thioperamide and alpha-methylhistamine

Recently we found that synthetic compounds containing amino group linked to hydrophobic or aromatic moiety are potent modulators of the proton-gated channels (ASICs). These structures have clear similarity with ligands of histamine receptors. We have also demonstrated that histamine potentiates homomeric ASIC1a by shifting its activation dependence to less acidic conditions. In the present work the action of a series of histamine receptors ligands on recombinant ASIC1a and ASIC2a was characterized. Two types of action were found for ASIC1a. 1-methylhistamine, N-alpha-methylhistamine, dimaprit and thioperamide caused significant potentiation, which was pH-dependent and voltage-independent. The H4R antagonist A943931 caused inhibition, which is likely due to voltage-dependent pore block. ASIC2a were virtually insensitive to the drugs tested. We conclude that ligands of histamine receptors should also be considered as ASIC modulators.

Topics: Acid Sensing Ion Channels; Animals; CHO Cells; Cricetulus; Dimaprit; Gene Expression Regulation; Histamine; Histamine Agonists; Histamine Antagonists; Humans; Hydrogen-Ion Concentration; Ligands; Methylhistamines; Patch-Clamp Techniques; Piperidines; Receptors, Histamine; Recombinant Proteins; Signal Transduction

The recently cloned histamine H(4) receptor is expressed predominantly in haematopoietic cells and has been found to modulate the function of mast cells, eosinophils, dendritic cells and T lymphocytes. It represents an attractive target for pharmacological interventions against a number of inflammatory and autoimmune disorders. In the present work we used two-electrode voltage-clamp to demonstrate histamine H(4) receptor modulation of G protein-coupled inward rectifier potassium (GIRK) channels heterologously expressed in Xenopus oocytes. In accordance with earlier findings in other effector systems, full agonism by histamine and (R)-alpha-methylhistamine, partial agonism by clobenpropit and inverse agonism by thioperamide were observed. Furthermore, in oocytes injected with low amounts of receptor cRNA, clobenpropit apparently acted as a neutral antagonist. We also used the high temporal resolution afforded by this system to study the differential time courses of response deactivation upon ligand washout for clobenpropit and (R)-alpha-methylhistamine. GIRK channels represent a novel effector system for histamine H(4) receptor modulation, which may be of physiological relevance and prove useful in the development of compounds targeting this receptor.

Topics: Animals; Electrophysiology; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; Methylhistamines; Oocytes; Patch-Clamp Techniques; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Thiourea; Xenopus

Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Galpha(i/o) proteins reducing adenosine 3', 5'-monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.

Topics: Animals; Bile Ducts; Bile Ducts, Intrahepatic; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Down-Regulation; Drug Therapy, Combination; Gene Expression Regulation, Enzymologic; Histamine; Histamine Agonists; Hyperplasia; Ligation; Liver; Male; MAP Kinase Signaling System; Methylhistamines; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphorylation; Piperidines; Protein Serine-Threonine Kinases; Rats; Rats, Inbred F344; Receptor, EphA8; Receptors, Histamine H3

This study analysed the effects of betahistine and thioperamide, two histamine H(3) receptor antagonists, on the recovery process after unilateral vestibular neurectomy (UVN) in the cat. In UVN animals untreated or treated with betahistine or thioperamide, recovery was evaluated by recording the horizontal spontaneous nystagmus and the postural and locomotor performances. The neurochemical effects of these drugs were determined by examining their impact on the histaminergic system. We quantified the mRNA coding for histidine decarboxylase (enzyme synthesizing histamine) by in situ hybridisation in the tuberomammillary nuclei, while binding density to histamine H(3) receptors was assessed using a histamine H(3) receptor agonist ([(3)H]N-alpha-methylhistamine) and autoradiography methods in the tuberomammillary and the vestibular nuclei. Relative to the UVN-untreated group, cats treated with betahistine or thioperamide showed strongly accelerated behavioural recovery. UVN-induced 1) an up-regulation of histidine decarboxylase mRNA in the tuberomammillary nuclei, strongly accentuated under betahistine and thioperamide, 2) a reduction of the binding to histamine H(3) receptors in the vestibular and tuberomammillary nuclei, also strongly enhanced in both groups of treated cats. This study demonstrates that betahistine and thioperamide strongly improve the recovery of vestibular functions in UVN cats by interacting with the histaminergic system.

Topics: Animals; Behavior, Animal; Betahistine; Cats; Histamine Agonists; Histamine Antagonists; Histidine Decarboxylase; Ligands; Methylhistamines; Nystagmus, Pathologic; Piperidines; Postural Balance; Receptors, Histamine H3; RNA, Messenger; Vestibular Nerve; Vestibular Nuclei

To investigate the effect of selective H3 receptor agonist(R)-alpha-methylhistamine and antagonist thioperamide on the respiratory response in asthmatic guinea pigs respectively.. Anesthesized guinea pigs were prepared with a implanted intracerebroventricular (icv) cannula and instrumented for the measurement of respiratory rate (RR) and diaphragmatic electric activity (DA). Substance P-like immunoreactive (SP-LI) substances in lower respiratory tract were detected by immunohistochemical method. Brain histamine contents were measured by fluorometric determination.. (1) Intravenous injection of ovalbumin caused tachypnea and significant decrease in DA magnitude. At the same time, SP-LI substances increased in trachea, bronchus and lung. (2) Administration of selective H3 receptor agonist (R)-alpha-methylhistamine (5 microg) icv immediately after i.v. ovalbumin could significantly ameliorate the changes in RR and DA induced by ovalbumin. In accordance, SP-LI substances in lower respiratory tract markedly decreased at 5 min and 10 min after (R)-alpha-methylhistamine microinjection. (3) Icv thioperamide (20 microg) caused a significant increase in RR and a decrease in DA. (4) Brain histamine contents increased in hypothalamus and cortex during asthma. After microinjection of thioperamide (20 microg) icv significant increase of histamine contents in hypothalamus and cortex was observed.. Brain histamine H3 receptors may be related to asthmatic respiratory responses.

Topics: Animals; Asthma; Brain; Guinea Pigs; Histamine Agonists; Histamine H3 Antagonists; Lateral Ventricles; Male; Methylhistamines; Muscle Contraction; Piperidines; Receptors, Histamine H3; Substance P; Trachea

Complications of sickle cell anaemia include vascular occlusion triggered by the adherence of sickle erythrocytes to endothelium in the postcapillary venules. Adherence can be promoted by inflammatory mediators that induce endothelial cell adhesion molecule expression and arrest flowing erythrocytes. The present study characterised the effect of histamine stimulation on the kinetics of sickle cell adherence to large vessel and microvascular endothelium under physiological flow. Increased sickle cell adherence was observed within minutes of endothelial activation by histamine and reached a maximum value within 30 min. At steady state, sickle cell adherence to histamine-stimulated endothelium was 47 +/- 4 adherent cells/mm(2), 2.6-fold higher than sickle cell adherence to unstimulated endothelial cells. Histamine-induced sickle cell adherence occurred rapidly and transiently. Studies using histamine receptor agonists and antagonists suggest that histamine-induced sickle cell adhesion depends on simultaneous stimulation of the H(2) and H(4) histamine receptors and endothelial P-selectin expression. These data show that histamine release may promote sickle cell adherence and vaso-occlusion. In vivo histamine release should be studied to determine its role in sickle complications and whether blocking of specific histamine receptors may prevent clinical complications or adverse effects from histamine release stimulated by opiate analgesic treatment.

