Role Of Histamine H1 Receptors Research Articles

The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3β Signaling Pathway in MK801-Induced Amnesia in Mice.

The role of histamine H3 receptors (H3Rs) in memory and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer's disease (AD), is well-accepted. Therefore, the procognitive effects of acute systemic administration of H3R antagonist E169 (2.5-10 mg/kg, i.p.) on MK801-induced amnesia in C57BL/6J mice using the novel object recognition test (NORT) were evaluated. E169 (5 mg) provided a significant memory-improving effect on MK801-induced short- and long-term memory impairments in NORT. The E169 (5 mg)-provided effects were comparable to those observed with the reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and were abrogated with the H3R agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that E169 ameliorated MK801-induced memory deficits by antagonism of H3Rs and by modulation of the level of disturbance in the expression of PI3K, Akt, and GSK-3β proteins, signifying that E169 mitigated the Akt-mTOR signaling pathway in the hippocampus of tested mice. Moreover, the results observed revealed that E169 (2.5-10 mg/kg, i.p.) did not alter anxiety levels and locomotor activity of animals in open field tests, demonstrating that performances improved following acute systemic administration with E169 in NORT are unrelated to changes in emotional response or in spontaneous locomotor activity. In summary, these obtained results suggest the potential of H3R antagonists such as E169, with good in silico physicochemical properties and stable retained key interactions in docking studies at H3R, in simultaneously modulating disturbed brain neurotransmitters and the imbalanced Akt-mTOR signaling pathway related to neurodegenerative disorders, e.g., AD.

Function and Role of Histamine H1 Receptor in the Mammalian Heart.

Histamine can change the force of cardiac contraction and alter the beating rate in mammals, including humans. However, striking species and regional differences have been observed. Depending on the species and the cardiac region (atrium versus ventricle) studied, the contractile, chronotropic, dromotropic, and bathmotropic effects of histamine vary. Histamine is present and is produced in the mammalian heart. Thus, histamine may exert autocrine or paracrine effects in the mammalian heart. Histamine uses at least four heptahelical receptors: H1, H2, H3 and H4. Depending on the species and region studied, cardiomyocytes express only histamine H1 or only histamine H2 receptors or both. These receptors are not necessarily functional concerning contractility. We have considerable knowledge of the cardiac expression and function of histamine H2 receptors. In contrast, we have a poor understanding of the cardiac role of the histamine H1 receptor. Therefore, we address the structure, signal transduction, and expressional regulation of the histamine H1 receptor with an eye on its cardiac role. We point out signal transduction and the role of the histamine H1 receptor in various animal species. This review aims to identify gaps in our knowledge of cardiac histamine H1 receptors. We highlight where the published research shows disagreements and requires a new approach. Moreover, we show that diseases alter the expression and functional effects of histamine H1 receptors in the heart. We found that antidepressive drugs and neuroleptic drugs might act as antagonists of cardiac histamine H1 receptors, and believe that histamine H1 receptors in the heart might be attractive targets for drug therapy. The authors believe that a better understanding of the role of histamine H1 receptors in the human heart might be clinically relevant for improving drug therapy.

Histamine H3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation.

NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNFα)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1β (IL-1β), and myogenesis markers were determined. TNFα reduced overall viability of C2C12 cells, and exposure to TNFα induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNFα-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNFα and increased the myogenesis marker expression. TNFα-induced secretion of mature IL-1β was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1β upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNFα-induced IL-1β secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.

Histamine H3 Receptor Antagonist Enhances Neurogenesis and Improves Chronic Cerebral Hypoperfusion-Induced Cognitive Impairments.

