlining mechanism is yet to be known. By using patch clamp recording on neuron in acute brain slice, present study tested if histaminergic H1 and H2 receptors play a role in the effect of propofol on the noradrenalin-inhibited neurons in ventrolateral preoptic nucleus. We found that the firing rate of noradrenalin-inhibited neurons were significantly augmented by propofol; the frequency of inhibitory postsynaptic currents of noradrenalin-inhibited neuron were evidently attenuated by propofol; such inhibition effect was suppressed by histamine; and both triprolidine (antagonist for H1 histamine receptor) and ranitidine (antagonist for H2 histamine receptor) were able to increase the inhibition rate of propofol in presence of histamine. Present study demonstrated that propofol-induced inhibition of inhibitory postsynaptic currents on noradrenalin-inhibited neurons were mediated by histaminergic H1 and H2 receptors.

Asp73-dependent and -independent regulation of the affinity of ligands for human histamine H1 receptors by Na.

The affinity of ligands for G-protein-coupled receptors (GPCRs) is allosterically regulated by Na+ via a highly conserved aspartate residue (Asp2.50) in the second transmembrane domain of GPCRs. In the present study, we examined the Na+-mediated regulation of the affinity of ligands for Gq/11-protein-coupled human histamine H1 receptors in Chinese hamster ovary cells. The affinities of 3 agonists and 20 antihistamines were evaluated by their displacement curves against the binding of [3H]-mepyramine to membrane preparations in the presence or absence of 100mM NaCl. The affinities of most drugs including histamine, an agonist, and d-chlorpheniramine, a first-generation antihistamine, were reduced by NaCl, with the extent of NaCl-mediated changes varying widely between drugs. In contrast, the affinities of some second-generation antihistamines such as fexofenadine were increased by NaCl. These changes were retained in intact cells. The mutation of Asp2.50 (Asp73) to asparagine abrogated NaCl-induced reductions in affinities for histamine and d-chlorpheniramine, but not NaCl-induced increases in the affinity for fexofenadine. Quantitative structure-activity relationship (QSAR) analyses showed that these Na+-mediated changes were explained and predicted by a combination of the molecular energies and implicit solvation energies of the compounds. These results suggest that Na+ diversely regulates the affinity of ligands for H1 receptors from the extracellular sites of receptors via Asp73-dependent and -independent mechanisms in a manner that depends on the physicochemical properties of ligands. These results may contribute to a deeper understanding of the fundamental mechanisms by which the affinity of ligands for their receptors is allosterically regulated by Na+.

Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms.

Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1-/-, Adora3-/-) mice. Confirming prior data, stimulation of the A3 adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H1 receptors. In contrast, A1AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A1AR agonists, including N6-cyclopentyladenosine (CPA), N6-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A1AR and A3AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N6-endo-norbornyladenosine], or using Adora3-/- mice allowed selective stimulation of A1AR. AMP-stimulated hypothermia can occur independently of A1AR, A3AR, and mast cells. A1AR and A3AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A1AR nor A3AR was required for fasting-induced torpor. A1AR and A3AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms.

C-terminal of human histamine H1 receptors regulates their agonist-induced clathrin-mediated internalization and G-protein signaling.

It has been suggested that the agonist-induced internalization of G-protein-coupled receptors from the cell surface into intracellular compartments regulates cellular responsiveness. We previously reported that Gq/11 -protein-coupled human histamine H1 receptors internalized via clathrin-dependent mechanisms upon stimulation with histamine. However, the molecular determinants of H1 receptors responsible for agonist-induced internalization remain unclear. In this study, we evaluated the roles of the intracellular C-terminal of human histamine H1 receptors tagged with hemagglutinin (HA) at the N-terminal in histamine-induced internalization in Chinese hamster ovary cells. The histamine-induced internalization was evaluated by the receptor binding assay with [3 H]mepyramine and confocal immunofluorescence microscopy with an anti-HA antibody. We found that histamine-induced internalization was inhibited under hypertonic conditions or by pitstop, a clathrin terminal domain inhibitor, but not by filipin or nystatin, disruptors of the caveolar structure and function. The histamine-induced internalization was also inhibited by truncation of a single amino acid, Ser487, located at the end of the intracellular C-terminal of H1 receptors, but not by its mutation to alanine. In contrast, the receptor-G-protein coupling, which was evaluated by histamine-induced accumulation of [3 H]inositol phosphates, was potentiated by truncation of Ser487, but was lost by its mutation to alanine. These results suggest that the intracellular C-terminal of human H1 receptors, which only comprises 17 amino acids (Cys471-Ser487), plays crucial roles in both clathrin-dependent internalization of H1 receptors and G-protein signaling, in which truncation of Ser487 and its mutation to alanine are revealed to result in biased signaling toward activation of G-proteins and clathrin-mediated internalization, respectively.