Topics: Analysis of Variance; Anemia, Sickle Cell; Cell Adhesion; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Erythrocytes; Famotidine; Histamine; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Imidazoles; Methylhistamines; P-Selectin; Piperidines; Pyrilamine; Stimulation, Chemical; Thiazoles; Thiourea; Venules

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H(3)-receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)-alpha-methylhistamine (RAMH) (5 microg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 microg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Catalepsy; Dose-Response Relationship, Drug; Haloperidol; Histamine Agonists; Histamine Antagonists; Methylhistamines; Mice; Models, Animal; Motor Activity; Piperidines; Receptors, Histamine H3; Schizophrenia; Stereotyped Behavior; Time Factors

This study was designed i) to investigate the role of histamine H3-receptor ligands on mouse modified forced swimming test, a method that distinguishes the catecholaminergic behaviour with that of serotonergic compounds and ii) to evaluate the role of free radicals in mediation of such effects. Swiss strain albino mice were treated with different doses of histamine H3-receptor antagonist thioperamide (3.75, 7.5 and 15 mg/kg intraperitoneally) and agonist (R)-alpha-methylhistamine (5 microg intracerebroventricularly). The climbing, swimming and immobility times were recorded for 6 min. Immediately after modified forced swimming test, the animals were sacrificed and parameters of oxidative stress were assessed in the brain by measuring the thiobarbituric acid reactive substance (TBARS), glutathione (GSH) and catalase levels. Thioperamide (7.5 and 15 mg/kg intraperitoneally) dose-dependently decreased immobility time and increased swimming time but not climbing time. The behaviour of mice treated with (R)-alpha-methylhistamine was similar to that of control mice. A significant reduction in GSH and an increase in catalase levels were observed in brains of mice exposed to modified forced swimming test. Thioperamide pretreatment dose-dependently reversed such an alteration in oxidative stress parameters. (R)-alpha-methylhistamine caused a reversal of altered catalase but not GSH levels. Thioperamide shows antidepressant effects in the modified forced swimming test and causes a reversal of the test-induced oxidative stress indicating its antioxidant potential. The antidepressant effect of thioperamide appears to be mediated via serotonergic and/or antioxidant mechanisms.

Topics: Animals; Antidepressive Agents; Brain; Catalase; Female; Glutathione; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Mice; Mice, Inbred Strains; Motor Activity; Oxidative Stress; Piperidines; Receptors, Histamine H3; Swimming; Thiobarbituric Acid Reactive Substances

Histamine is one of the most common chemical mediators causing pruritus, and H1 receptor antagonists have been used as a first choice in its treatment. On the other hand, although the presence of H3 receptors has been identified in the skin, few studies have investigated the involvement of H3 receptors on pruritus.. The purpose of this study was to examine whether H3 receptor agonist or antagonist influences the incidence of scratching behaviour in ICR or mast cell-deficient WBB6F1-W/WV mice.. The mice were given an intradermal injection of H3 receptor agonist or antagonist into the rostral part of the back, and the occurrence of scratching behaviour at the injected site by the hind paws was counted over 60 min.. H3 receptor antagonists, thioperamide and AQ0145 significantly increased the incidence of scratching behaviour in ICR mice. H3 receptor agonist, (R)-alpha-methylhistamine, had no effect. On the other hand, (R)-alpha-methylhistamine significantly inhibited thioperamide or AQ0145-induced scratching behaviour. In addition, both thioperamide and AQ0145 elicited scratching behaviour in mast cell-deficient WBB6F1-W/WV mice.. From these results, it may be concluded that H3 receptors are involved in the modulation of pruritus in the skin, and mast cells are not essential in this response. In addition, H3 receptor agonists can be useful as a novel therapeutic approach against pruritus.

Topics: Adamantane; Amidines; Animals; Female; Histamine Agonists; Histamine H2 Antagonists; Imidazoles; Mast Cells; Methylhistamines; Mice; Mice, Inbred ICR; Mice, Mutant Strains; Piperidines; Pruritus; Receptors, Histamine H3; Skin

The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.

Topics: Amygdala; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Epilepsy, Tonic-Clonic; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraventricular; Isothiuronium; Kindling, Neurologic; Lateral Ventricles; Male; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Seizures; Thiourea

On-line microdialysis of histamine in 10-min samples of the prefrontal cortex of the conscious rat is described. The HPLC-fluorescent assay for histamine in dialysates has been significantly simplified by using only one postcolumn reagent line instead of the three reagent lines described in earlier methods. The method is selective, sensitive (detection limit: 2-3 fmol on column), and linear over a large concentration range. Basal values of histamine decreased to about 50% of basal levels during infusion of tetrodotoxin (5 x 10(-6) M). Handling rats for 15 min increased histamine in dialysates to about 300% of basal levels. When tetrodotoxin (10(-6) M) was applied during handling the increase in histamine release was strongly (about 80%) suppressed. The handling-induced increase in histamine was used as a paradigm to investigate the functional activity of histamine H3 autoreceptors during mild stress or arousal. An H3 receptor specific agonist (alpha-methylhistamine; 10(-5) M) and antagonist (thioperamide; 10(-5) M) were infused into the frontal cortex via the microdialysis probe. The effect of handling on histamine release was potentiated during infusion of thioperamide and fully suppressed during infusion of alpha-methylhistamine. These results clearly illustrate the efficacy of the H3 autoreceptor in modulating stimulated histamine release during natural stimulatory conditions.

Topics: Animals; Autoreceptors; Biological Assay; Chromatography, High Pressure Liquid; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Microdialysis; Neurons; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, Histamine H3; Stress, Physiological; Synaptic Transmission; Tetrodotoxin

Production of N-alpha-methyl-histamine (NAMH), a histamine H(3) receptor (H3R) agonist, is reportedly promoted in Helicobacter pylori infected human gastric mucosa. NAMH was suggested to act directly on histamine H(2) receptors (H2Rs) in animals to stimulate acid secretion and to be a H2R agonist. As H2Rs and H3Rs play different roles in gastric acid secretion, it is very important to verify that NAMH is a H2R agonist.. To determine whether NAMH is a H2R agonist, as well as a H3R agonist.. We used a Chinese hamster ovary (CHO) cell line expressing human H2Rs (CHO-H2R) and control CHO cells. Expression of human H2Rs was confirmed by tiotidine binding. cAMP production in CHO-H2R and control cells in response to histamine or NAMH was measured. cAMP production in response to 10(-7) M NAMH was also measured in the presence or absence of the H2R antagonist famotidine and the H3R antagonist thioperamide.. NAMH dose dependently stimulated cAMP productions in CHO-H2R cells. This production was inhibited by famotidine but not by thioperamide. Control CHO cells were unresponsive to either histamine or NAMH. In addition, the effect of NAMH, in terms of cAMP production in CHO-H2R cells, was more potent than that of histamine-that is, with a lower EC(50) concentration and higher maximal cAMP production. Both NAMH and histamine, but not R-alpha-methyl-histamine, effectively inhibited [(3)H] tiotidine binding to CHO-H2R cells.. NAMH, which is produced in the gastric mucosa by H pylori, is a potent H2R agonist as well as a H3R agonist.