Chronic cerebral hypoperfusion (CCH) is a neurodegenerative disease, which induces cognitive impairments in the central nervous system (CNS). Histamine H3 receptor (H3R) is an autoreceptor involved in the modulation of neurogenesis and synaptic plasticity in the CNS. However, the role of H3R in CCH-induced injury and the related mechanisms remain to be clarified. Here, we found that thioperamide (THIO), a H3R antagonist, promotes the proliferation of NE-4C stem cells under either normal or oxygen-glucose deprivation (OGD) condition in vitro. Thioperamide promotes the phosphorylation of cAMP-response element binding (CREB), and thereby upregulates the expression and release of brain-derived neurotrophic factor (BDNF). However, H89, an inhibitor of protein kinase A (PKA)/CREB, reverses the effects of thioperamide on either BDNF expression and release or cell proliferation in NE-4C stem cells. Moreover, thioperamide has protective effects on OGD-induced impairment of cell viability and neuronal morphology in primary neurons in vitro. Furthermore, thioperamide enhanced neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ) regions in vivo, and ameliorated CCH-induced cognitive impairments. Taken together, these findings showed that thioperamide protects primary neurons against OGD-induced injury and promotes the proliferation of neural stem cells in DG and SVZ regions through CREB/BDNF pathways, thereby improving cognitive deficit.

Influence of the Novel Histamine H3 Receptor Antagonist/Inverse Agonist M39 on Gastroprotection and PGE2 Production Induced by (R)-Alpha-Methylhistamine in C57BL/6 Mice.

The role of histamine H3 receptors (H3Rs) in the regulation of gastroprotection and production of prostaglandin E2 (PGE2) as well as somatostatin remains contradictory. Therefore, the effects of the H3R antagonist/inverse agonist M39 on in vivo acidified ethanol-induced gastric ulcers and gastric acid secretion in the C57BL/6 mice were assessed. Results showed that acute systemic administration of H3R agonist (R)-α-methylhistamine (RAMH, 100 mg/kg, i.g.) significantly reduced the severity of ulcer index, increased gastric acid output, and increased mucosal PGE2 production without any alteration of somatostatin concentration in gastric juice. However, only acute systemic administration of the H2R agonist dimaprit (DIM, 10 mg/kg, p.o.) significantly decreased the level of somatostatin measured in gastric juice. Moreover, acute systemic administration of M39 (0.3 mg/kg, i.g.) abrogated the RAMH-induced increase of acid output as well as PGE2 production, but not the DIM (10 mg/kg, i.g.)-stimulated acid secretion, indicating that RAMH as well as M39 modulate the gastroprotective effects through interactions with histamine H3Rs. The present findings indicate that agonistic interaction with H3Rs is profoundly involved in the maintenance of gastric mucosal integrity by modulating PGE2 as well as gastric acid secretion, with no apparent role in the regulation of the inhibitory influence of somatostatin.

Initial Characterization of Transgenic Mice Overexpressing Human Histamine H2 Receptors.

In an integrative approach, we studied the role of histamine H2 receptors in the mouse heart. We noted that histamine, added cumulatively to the organ bath, failed to affect the force of contraction in left atrial preparations and did not change spontaneous heart rate in right atrial preparations from wild-type mice. By contrast, in the same preparations from mice that overexpressed the human H2 receptor in a cardiac-specific way, histamine exerted concentration- and time-dependent positive inotropic and positive chronotropic effects. Messenger RNA of the human H2 receptor was only detected in transgenic mice. Likewise, immunohistology and autoradiography only gave signals in transgenic but not in wild-type cardiac preparations. Similarly, a positive inotropic and positive chronotropic effect was observed with histamine in echocardiography of living transgenic mice and isolated perfused hearts (Langendorff preparation). Phosphorylation of phospholamban was increased in atrial and ventricular preparations from transgenic mice, but not in wild-type animals. The effects of histamine were mimicked by dimaprit and amthamine and antagonized by cimetidine. In summary, we generated a new model to study the physiologic and pathophysiologic cardiac role of the human H2 receptor.

The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats.