Central histaminergic transmission modulates the ethanol induced anxiolysis in mice.

Intrigued by the report demonstrating an increase in brain histamine levels by ethanol administration and central histamine transmission to affect the anxiety related behaviors, the present study examined the permissive role of central histaminergic transmission in the acute anxiolytic-like effect of the ethanol on elevated plus maze (EPM) in mice. Results demonstrated that prior administration of the agents that are known to enhance the brain histamine transmission, i.e. low dose of histamine (0.1µg/mouse, i.c.v.) or histamine precursor, l-histidine (500, 1000mg/kg, i.p.) or low dose of histamine releasing agent (H3 receptor inverse agonist), thioperamide (2µg/mouse) attenuated the acute anitanxiety-like effect of ethanol (2g/kg, i.p, 8% w/v) in mice on EPM. However, pre-treatment with the H1 receptor antagonist, cetirizine (0.1µg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50µg/mouse, i.c.v.) failed to affect the attenuating effect of low dose of histamine on ethanol induced anxiolysis. On the other hand, only H1 receptor antagonist, cetirizine (0.1µg/mouse, i.c.v.) was able to partially reverse the attenuation of ethanol induced anxiolysis by l-histidine (1000mg/kg, i.p.). Surprisingly, in mice pre-treated with the higher dose of histamine (50µg/mouse, i.c.v.) or thioperamide (10µg/mouse, i.c.v.), the ethanol (2g/kg, i.p.) induced antianxiety-like effect was further enhanced on EPM. Furthermore, this potentiating effect of high dose of histamine on the ethanol (2g/kg, i.p.) was exacerbated on pre-treatment with the H1 receptor antagonist, cetirizine, while H2 receptor antagonist, ranitidine completely reversed this action of high dose of histamine on ethanol. Supportive to these results, i.c.v. pre-treatment with H1 receptor agonist, FMPH (2, 6.5µg/mouse, i.c.v.) attenuated while H2 receptor agonist, amthamine (0.1, 0.5µg/mouse, i.c.v.) enhanced the ethanol induced anxiolysis in mice. Thus, it is reasonable to contemplate that central histaminergic transmission functions to negatively modulate the acute ethanol-induced anxiolysis probably via stimulation of postsynaptic H1 receptor and histamine might contribute to the anxiolytic action of ethanol via H2 receptor activation.

Evidence of a broad histamine footprint on the human exercise transcriptome.

KEY POINTS: Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors, in a variety of pathways that probably predate its more recent role in innate and adaptive immunity. Although histamine is normally associated with pathological conditions or allergic and anaphylactic reactions, it may contribute beneficially to the normal changes that occur within skeletal muscle during the recovery from exercise. We show that the human response to exercise includes an altered expression of thousands of protein-coding genes, and much of this response appears to be driven by histamine. Histamine may be an important molecular transducer contributing to many of the adaptations that accompany chronic exercise training. ABSTRACT: Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors. In humans, aerobic exercise is followed by a post-exercise activation of histamine H1 and H2 receptors localized to the previously exercised muscle. This could trigger a broad range of cellular adaptations in response to exercise. Thus, we exploited RNA sequencing to explore the effects of H1 and H2 receptor blockade on the exercise transcriptome in human skeletal muscle tissue harvested from the vastus lateralis. We found that exercise exerts a profound influence on the human transcriptome, causing the differential expression of more than 3000 protein-coding genes. The influence of histamine blockade post-exercise was notable for 795 genes that were differentially expressed between the control and blockade condition, which represents >25% of the number responding to exercise. The broad histamine footprint on the human exercise transcriptome crosses many cellular functions, including inflammation, vascular function, metabolism, and cellular maintenance.

Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.

Superficial Layer-Specific Histaminergic Modulation of Medial Entorhinal Cortex Required for Spatial Learning.