Topics: Animals; CHO Cells; Cimetidine; Cricetinae; Cyclic AMP; Famotidine; Female; Histamine Agonists; Histamine Antagonists; Histamine H2 Antagonists; Methylhistamines; Ovary; Piperidines; Receptors, Histamine H2; Receptors, Histamine H3

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.

Topics: Animals; Charcoal; Clonidine; Histamine Agonists; Histamine Antagonists; Idazoxan; Ileum; Imidazoles; In Vitro Techniques; Male; Methylhistamines; Mice; Peristalsis; Piperidines; Receptors, Adrenergic, alpha-2; Receptors, Histamine H3

Drugs interfering with the histaminergic system facilitate behavioral recovery after vestibular lesion, likely by increasing histamine turnover and release. The effects of betahistine (structural analogue of histamine) on the histaminergic system were tested by quantifying messenger RNA for histidine decarboxylase (enzyme synthesizing histamine) by in situ hybridization and binding to histamine H(3) receptors (mediating, namely, histamine autoinhibition) using a histamine H(3) receptor agonist ([(3)H]N-alpha-methylhistamine) and radioautography methods. Experiments were done in brain sections of control cats (N=6) and cats treated with betahistine for 1 (N=6) or 3 (N=6) weeks. Betahistine treatment induced symmetrical changes with up-regulation of histidine decarboxylase mRNA in the tuberomammillary nucleus and reduction of [(3)H]N-alpha-methylhistamine labeling in both the tuberomammillary nucleus, the vestibular nuclei complex and nuclei of the inferior olive. These findings suggest that betahistine upregulates histamine turnover and release, very likely by blocking presynaptic histamine H(3) receptors, and induces histamine H(3) receptor downregulation. This action on the histaminergic system could explain the effectiveness of betahistine in the treatment of vertigo and vestibular disease.

Topics: Administration, Oral; Animals; Autoradiography; Betahistine; Binding Sites; Binding, Competitive; Cats; Histamine; Histamine Agonists; Histidine Decarboxylase; Hypothalamic Area, Lateral; In Situ Hybridization; Methylhistamines; Piperidines; Radioligand Assay; Receptors, Histamine H3; RNA, Messenger; Vestibule, Labyrinth

To investigate the possible involvement of histamine H(3) receptors in renal noradrenergic neurotransmission, effects of (R)alpha-methylhistamine (R-HA), a selective H3-receptor agonist, and thioperamide (Thiop), a selective H3-receptor antagonist, on renal nerve stimulation (RNS)-induced changes in renal function and norepinephrine (NE) overflow in anesthetized dogs were examined. RNS (0.5-2.0 Hz) produced significant decreases in urine flow and urinary sodium excretion and increases in NE overflow rate (NEOR), without affecting renal hemodynamics. When R-HA (1 microg x kg(-1) x min(-1)) was infused intravenously, mean arterial pressure and heart rate were significantly decreased, and there was a tendency to reduce basal values of urine flow and urinary sodium excretion. During R-HA infusion, RNS-induced antidiuretic action and increases in NEOR were markedly attenuated. Thiop infusion (5 microg x kg(-1) x min(-1)) did not affect basal hemodynamic and excretory parameters. Thiop infusion caused RNS-induced antidiuretic action and increases in NEOR similar to the basal condition. When R-HA was administered concomitantly with Thiop infusion, R-HA failed to attenuate the RNS-induced antidiuretic action and increases in NEOR. However, in the presence of pyrilamine (a selective H1-receptor antagonist) or cimetidine (a selective H2-receptor antagonist) infusion, R-HA attenuated the RNS-induced actions, similarly to the case without these antagonists. Thus functional histamine H3 receptors, possibly located on renal noradrenergic nerve endings, may play the role of inhibitory modulators of renal noradrenergic neurotransmission.

Topics: Animals; Blood Pressure; Dogs; Electric Stimulation; Electromagnetic Fields; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Histamine Agonists; Histamine Antagonists; Kidney; Male; Methylhistamines; Nerve Fibers; Norepinephrine; Piperidines; Receptors, Histamine H3; Regional Blood Flow; Renal Circulation; Sodium; Synaptic Transmission; Urodynamics

The effects of an H3 agonist, R-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in the hypothalamus of rat, monkey and human brains were compared in vitro. The histamine H(3)-receptor ligands competitively inhibited MAO-B, but noncompetitively inhibited MAO-A in all three mammalian species. However, alpha-MeHA inhibited MAO-A more potently than MAO-B at high concentrations in all three species. The K(i) values for MAO-A of alpha-MeHA in hypothalamic homogenates of rat, monkey and human brains were estimated to be 1.1, 1.2 and 1.9 mM, respectively, suggesting that alpha-MeHA cannot behave as a substrate for the MAO inhibitor. In contrast, rat, monkey and human brain MAO-B activities were inhibited by thioperamide, with respective K(i) values of 174.6, 8.2 and 10.8 microM, more potently than MAO-A activity. These results indicate that thioperamide, which elicits a strong activation of histamine release and turnover to N-tele-methylhistamine from histamine, competitively inhibits the conversion of N-tele-methylhistamine to N-tele-methylimidazoleacetic acid in human and monkey brains where MAO-B predominates.

Topics: Aged; Animals; Binding, Competitive; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine Antagonists; Humans; Hypothalamus; Imidazoles; Ligands; Macaca; Methylhistamines; Middle Aged; Monoamine Oxidase; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Subcellular Fractions; Synaptic Transmission

We investigated the peripheral effects of an H3-receptor agonist and an H3-receptor antagonist (R)alpha-methylhistamine (Ralpha-MeHA) and thioperamide, respectively, on basal feeding and the CCK8-induced inhibition of food intake in rat. Intraperitoneal injection of thioperamide reduced food intake in a dose-dependent manner with maximal inhibition (35%, P<0.01 vs saline) at 3 mg/kg. (R)alpha-MeHA (0.3-3 mg/kg i.p.), an H3-receptor agonist alone had no effect on feeding but reversed the thioperamide-induced inhibition of food intake in a dose-dependent manner. The maximal feeding inhibitory dose of thioperamide (3 mg.kg i.p) increased by 40% and 22 % (P<0.01 vs saline) brain and stomach histamine contents, respectively. Histamine (0.3 - 6 mg/kg i.p.) and CCK-8 (3 - 30 microg/kg i.p) also inhibited food intake in a dose-dependent manner. Inhibition was 20% to 40% for histamine and 40% to 80% (P<0.01 vs saline) for CCK8. CCK-8 inhibition of feeding was increased by thioperamide and prevented by (R)alpha-MeHA in a dose-dependent way. In addition, CCK-8 did not reduce food intake if rats were pretreated with pyrilamine or ranitidine postsynaptic H1- and H2-receptor antagonists respectively. Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect.