The role of Histamine H3 receptors (H3Rs) in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP) and novel object recognition (NOR) task in adult male rats, using donepezil (DOZ) as a standard drug. Acute systemic pretreatment with DL77 (2.5, 5, and 10 mg/kg, i.p.) significantly ameliorated memory deficits induced with MK801 in PAP (all P < 0.05, n = 7). The ameliorative effect of most promising dose of DL77 (5 mg/kg, i.p.) was reversed when rats were co-injected with the H3R agonist R-(α)-methylhistamine (RAMH, 10 mg/kg, i.p.) (p = 0.701 for MK801-amnesic group vs. MK801+DL77+RAMH group, n = 6). In the NOR paradigm, DL77 (5 mg/kg, i.p.) counteracted long-term memory (LTM) deficits induced with MK801 (P < 0.05, n = 6–8), and the DL77-provided effect was similar to that of DOZ (p = 0.788, n = 6–8), and was reversed when rats were co-injected with RAMH (10 mg/kg, i.p.) (p = 0.877, n = 6, as compared to the (MK801)-amnesic group). However, DL77 (5 mg/kg, i.p.) did not alter short-term memory (STM) impairment in NOR test (p = 0.772, n = 6–8, as compared to (MK801)-amnesic group). Moreover, DL77 (5 mg/kg) failed to modify anxiety and locomotor behaviors of animals innate to elevated-plus maze (EPM) (p = 0.67 for percentage of time spent exploring the open arms, p = 0.52 for number of entries into the open arms, p = 0.76 for percentage of entries into the open arms, and p = 0.73 number of closed arm entries as compared to saline-treated groups, all n = 6), demonstrating that the procognitive effects observed in PAP or NOR tests were unconnected to alterations in emotions or in natural locomotion of tested animals. These results signify the potential involvement of H3Rs in modulating neurotransmitters related to neurodegenerative disorders, e.g., AD.

Histamine H3 Receptors and Its Antagonism as a Novel Mechanism for Antipsychotic Effect : A Current Preclinical and Clinical Perspective

Histamine H3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia. These medications works through diverse mechanisms which include agonism at metabotropic glutamate receptor (mGluR2/3), partial agonism at dopamine D2, D3 and serotonin 5-HT1A receptors, antagonism at D2, 5-HT2A, 5-HT2B and 5-HT7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo-dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H3 receptors as a target of antiobesity therapeutics which is one of the limiting adverse effects of second generation schizophrenia medications. The recent failures of two promising H3 compounds in clinical trial dampened the interest in seeking antipsychotic like activities of H3 receptor antagonists. However, due to the inconclusive nature of many of these studies, the development of H3 compounds via H3 antagonism/inverse agonism approach still hold lot of promises and may be developed as a novel class of drugs for schizophrenia and its related complications e.g. weight gain.

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.

Cardioprotective role of H3R agonist imetit on isoproterenol-induced hemodynamic changes and oxidative stress in rats

The cardioprotective role of histamine H3 receptor (H3R) agonist imetit (IMT) in isoproterenol (ISO)-induced alterations of hemodynamic and oxidative stress was investigated in Wistar rats. In this study, rats were treated with IMT (5 and 10 mg/kg, per orally [p.o.]), carvedilol (10 mg/kg, p.o.) and ISO control group (normal saline) for 7 d, with concurrent subcutaneous administration of ISO (85 mg/kg) at 24 h interval on last two consecutive days whereas control group was administered with vehicle only. ISO significantly attenuated cardiac antioxidant enzymes superoxide dismutase, catalase and increased plasma cardiac injury biomarkers creatine kinase-MB, alanine transaminase and aspartate transaminase. ISO also altered cardiac activity as evidenced by decrease in blood pressure (34.60%) and increase in heart rate (11.40%). The damage due to oxidative stress was revealed by histopathology alterations such as myocyte necrosis, myofibrillar degeneration and pyknotic nucleus. However, pre-treatment with IMT demonstrated restoration of hemodynamic alterations along with significant preservation of antioxidants and myocyte injury-specific marker enzymes. Furthermore, protective effect of IMT was reconfirmed by the histopathological salvage of myocardium. Results of the present study demonstrated the cardioprotective potential of IMT, as evidenced by favorable improvement in ISO-induced hemodynamic, plasma cardiac biomarkers and tissue antioxidant status along with maintenance of integrity of myocardium.