The medial entorhinal cortex (MEC) plays a crucial role in spatial learning and memory. Whereas the MEC receives a dense histaminergic innervation from the tuberomamillary nucleus of the hypothalamus, the functions of histamine in this brain region remain unclear. Here, we show that histamine acts via H1Rs to directly depolarize the principal neurons in the superficial, but not deep, layers of the MEC when recording at somata. Moreover, histamine decreases the spontaneous GABA, but not glutamate, release onto principal neurons in the superficial layers by acting at presynaptic H3Rs without effect on synaptic release in the deep layers. Histamine-induced depolarization is mediated via inhibition of Kir channels and requires the activation of protein kinase C, whereas the inhibition of spontaneous GABA release by histamine depends on voltage-gated Ca(2+) channels and extracellular Ca(2+). Furthermore, microinjection of the H1R or H3R, but not H2R, antagonist respectively into the superficial, but not deep, layers of MEC impairs rat spatial learning as assessed by water maze tasks but does not affect the motor function and exploratory activity in an open field. Together, our study indicates that histamine plays an essential role in spatial learning by selectively regulating neuronal excitability and synaptic transmission in the superficial layers of the MEC.

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.

Itching for answers: how histamine relaxes lymphatic vessels.

In the current issue of Microcirculation, studies by Kurtz et al. and Nizamutdinova et al. together provide new evidence supporting a role for histamine as an endothelial-derived molecule that inhibits lymphatic muscle contraction. In particular, Nizamutdinova et al. show that the effects of flow-induced shear stress on lymphatic endothelium are mediated by both nitric oxide and histamine, since only blockade of both prevents contraction strength and frequency from being altered by flow. Separately, Kurtz et al. used confocal microscopy to determine a preferential expression of histamine receptors on the lymphatic endothelium and demonstrated that histamine applied to spontaneously contracting collecting lymphatics inhibits contractions. Previous studies disagreed on whether histamine stimulates or inhibits lymphatic contractions, but also used differing concentrations, species, and preparations. Together these new reports shed light on how histamine acts within the lymphatic vasculature, but also raise important questions about the cell type on which histamine exerts its effects and the signaling pathways involved. This editorial briefly discusses the contribution of each study and its relevance to lymphatic biology.

Histamine induces human lung fibroblast-mediated collagen gel contraction via histamine H1 receptor.

BACKGROUND: Airway remodeling is implicated in irreversible airflow limitation of refractory asthma, which includes increased smooth muscle mass and subepithelial fibrosis. Activated fibroblasts acquire contractile phenotype to participate in tissue contraction and structural alteration of extracellular matrices. Histamine is a potent mediator of allergic inflammation, substantially involved in asthmatic pathophysiology. OBJECTIVE: We hypothesized that histamine might play a role in airway remodeling, and investigated its effect on fibroblast-mediated collagen gel contraction. METHODS: Fibroblast-mediated collagen gel contraction was studied. Histamine's regulation of collagen gel contraction was characterized by using specific histamine-receptor antagonists, an IP3 receptor antagonist and a PKC inhibitor. RESULTS: Histamine induced contraction of collagen gels embedded with human lung fibroblasts, in a time-dependent manner, and at the concentration more than 10(-6) M, both in four primary cultured adult lung fibroblasts and three fetal lung fibroblast cell lines. This effect was attenuated by H1 receptor antagonist, whereas those for H2 to H4 receptors failed to show an inhibitory effect. Furthermore, IP3 receptor-mediated Ca(2+) mobilization was implicated in histamine's action on collagen gel contraction. CONCLUSIONS: Our results suggest that histamine is involved in airway remodeling through its action on lung fibroblasts, and antihistamine drugs, especially H1 receptor antagonists, might be potentially beneficial for a subset of asthmatic patients.

Involvement of H1 and H2 receptors and soluble guanylate cyclase in histamine-induced relaxation of rat mesenteric collecting lymphatics.

OBJECTIVE: This study investigated the roles of the H1 and H2 histamine receptors, NO synthase, and sGC cyclase in histamine-induced modulation of rat mesenteric collecting lymphatic pumping. METHODS: Isolated rat mesenteric collecting lymphatics were treated with 1- to 100-µM histamine. Histamine receptors were blocked with either the H1 antagonist mepyramine or the H2 antagonist cimetidine. The role of NO/sGC signaling was tested using the arginine analog L-NAME, the sGC inhibitor ODQ, and SNP as a positive control. RESULTS: Histamine applied at 100 µM decreased tone and CF of isolated rat mesenteric collecting lymphatics. Pharmacologic blockade of either H1 or H2 histamine receptors significantly inhibited the response to histamine. Pretreatment with ODQ, but not L-NAME, completely inhibited the histamine-induced decrease in tone. ODQ pretreatment also significantly inhibited SNP-induced lymphatic relaxation. CONCLUSIONS: H1 and H2 histamine receptors are both involved in histamine-induced relaxation of rat mesenteric collecting lymphatics. NO synthesis does not appear to contribute to the histamine-induced response. However, sGC is critical for the histamine-induced decrease in tone and contributes to the drop in CF.