Topics: Animals; Brain; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Gastric Mucosa; Histamine; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Male; Methylhistamines; Piperidines; Pyrilamine; Ranitidine; Rats; Rats, Wistar; Receptors, Histamine H3; Sincalide; Stomach

The interaction of selective histamine H3-receptor agonist R(alpha)-methyl-histamine (RAMH) and antagonist thioperamide (THP) with some antiepileptic drugs [AED; phenytoin (PHT), carbamazepine (CBZ), sodium valproate (SVP), and gabapentin (GBP)] was studied on seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in mice. It was found that subeffective dose of THP in combination with the subeffective doses of PHT and GBP provided protection against MES and/or PTZ-induced seizures. Further, RAMH reversed the protection afforded by either PHT or GBP on MES and/or PTZ seizures. In another set of experiments, the histamine content was measured in the whole brain and in different brain regions including cerebral cortex, hypothalamus, brain stem and cerebellum following convulsant (MES and PTZ) and AED treatment. It was seen that while MES exhibited a tendency to enhance brain histamine levels, PTZ showed the opposite effect. AEDs either increased (PHT and GBP) or decreased (SVP) brain histamine content in different regions to varying degrees. The results indicate a role for histamine in seizures and in the action of AEDs and suggest that selective H3-receptor antagonists may prove to be of value as adjuncts to conventional AEDs.

Topics: Animals; Anticonvulsants; Brain; Convulsants; Drug Synergism; Epilepsy; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Mice; Pentylenetetrazole; Piperidines; Receptors, Histamine H3

We studied the effects of histamine H(3) receptor ligands on the release of endogenous acetylcholine from the isolated, vascularly perfused rat stomach. The stomach was perfused via the celiac artery with modified Krebs-Ringer solution containing physostigmine. Released acetylcholine from the portal vein was electrochemically measured using high-performance liquid chromatography and an enzyme system. Vagus nerves were electrically stimulated twice for 2 min (0.5 or 2.5 Hz). Acetylcholine release evoked at 2.5 Hz was slightly inhibited by histamine and effectively potentiated by thioperamide, a histamine H(3) receptor antagonist. Acetylcholine release evoked at 0.5 Hz in the presence of atropine was not influenced by thioperamide, but effectively inhibited by histamine, R-alpha-methylhistamine or imetit, histamine H(3) receptor agonists. These inhibitory effects were abolished by thioperamide or pertussis toxin. These results suggest that histamine attenuates acetylcholine release from vagus nerves through histamine H(3) receptor-mediated and pertussis toxin-sensitive mechanisms in the rat stomach.

Topics: Acetylcholine; Animals; Atropine; Gastric Mucosa; GTP-Binding Proteins; Histamine; Imidazoles; Male; Methylhistamines; Perfusion; Pertussis Toxin; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea; Vagus Nerve; Virulence Factors, Bordetella

1. The modifications of hippocampal release of norepinephrine following the administration of R-(-)-alpha-methylhistamine and thioperamide, respectively agonist and antagonist of histamine H3 receptors, were assessed in freely moving rats by microdialysis. 2. Both the systemic (2 mg/kg i.p.) and local (100 microM via the probe) administration of thioperamide caused no modifications of basal release, indicating that the histaminergic system is not tonically involved in regulating the hippocampal noradrenergic activity. 3. R-(-)-alpha-methylhistamine (1 and 100 microM) produced a slight, short-lasting and dose-dependent reduction of norepinephrine release antagonized by local perfusion (100 microM) and prevented by systemic administration of thioperamide 2 mg/kg. 4. The results seem to indicate that the modulation of norepinephrine release through presynaptic H3-receptors in the rat hippocampus plays a minor role in the memory-enhancing effects of thioperamide.

Topics: Animals; Dose-Response Relationship, Drug; Hippocampus; Histamine Antagonists; Male; Memory; Methylhistamines; Norepinephrine; Piperidines; Rats; Rats, Wistar; Receptors, Histamine

The effect of selective histamine H3-receptor antagonist thioperamide was studied on PTZ-induced seizures in mice. Thioperamide significantly protected clonic seizures induced by PTZ in a dose-dependent manner. The effect of thioperamide was completely countered by pretreatment with R (alpha)-methylhistamine (RAMH), a selective H3-receptor agonist suggesting that the observed effect of thioperamide was elicited by histamine H3-receptors. RAMH alone did not significantly modify PTZ seizures. The findings are consistent with a role for the histaminergic neuronal system in seizures and suggest that H3-receptors may play an important role in modulating clonic seizures induced by PTZ in mice.

Topics: Animals; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Methylhistamines; Mice; Pentylenetetrazole; Piperidines; Protective Agents; Receptors, Histamine H3; Seizures

Conventional intracellular microelectrodes and marker injection techniques were used to study the actions of histamine on inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine. Bath application of histamine (1-300 microM) reversibly suppressed both noradrenergic and non-adrenergic slow inhibitory postsynaptic potentials in a concentration-dependent manner. These effects of histamine were mimicked by the selective histamine H(3) receptor agonist R(-)-alpha-methylhistamine but not the selective histamine H(1) receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT dimaleate), or the selective histamine H(2) receptor agonist, dimaprit. The histamine H(3) receptor antagonist, thioperamide, blocked the effects of histamine. Histamine H(1) and H(2) receptor antagonists did not change the action of histamine. Hyperpolarizing responses to focal application of norepinephrine or somatostatin by pressure ejection from micropipettes were unaffected by histamine and R(-)-alpha-methylhistamine. The results suggest that histamine acts at presynaptic histamine H(3) receptors on the terminals of sympathetic postganglionic fibers and intrinsic somatostatinergic nerves in the small intestine to suppress the release of the inhibitory neurotransmitters, norepinephrine and somatostatin.

Topics: Animals; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Intestine, Small; Male; Methylhistamines; Norepinephrine; Phentolamine; Piperidines; Receptors, Histamine H3; Submucous Plexus; Synaptic Transmission

The distribution of histaminergic fibers in the zebrafish brain was recently shown to resemble that in mammals. Expression of L-histidine decarboxylase (HDC) mRNA was shown only in the area corresponding to that expressing HDC in mammals. This indicates that the zebrafish could be a useful model for studies on the function of the brain histaminergic system. In this study an H(3)-like receptor is identified in zebrafish brain. With binding studies using N-alpha-[(3)H]methylhistamine on zebrafish brain sections, signals were observed in several regions. Highest densities were detected in optic tectum and hypothalamus. The autoradiographic signal was abolished completely by the H(3)-specific antagonist clobenpropit and significantly reduced by another H(3) antagonist, thioperamide. Histamine and immepip induced an increase of guanosine 5'-(gamma-[(35)S]thio)triphosphate binding in several areas of the zebrafish brain. The activation was blocked with clobenpropit but not with cimetidine or mepyramine. These results indicate that the zebrafish has a histamine H(3)-like receptor that functionally interacts with the inhibitory, G(i)/G(o), class of G proteins. No previous evidence for a histamine receptor in zebrafish exists. The receptor described here is apparently similar to the mammalian H(3) receptor, making this the first description of a histamine H(3)-like receptor in a lower vertebrate.