Role of histamine H3 receptor in glucagon-secreting αTC1.6 cells

Pancreatic α-cells secrete glucagon to maintain energy homeostasis. Although histamine has an important role in energy homeostasis, the expression and function of histamine receptors in pancreatic α-cells remains unknown. We found that the histamine H3 receptor (H3R) was expressed in mouse pancreatic α-cells and αTC1.6 cells, a mouse pancreatic α-cell line. H3R inhibited glucagon secretion from αTC1.6 cells by inhibiting an increase in intracellular Ca2+ concentration. We also found that immepip, a selective H3R agonist, decreased serum glucagon concentration in rats. These results suggest that H3R modulates glucagon secretion from pancreatic α-cells.

Histamine H3 receptor antagonist JNJ-39220675 modulates locomotor responses but not place conditioning by dopaminergic drugs.

Brain histaminergic system is involved in the regulation of the dopaminergic circuitry. The role of histamine H3 receptor (H3R) in behaviors linked to amphetamine addiction and other behaviors induced by dopaminergic compounds has remained unclear. Our aim was to study whether H3R antagonist JNJ-39220675 inhibits amphetamine-induced stimulation and reward. The effects of JNJ-39220675 on dopamine D2-like receptor (D2R-like) agonist quinpirole-induced behaviors were also investigated in order to clarify whether the possible effects of H3R antagonists are D2R-like dependent. The effects of JNJ-39220675 on amphetamine and quinpirole-induced behavioral responses in mice were studied assessing the locomotor activation after both acute and repeated administrations of amphetamine and quinpirole. The place conditioning paradigm was also used as a measure of reward or aversion. JNJ-39220675 inhibited amphetamine-induced stimulation acutely but not after repeated administrations. Amphetamine (2 mg/kg) induced conditioned place preference that was not affected by either of the tested doses of JNJ-39220675 (1 and 10 mg/kg). Quinpirole (0.5 mg/kg) induced conditioned place aversion to which the pretreatment by JNJ-39220675 (10 mg/kg) had no effect. In repeated administration, JNJ-39220675 did, however, inhibit quinpirole-induced tolerance to hypokinesia. Our results show that although H3R antagonists inhibit ethanol reward, they may not possess the same ability on psychostimulants, such as amphetamine. However, if H3R antagonists will become clinically available, it is of importance that these compounds potentiate neither the rewarding nor aversive effects of other drugs.

Evidence for the Role of Histamine H3 Receptor in Alcohol Consumption and Alcohol Reward in Mice

Recent research suggests that histamine H3 receptor (H3R) antagonism may diminish motivational aspects of alcohol dependence. We studied the role of H3Rs in alcohol-related behaviors using H3R knockout (KO) mice and ligands. H3R KO mice consumed less alcohol than wild-type (WT) mice in a two-bottle free-choice test and in a 'drinking in the dark' model. H3R antagonist ciproxifan suppressed and H3R agonist immepip increased alcohol drinking in C57BL/6J mice. Impairment in reward mechanisms in H3R KO mice was confirmed by the lack of alcohol-evoked conditioned place preference. Plasma alcohol concentrations of H3R KO and WT mice were similar. There were no marked differences in brain biogenic amine levels in H3R KO mice compared with the control animals after alcohol drinking. In conclusion, the findings of this study provide evidence for the role of H3R receptor in alcohol-related behaviors, especially in alcohol drinking and alcohol reward. Thus, targeting H3Rs with a specific antagonist might be a potential means to treat alcoholism in the future.