Topics: Animals; Autoradiography; Brain; Cimetidine; Female; Guanosine 5'-O-(3-Thiotriphosphate); Histamine Agonists; Histamine Antagonists; Imidazoles; Kinetics; Male; Methylhistamines; Piperidines; Pyrilamine; Radioligand Assay; Receptors, Histamine H3; Sulfur Radioisotopes; Thiourea; Tritium; Zebrafish

Studies were performed to assess the functional activity of histamine H3 receptors on neurogenic sympathetic end organ responses in cryopreserved human saphenous vein. (R)-alpha-methylhistamine inhibited electrical field stimulation-evoked contractile responses in a dose dependent manner (pD2 = 8.20). Prazosin (1 microM) and tetrodotoxin (1 microM) blocked the electrical field stimulation-evoked contractile responses in human saphenous vein indicating a sympathetic neural origin of these contractions. The histamine H3 antagonists thioperamide (pA2 = 8.41) and clobenpropit (pA2 = 10.10) produced parallel rightward shifts in the concentration response curve to (R)-alpha-methylhistamine in human saphenous vein and guinea pig ileum (pA2 = 8.59 and 9.83, respectively). Pretreatment with (R)-alpha-methylhistamine (1 microM) did not alter contractions to exogenous norepinephrine in human saphenous vein. In addition, clonidine (pD2 = 10.28) inhibited electrical field stimulation-evoked contractile responses in human saphenous vein which were blocked by yohimbine (30 nM, pA2 = 9.92) but did not alter the (R)-alpha-methylhistamine dose response curve. These results demonstrate the presence of functional presynaptic histamine H3 heteroreceptors on cryopreserved human saphenous vein sympathetic nerves that, upon activation, attenuate electrical field stimulation-evoked contractile responses in this vessel.

Topics: Adrenergic alpha-Antagonists; Aged; Animals; Dose-Response Relationship, Drug; Electric Stimulation; Female; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Humans; Ileum; Imidazoles; In Vitro Techniques; Male; Methylhistamines; Middle Aged; Muscle Contraction; Piperidines; Prazosin; Receptors, Histamine H3; Saphenous Vein; Tetrodotoxin; Thiourea; Yohimbine

Histamine H3 receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H3 receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated i.p. with the histamine H3 receptor agonist R-alpha-methylhistamine (10 mg/kg) or the histamine H3 receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the i.p. administration of R-alpha-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H3 receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-alpha-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-alpha-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2-10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H3 receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H3 receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied.

Topics: Analysis of Variance; Animals; Anxiety; Depression; Disease Models, Animal; Histamine Agonists; Histamine Antagonists; Imidazoles; Ligands; Male; Maze Learning; Methylhistamines; Mice; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Swimming; Thiourea

In previous research we found that pre-training administration of histamine H3 receptor agonists such as (R)-alpha-methylhistamine and imetit impaired rat performance in object recognition and a passive avoidance response at the same doses at which they inhibited the release of cortical acetylcholine in vivo. Conversely, in the present study we report that the post-training administration of (R)-alpha-methylhistamine and imetit failed to affect rat performance in object recognition and a passive avoidance response, suggesting that H3 receptor influences the acquisition and not the recall processes. We also investigated the effects of two H3 receptor antagonists, thioperamide and clobenpropit, in the same behavioral tasks. Pre-training administration of thioperamide and clobenpropit failed to exhibit any procognitive effects in normal animals but prevented scopolamine-induced amnesia. However, also post-training administration of thioperamide prevented scopolamine-induced amnesia. Hence, the ameliorating effects of scopolamine-induced amnesia by H3 receptor antagonism are not only mediated by relieving the inhibitory action of cortical H3 receptors, but other mechanisms are also involved. Nevertheless, H3 receptor antagonists may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Cognition; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Methylhistamines; Pattern Recognition, Visual; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Scopolamine; Thiourea

High levels of histamine can be found in the airways of asthma patients. This study describes the effects of histamine on anti-CD3-induced production of IL-4, IL-5, and IFN-gamma by T cell clones from subjects with allergic asthma and healthy subjects. T cell clones were obtained from bronchoalveolar lavage (BAL) fluid and blood. The number of clones tested, and the percentage of clones in which histamine inhibited or enhanced cytokine production by more than 25%, were as follows: IL-4, 47, 8.5%, and 4.3%; IL-5, 43, 14%, and 30%; and IFN-gamma, 52, 40%, and 15%. Inhibition of IL-5 and IFN-gamma production was reversed by IL-2. The enhancement of IFN-gamma production was associated with an enhancement of both IL-2 production and proliferation. In 21% of the clones a combined effect consisting of inhibition of IFN-gamma production and enhancement of IL-5 production was found. This response was reversed by H2-receptor antagonists and was significantly associated with a histamine-induced increase in intracellular levels of cAMP. The role of cAMP in mediating the histamine effects was supported by the observations that the beta2-agonist salbutamol had effects similar to histamine and that high concentrations of PGE2 mimicked the inhibitory effects of histamine. Clones from BAL fluid and blood showed similar responses, as did clones from patients with asthma and from control subjects. The enhancement of IFN-gamma production by histamine, however, was found only in clones from healthy subjects. The results warrant further investigations on the role of cAMP in the regulation of cytokine production.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Albuterol; Asthma; Bronchoalveolar Lavage Fluid; Clone Cells; Cyclic AMP; Dinoprostone; Enzyme Activation; Famotidine; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Impromidine; Interferon-gamma; Interleukin-2; Interleukin-4; Interleukin-5; Lung; Methylhistamines; Piperidines; Pyridines; Ranitidine; T-Lymphocytes; Triprolidine

The effects of histamine on high-voltage-activated Ca2+ channels in the histaminergic neurons acutely dissociated from the rat tuberomammillary nucleus were investigated in the nystatin-perforated patch recording mode under voltage-clamp conditions. Histamine suppressed the high-voltage-activated Ca2+ channel currents in neurons which were positive for histidine decarboxylase with immunocytochemistry. The half-maximum inhibitory concentration and maximum inhibition were 2.6 x 10(-7) M and 16.6+/-1.90%, respectively. An H3 receptor agonist, R(-)-alpha-methylhistamine, mimicked the response to histamine, and thioperamide, an H3 receptor antagonist, inhibited the response to histamine. On the other hand, neither 2-methylhistamine, an H1 receptor agonist, nor dimaprit, an H2 receptor agonist, had a significant effect on the Ca2+ channel currents. Pretreatment with pertussis toxin blocked the inhibitory effect of histamine on Ca2+ channels, suggesting the involvement of Gi/Go proteins in the action of histamine. Omega-conotoxin-GVIA, omega-agatoxin-IVA, nicardipine, and omega-conotoxin-MVIIC blocked the high-voltage-activated Ca2+ channel currents by 15.6, 4.3, 27.1, and 31.2% of the total current, respectively, suggesting the existence of N-, P-, L-, and Q-type Ca2+ channels. A current that was insensitive to these blockers was also found. This residual current, "R-type", was completely suppressed by the addition of 200 microM Cd2+. Histamine significantly inhibited both the N- and P-type current components among these five types of Ca2+ channel currents. We concluded that histamine suppresses the N- and P-type Ca2+ channels in histaminergic neurons through an H3 receptor which is linked to a pertussis toxin-sensitive G-protein.

Topics: Animals; Calcium; Calcium Channels; Calcium Channels, N-Type; Depression, Chemical; Dimaprit; Histamine; Histamine Agonists; Histamine Antagonists; Ion Channel Gating; Mammillary Bodies; Methylhistamines; Nerve Tissue Proteins; Neurons; Nicardipine; omega-Agatoxin IVA; omega-Conotoxin GVIA; omega-Conotoxins; Patch-Clamp Techniques; Peptides; Pertussis Toxin; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Spider Venoms; Tuber Cinereum; Virulence Factors, Bordetella

In order to assess the role of histamine H3 receptors in the discriminative-stimulus effects of methamphetamine, rats were trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food presentation. The histamine H3 receptor antagonist thioperamide (1.0 mg/kg s.c.), which facilitates histamine release, significantly shifted the methamphetamine dose-response curve to the left when tested together with different doses of methamphetamine and markedly extended the time-course of methamphetamine's discriminative-stimulus effects. The histamine H3 receptor agonist R-alpha-methylhistamine (3.0 mg/kg i.p.), which blocks histamine release, did not produce any effects when given alone, but it attenuated the effects of thioperamide on the methamphetamine dose-response curve when both drugs were given together. Thus, methamphetamine's discriminative-stimulus effects are markedly potentiated by the blockade of histamine H3 receptors by thioperamide. This is likely due to thioperamide's actions at histamine H3 autoreceptors on histaminergic neurons to facilitate release of histamine by methamphetamine or at histamine H3 heteroreceptors on other monoaminergic neurons (e.g., dopaminergic, serotonergic or noradrenergic) to facilitate release of other neurotransmitters.

Topics: Animals; Central Nervous System Stimulants; Discrimination Learning; Dose-Response Relationship, Drug; Drug Synergism; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methamphetamine; Methylhistamines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Time Factors

Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions.. We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge.. Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity.. These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.

Topics: Amine Oxidase (Copper-Containing); Animals; Asthma; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoproteins; Guanidines; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine N-Methyltransferase; Male; Methylhistamines; Mucus; Piperidines; Pyrilamine; Recombinant Proteins; Trachea

The effects of intra-arterial injection of different doses of the selective histamine H3-receptor agonist R-alpha-methylhistamine and the selective histamine H3-receptor antagonist thioperamide on basal and electrically evoked noradrenaline overflow in the portal vein as well as on mean arterial pressure (MAP) and heart rate (HR) were investigated in permanently instrumented freely moving rats. R-alpha-Methylhistamine (0.01, 0.1 and 1 mumol/kg) inhibited the evoked noradrenaline overflow up to 43%, the ED50 value being 0.013 mumol/kg. Thioperamide (0.1, 0.5 and 1.0 mumol/kg) antagonized the effect of 1.0 mumol/kg R-alpha-methylhistamine dose-dependently, evoked overflow returning to control values at 1.0 mumol/kg of the antagonist; thioperamide alone had no effect on electrically evoked noradrenaline overflow. Basal noradrenaline levels, blood pressure and heart rate were not at all influenced by R-alpha-methylhistamine and thioperamide, alone or in combination. The results clearly show the presence of prejunctional histamine H3-receptors inhibiting the electrically evoked noradrenaline overflow from vascular sympathetic nerve terminals in the portal vein of freely moving rats.

Topics: Animals; Blood Pressure; Electric Stimulation; Heart Rate; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Norepinephrine; Piperidines; Portal Vein; Rats; Rats, Wistar; Receptors, Histamine H3

Our previous results demonstrate the occurrence of presynaptic inhibitory histamine H3 receptors on sympathetic neurons innervating resistance vessels of the pithed rat. The present study, in which new H3 receptor ligands with increased potency and selectivity (imetit, clobenpropit) were used, was designed to further explore the role of H3 receptors in the regulation of the rat cardiovascular system. In particular we were interested whether these receptors may be activated by endogenous histamine and whether they are detectable in an experimental model of hypertension. All experiments were performed on pithed and vagotomized rats treated with rauwolscine 1 mumol/kg. In normotensive Wistar rats the electrical (1 Hz, 1 ms, 50 V for 20 s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure by about 35 mmHg. Two H3 receptor agonists, R-(-)-alpha-methylhistamine and imetit, inhibited the electrically induced increase in diastolic blood pressure in a dose-dependent manner. The maximal effect (about 25%) was obtained for R-(-)-alpha-methylhistamine at about 10 mumol/kg and for imetit at about 1 mumol/kg. Two H3 receptor antagonists, thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg and decreased by 25% by the histamine methyltransferase inhibitor metoprine 37 mumol/kg. R-(-)-alpha-Methylhistamine, imetit, thioperamide, clobenpropit and metoprine did not affect the vasopressor response to exogenously added noradrenaline 0.01 mumol/kg (which increased diastolic blood pressure by about 40 mmHg). Metoprine had only a very low affinity for H3 binding sites (labelled by 3H-N alpha-methylhistamine; pKi 4.46). In pithed Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats, electrical (1 Hz, 1 ms, 50 V for 10 s) stimulation increased diastolic blood pressure by 28 and 37 mmHg, respectively. Imetit inhibited the neurogenic vasopressor response to about the same extent in WKY and SHR rats (maximal effect of about 30%). The inhibitory influence of imetit was diminished by thioperamide 1 mumol/kg to about the same degree in rats of either strain. The present study confirms the occurrence of presynaptic H3 receptors on sympathetic nerve fibres involved in the inhibition of the neurogenic vasopressor response. Moreover, it demonstrates that these H3 receptors are

Topics: Adrenergic Fibers; Animals; Blood Pressure; Decerebrate State; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; Hypertension; Imidazoles; Male; Methylhistamines; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea; Vagotomy; Vascular Resistance

A recent study showed that SKF92374, a structural analog of the histamine H2 receptor antagonist cimetidine, induces antinociception after intraventricular (i.v.t.) administration in the rat. SKF92374 lacked significant activity on H1 or H2 receptors, but had weak activity on H3 receptors. To test the hypothesis that SKF92374-induced antinociception is mediated by an action on H3 receptors, the effects of the H3 agonist R-alpha-methylhistamine (RAMH) and the H3 antagonist thioperamide (both by i.v.t. administration) were investigated on SKF92374 antinociception. SKF92374-induced antinociception was slightly enhanced by thioperamide (30 microg), but unaffected by a range of doses of RAMH (up to 2 microg). Furthermore, SKF92374-induced antinociception was not reduced by large doses of systemically-administered antagonists of H1 (pyrilamine), H2 (zolantidine), H3 (GT-2016), or opioid (naltrexone) receptors. These findings show that the novel compound SKF92374 induces antinociception by a non-opioid mechanism that does not utilize brain H1, H2 or H3 receptors.