Role of Histamine H1 Receptors in Vestibular Nucleus in Motion Sickness

ObjectivesTo investigate the expression of histamine H1 receptors (H1R) in the vestibular nucleus of brainstem in rats and the role of H1R in motion sickness (MS). MethodsA total of 24 healthy Sprague–Dawley rats were divided randomly into four groups (n=6 each) which determined if the animals would receive induction of MS or drug (promethazine) treatment: MS(–)/Drug(–); MS(+)/Drug(–); MS(–)/Drug(+ at 0.25 mg); and MS(+)/Drug(+). MS was induced by complex motion stimulation and the conditioned taste aversion was used as a behavioral indicator of MS. The volume of 0.15% sodium saccharin solution (SS) intake within 45 minutes after motion stimulation was measured. H1R in the vestibular nucleus was examined by immunofluorescence staining. The expression of H1R protein in brainstem tissue at vestibular nucleus level was detected by western blot. ResultsThe mean SS intake volume in the MS(+)/Drug(–) group (8.8 ml) was significantly less than that of the MS (–)/Drug(–) group (15.1 ml) (P < 0.01). The mean SS intake volume of the MS(–)/Drug(+) group (14.8 ml) was similar to that of the MS(–)/Drug(–) group. The mean SS intake volume (9.6 ml) of the MS(+)/Drug(+) group was more than that of the MS (+)/Drug(–) group (P < 0.01), but less than that of the MS (–)/Drug(–) group or MS (–)/Drug(+) group (P < 0.01). Immunofluorescence staining showed positive expression of H1R in the vestibular nucleus of brainstem and the expression was enhanced by motion stimulation. Western blot analysis showed that H1R protein expressed in the brainstem tissue at vestibular nucleus level and the expression also increased significantly after motion stimulation. The MS–induced increase of H1R was not affected significantly by promethazine. ConclusionsH1Rs exist in the vestibular nucleus in rats and H1R expression is up–regulated by motion stimulation, but not affected by promethazine. The findings indicate that the histaminergic system is involved in MS. Promethazine, as an H1R blocker, may play its anti–MS role by competing the binding site on H1Rs with histamine rather than inhibiting H1R expression.

Enhanced morphine-induced antinociception in histamine H3 receptor gene knockout mice

Previous studies have implicated a potential role for histamine H3 receptor in pain processing. There have been conflicting data, however, on the roles of H3 receptors in pain perception, and little information is available about the role of spinal histamine H3 receptors in morphine-induced antinociception. In the present study we examined the role of histamine H3 receptor in morphine-induced antinociception using histamine H3 receptor knockout mice and a histamine H3 receptor antagonist. Anitinociception was evaluated by assays for four nociceptive stimuli: hot-plate, tail-flick, paw-withdrawal, and formalin tests. Antinociception induced by morphine (0.125 nmol/5 μl, i.t.) was significantly augmented in histamine H3 receptor knockout (−/−) mice compared to the wild-type (+/+) mice in all four assays of pain. Furthermore, the effect of intrathecally administered morphine with thioperamide, a histamine H3 antagonist, was examined in C57BL/6J mice. A low dose of i.t. administered thioperamide (0.125 nmol/5 μl) alone had no significant effect on the nociceptive response. In contrast, the combination of morphine (0.125 nmol/5 μl, i.t.) with the same dose of thioperamide resulted in a significant reduction in the pain-related behaviors in all four nociceptive tests. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H3 receptors at the spinal level.

The roles of histamine H1 receptors on cognition

Histamine neurons are located exclusively in the posterior hypothalamus, from where they project diffusely to all regions of brain. Neuronal histamine has been implicated in a variety of brain functions including wakefulness, learning and memory [1]. Although it is well known that sedative antihistamines induce cognitive decline in humans through blockage of H1 receptor [2], both facilitatory and inhibitory effects of neuronal histamine on learning and memory have been described in animal behavioral studies [3, 4]. Histaminergic neurotransmission has been also implicated in pathophysiology of stress-related psychiatric diseases [5]. Although several atypical antipsychotics are potent H1 antagonists [6], the clinical signifi cance of interaction between atypical antipsychotics and H1 receptors is still unknown. The aim of this study was to investigate the role of histamine H1 receptors on cognition in normal conditions using H1 receptor gene knockout mice (H1KO). We also investigated the effects of H1 receptor blockade on social isolation-induced behavioral and neurochemical changes in H1KO mice and their wild-type (WT) mice.

Time-Dependent Ventilatory Response to Poikilocapnic Hypoxia during Light and Dark Periods and the Role of Histamine H1 Receptors in Mice

We tested the hypothesis that the biphasic ventilatory response to poikilocapnic hypoxia shows circadian variation and contribution of histamine H1 receptors in mice. Initial increases in ventilation were augmented during dark periods. H1 receptors had no major relationship with circadian variation, but affected the declined phase.

Role of histamine H3 receptors during ischemia/reperfusion in isolated rat hearts.

Histamine H3 receptors are involved in regulating the release of norepinephrine (NE), in both central and peripheral nervous systems. We investigated the effect of R-alpha-methylhistamine (R-HA), a selective H3 receptor agonist, and thioperamide (Thiop), a selective H3 receptor antagonist, on ischemia/reperfusion-induced changes in carrier-mediated NE release and cardiac function in isolated rat heart. Hearts were subjected to 40-minute ischemia followed by 30-minute reperfusion. Ischemia/reperfusion evoked massive NE release, which was markedly suppressed by the treatment with desipramine (DMI), a neuronal NE transporter blocker. Ischemia/reperfusion-induced cardiac dysfunction (decreases in left ventricular developed pressure, LVDP, and the first derivative of left ventricular pressure, dP/dt, and a rise in left ventricular end diastolic pressure, LVEDP) was also improved by the DMI treatment. The treatment with R-HA also significantly decreased the excessive NE release induced by the ischemia/reperfusion, improved the recovery of LVDP and dP/dt, and suppressed the rise in LVEDP. Thiop did not affect NE release and cardiac function after the reperfusion. When R-HA was administered concomitantly with Thiop, R-HA failed to attenuate ischemia/reperfusion-induced NE release and cardiac dysfunction. Thus, it seems likely that the ischemia/reperfusion-induced carrier-mediated NE release in rat hearts is negatively regulated by the activation of H3 receptors, probably located on cardiac noradrenergic nerve endings.

Involvement of histamine H3 receptors in scratching behaviour in mast cell-deficient mice.

Although the roles of histamine H3 receptors have been studied in several tissues such as the brain, lung, spleen, colon and peripheral sensory nerve endings, the involvement of H3 receptors in skin responses particularly in relation to scratching behaviour are not well documented. This work was performed to study the effects of histamine H3 antagonists on scratching behaviour in mast cell-deficient mice. Histamine H3 antagonists iodophenpropit and clobenpropit, histamine and substance P were injected intradermally into the rostral part of the back of mast cell-deficient (WBB6F1 W/Wv) and wild-type (WBB6F1+/+) mice and scratching behaviour was measured for 60 min. The effects of H1 antagonists on scratching behaviour induced by H3 antagonists were also investigated. Intradermal injection of iodophenpropit and clobenpropit at doses of 10 and 100 nmol per site caused significant increases in scratching behaviour in both mast cell-deficient and wild-type mice. Histamine also caused a dose-related increase in the incidence of scratching behaviour, and a significant effect was observed at a dose of 100 nmol per site in both mast cell-deficient and wild-type mice. Substance P was also effective in causing scratching behaviour in both mast cell-deficient and wild-type mice. However, histamine H1 antagonists diphenhydramine and chlorphenamine failed to inhibit H3 antagonist-induced scratching behaviour in both types of mice. Our results indicated that intradermal injection of H3 antagonists induces scratching behaviour and that chemical mediators other than histamine seem to be involved in the response.

Role of histamine H3 receptors in control of mouse intestinal motility in vivo and in vitro: comparison with alpha2-adrenoceptors.

We tested drugs acting at histamine H3 receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations. The agonist (R)-alpha-methylhistamine (100 micromol/kg) caused a maximum 25% reduction of gastrointestinal transit, an effect mimicked by immepip (100 micromol/kg) and antagonized by thioperamide (20 micromol/kg) or clobenpropit (20 micromol/kg). In the isolated ileum, (R)-alpha-methylhistamine (10-100 microM) caused a slight, thioperamide-insensitive, reduction (maximum 15%) of electrically evoked cholinergic contractions. In comparison, the alpha2-adrenoceptor agonist clonidine (0.1 micromol/kg) caused a 35.2% inhibition of the gastrointestinal transit and almost completely reduced (maximum 82% at 1 microM) the cholinergic contraction of the isolated ileum, both effects being antagonized by idazoxan (0.4 micromol/kg and 1 microM, respectively). These results suggest that histamine H3 receptors, located outside the myenteric plexus, mediate an inhibition of the gastrointestinal transit in vivo. Conversely, the presence of a2-adrenoceptors in the cholinergic nerve endings and their inhibitory role in the control of gastrointestinal propulsion is confirmed.