Topics: Analgesics, Non-Narcotic; Animals; Cimetidine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Naltrexone; Narcotic Antagonists; Nociceptors; Piperidines; Rats; Rats, Sprague-Dawley; Stereoisomerism

In this study, we have characterized the phenotype of mast cells in rat dura mater and their topological and functional relationships with C-fibers in normal and inflammatory conditions. Three mast cell populations with different size, morphology and localization were characterized by their content of specific neutral serine proteases. They showed immunoreactivity corresponding to rat mast cell protease I, rat mast cell protease II, or both proteases. Using confocal microscopy, all three mast cell types were observed in close apposition (distance less than 100 nm) to calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in both controls and rats infected with the nematode Nippostrongylus brasiliensis. After nematode infection or neonatal treatment with capsaicin, a large increase in the number of rat mast cell protease II-immunoreactive mast cells was found within dura mater segments (+1478% and +596%, respectively), without concomitant changes of rat mast cell protease I- or rat mast cell protease I/II-immunoreactive mast cells. Under both these conditions, the increase in mast cell number was accompanied by a significant increase in rat mast cell protease II level within tissue extracts (+281% after nematode infection and +36% after capsaicin treatment). The functional interaction of mast cells with sensory nerve fibers in the dura mater was assessed by evaluating [3H]histamine synthesis after administration of L-[3H]histidine, an index of mast cell activity. The H3 receptor agonist (R)-alpha-methylhistamine (15 mg/kg, i.p.) had no effect, but administration of the H3 receptor antagonist, thioperamide (10 mg/kg, i.p.), resulted in a significant increase of [3H]histamine synthesis (+62%). This effect was reduced in neonatal capsaicin-treated rats, but not completely suppressed (+35%), very likely because of partial denervation, as assessed by monitoring calcitonin gene-related peptide immunoreactivity. It is concluded that, in the dura mater, as in peripheral tissues, sensory nerve fibers and mast cells actively synthesizing and releasing histamine form a short inhibitory feedback loop involving prejunctional H3 receptors that could regulate the release of pro-inflammatory mediators, thus limiting the extent of inflammatory reactions.

Topics: Animals; Animals, Newborn; Capsaicin; Cerebral Cortex; Chymases; Denervation; Dura Mater; Enzyme-Linked Immunosorbent Assay; Histamine; Histamine Antagonists; Inflammation; Male; Mast Cells; Methylhistamines; Nerve Fibers; Neurons, Afferent; Nippostrongylus; Piperidines; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Serine Endopeptidases; Strongylida Infections

Topics: Animals; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Imidazoles; Intestine, Small; Male; Methylhistamines; Muscle Contraction; Peristalsis; Piperidines; Receptors, Histamine H3; Thiourea

The present study was designed to examine the functional linkage between histamine and somatostatin secretion in the fundus of the stomach. In segments of rat fundic mucosa, superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased histamine secretion; superfusion with (R)(-)-alpha-methylhistamine (H3 agonist) had the opposite effect, decreasing somatostatin and increasing histamine secretion. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion. Superfusion with somatostatin antibody (1:250) increased histamine secretion, implying that endogenous somatostatin, in turn, exerts an inhibitory paracrine influence on histamine secretion. Somatostatin antibody also abolished the decrease in histamine secretion induced by thioperamide and the increase in histamine secretion induced by (R)(-)-alpha-methylhistamine, implying that changes in histamine secretion induced by activation of H3 receptors reflect changes in somatostatin secretion. Superfusion with the muscarinic agonist methacholine alone and in the presence of either H3 agonist or H3 antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine. We conclude that fundic histamine and somatostatin secretion are linked via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.

Topics: Animals; Antibodies; Gastric Fundus; Gastric Mucosa; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; In Vitro Techniques; Kinetics; Methacholine Chloride; Methylhistamines; Piperidines; Rats; Receptors, Histamine H3; Somatostatin; Virulence Factors, Bordetella

The synthesis and biological evaluation of new histamine H3 receptor antagonists with an iodinated aryl partial structure are described as part of an extensive research program to find model compounds for the development of a new radioligand with high H3 receptor affinity and specific activity. All compounds were tested for their H3 receptor antagonist activity in a [3H]-histamine-release assay with synaptosomes from rat cerebral cortex. The new leads with potent H3 receptor antagonist activity belong to a series of derivatives of 3-(1H-imidazol-4-yl)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as functional groups. Structure-activity relationships are discussed. The most active compound in the functional test (-log Ki = 8.3) and in binding studies with [3H]-(R)-alpha-methylhistamine on rat cerebral cortex (-log Ki = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl (4-iodophenyl)methyl ether (iodoproxyfan, 19) exhibiting no central H3 receptor antagonist activity in vivo. The potency of iodoproxyfan is more than 300 times lower at H1, H2, alpha1, alpha2, beta1, 5-HT2A, 5-HT3, and M3 receptors than at histamine H3 receptors. Because of the high potency and selectivity of 19, this compound has also been prepared in the [125I]-iodinated form by a nucleophilic halogen exchange reaction using the corresponding bromo derivative 22 as a precursor. The newly prepared [125I]iodoproxyfan (23) possesses advantageous pharmacological properties and fulfills all criteria of a useful radioligand.

Topics: Animals; Cerebral Cortex; Guinea Pigs; Histamine Antagonists; Imidazoles; In Vitro Techniques; Iodine Radioisotopes; Methylhistamines; Radioligand Assay; Rats; Structure-Activity Relationship

The histamine forming capacity (HFC) of acutely challenged airways from sensitised guinea pigs was investigated. After exposure to nebulised bovine serum albumin (BSA) or normal saline, animals were sacrificed, the pulmonary HFC determined and concurrent in vitro histamine log concentration response curves were constructed for parenchymal strips and tracheal muscle, the latter was field stimulated to record neurogenic responses. Exposure to BSA increased the HFC above controls for 24 hours (p < 0.001) and log concentration response curves for the parenchymal strips were shifted slightly to the left with an increased maximum response. This change appeared 3 hours after exposure and remained elevated at 24 hours. Similar changes did not occur with the trachea. Pre-treatment with thioperamide augmented (p < 0.02) HFC and this increase was inhibited by alpha-methylhistamine (p < 0.05). A possible relationship may exist between increased responsiveness of lower airways to exogenous histamine and a raised endogenous formation, regulated by the H3 receptor.

Topics: Animals; Binding Sites; Bronchial Hyperreactivity; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Ligands; Lung; Male; Methylhistamines; Muscle, Smooth; Piperidines; Receptors, Histamine H3; Serum Albumin, Bovine; Trachea

Topics: Acetylcholine; Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Dimaprit; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Microdialysis; Neurons; Parietal Lobe; Piperidines; Potassium; Rats; Rats, Wistar; Receptors, Histamine H3; Thiazoles

Topics: Analysis of Variance; Animals; Brain; Dopamine; Histamine; Histamine Agonists; Histamine Antagonists; Homovanillic Acid; Hydroxyindoleacetic Acid; Hypothalamus; Injections, Intraventricular; Male; Methylhistamines; Norepinephrine; Piperidines; Portacaval Shunt, Surgical; Prolactin; Rats; Rats, Wistar; Receptors, Histamine H3; Serotonin

Thioperamide (2 mg/kg, l.p.), a histamine H3-receptor antagonist, increased the number of somatostatin (SS) receptors, with no change in the affinity constant, in the rat frontoparietal cortex. This effect was prevented by treatment with (R)-alpha-methylhistamine (3.2 mg/kg, l.p.), a histamine H3-receptor agonist. Thioperamide also induced an increase in SS binding in rats pretreated with mepyramine, a histamine H1-receptor antagonist, or cimetidine, a histamine H2-receptor antagonist. Pretreatment with mepyramine plus cimetidine administered simultaneously antagonized the thioperamide effect on SS binding. The increase in the number of SS receptors was accompanied by a greater SS-mediated inhibition of basal and forskolin-stimulated adenylyl cyclase (AC) activity in frontoparietal cortical membranes in the thioperamide group. Furthermore, the functional activity of the guanine nucleotide-binding inhibitory protein (G1 protein) was not altered by thioperamide or (R)-alpha-methylhistamine administration in frontoparietal cortical membranes. In rats treated with mepyramine plus thioperamide or cimetidine plus thioperamide, the increase in the number of SS receptors was also accompanied by an increased SS inhibition of AC activity. Thioperamide induced a significant increase in SS-like immunoreactivity content in the frontoparietal cortex. Altogether, these results suggest that frontoparietal cortical histamine may play, at least in part, a role in the regulation of the somatostatinergic system.

Topics: Adenylyl Cyclases; Animals; Colforsin; Frontal Lobe; GTP-Binding Proteins; Histamine Agonists; Histamine Antagonists; Methylhistamines; Parietal Lobe; Piperidines; Presynaptic Terminals; Rats; Rats, Wistar; Receptors, Histamine H3; Receptors, Somatostatin; Somatostatin

The histamine H3 receptor has been shown to inhibit pentagastrin-induced gastric acid secretion in dogs. Since pentagastrin releases histamine in dogs, we have now assessed whether the effects of H3-receptor ligands may be indirectly mediated by changes in gastric histamine release.. Pentagastrin infusions (1 or 6 micrograms/kg/h), alone or together with the H3-receptor agonist (R) alpha-methylhistamine (1.2 mumol/kg/h) or the antagonist thioperamide (0.1 mumol/kg/h), were performed in dogs. One group (anaesthetized) was used for enzyme immunoassays of plasma histamine and, when required. (R) alpha-methylhistamine in the gastrosplenic vein, and another group (non-anaesthetized) for measurement of gastric acid secretion.. Histamine levels were increased five- and eight-fold after 1 and 6 micrograms/kg/h pentagastrin, respectively, whereas acid output was nearly maximal at the lower dosage. (R) alpha-methylhistamine, at a plasma concentration of 0.15 microM, inhibited histamine release by 78% (P < 0.007) and 37% (not significant) and the total acid output by 44% (P < 0.05) and 19% (not significant) after infusion of 1 and 6 micrograms/kg/h pentagastrin, respectively. Thioperamide, together with pentagastrin in low dose, significantly increased histamine release by 212% (P < 0.05), whereas acid output increased by 34% (not significant).. The histamine H3 receptor mediates a negative feedback control of pentagastrin-induced release of gastric histamine. It is tonically activated by endogenous histamine after pentagastrin in low dosage. The control of acid secretion by the H3 receptor seems to involve modulation of endogenous histamine release, possibly by means of enterochromaffin-like cells.

Topics: Animals; Dogs; Female; Gastric Acid; Gastric Mucosa; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; Male; Methylhistamines; Pentagastrin; Piperidines; Receptors, Histamine H3

The aim of this study was to investigate the possible involvement of the histamine H3 receptor in control of exocrine pancreatic secretion from the guinea-pig. In in vitro experiments, the H3 receptor agonist (R)-alpha-methylhistamine (0.01-10 microM) elicited a concentration-dependent decrease in the release of alpha-amylase. (R)-alpha-Methylhistamine concentrations above 10 microM evoked a concentration-dependent increase in alpha-amylase secretion. Application of mepyramine (1 microM) partially blocked this increase. The H3 receptor antagonist thioperanide (1 microM) blocked the effects of (R)-alpha-methylhistamine below 10 microM. Histamine and (R)-alpha-methylhistamine attenuated both protein release elicited during electrical-field stimulation and the release of tritiated choline, and these effects were reversed by thioperamide. In an in vivo study, (R)-alpha-methylhistamine increased juice secretion and total protein content of the juice by 40%. Histamine H1 and H2 receptor antagonists blocked this increase and uncovered an attenuation of the secretory parameters (juice flow 28%, total protein content 44%). This attenuation was blocked by thioperamide. These observations suggest that stimulation of the histamine H3 receptor in the pancreas results in a decreased fluid and enzyme release by inhibition of acetylcholine release from intrinsic pancreatic nerves.

Topics: alpha-Amylases; Animals; Choline; Electric Stimulation; Female; Guinea Pigs; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Pancreas; Piperidines; Pyrilamine; Receptors, Histamine H3; Tritium

To study the histamine H3 receptors mediated inhibition of norepinephrine (NE) release from cardiac sympathetic terminals of guinea pig isolated atria.. Release of NE induced by electric field stimulation (50 mA, 5 ms) in the bath solution was measured by HPLC-ECD.. The release of NE caused by field stimulation was attenuated by (R)-alpha-methyl-histamine (alpha-MeHA, 0.1 nmol.L-1(-10) mumol.L-1) in a concentration-dependent manner. Thioperamide concentration-dependently antagonized the inhibition of alpha-MeHA. Blockade of H1, H2, alpha 2, beta 2-receptors failed to prevent the inhibitory effect of alpha-MeHA. Thioperamide (1 nmol.L-1(-10) mumol.L-1), when used alone, concentration-dependently facilitated the release of NE evoked by field stimulation.. The presynaptic histamine H3-receptors inhibited the NE release from cardiac sympathetic terminals.

Topics: Adrenergic Fibers; Animals; Dose-Response Relationship, Drug; Female; Guinea Pigs; Heart Atria; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Norepinephrine; Piperidines; Receptors, Histamine H3; Sympathetic Nervous System

The ability of (R)-alpha-methylhistamine, the selective agonist of histamine H3 receptors, to reduce ethanol-induced gastric damage was examined in the rat. (R)-alpha-methylhistamine (1-100 mg/kg intragastrically) caused a dose-related reduction in the amount of damage produced by ethanol. This protective effect was not shared by the S enantiomer of alpha-methylhistamine. Thioperamide, selective H3 receptor antagonist, inhibited the protective effect of 10 but not 100 mg/kg of (R)-alpha-methylhistamine. Pretreatment with (R)-alpha-methylhistamine, 100 mg/kg i.g., resulted in a significant increase in the thickness of adherent mucus gel layer, which may contribute to the protective action of the compound.

Topics: Analysis of Variance; Animals; Drug Interactions; Ethanol; Gastric Mucosa; Histamine Agonists; Male; Methylhistamines; Mucus; Piperidines; Rats; Rats, Wistar; Surface Properties; Time Factors

The involvement of the histamine H3 receptor in the regulation of substance P release in neurogenic inflammation was studied by using rat hindpaw skin. R-(-)-alpha-Methylhistamine, a specific histamine H3 receptor agonist, significantly inhibited the increased vascular permeability induced by antidromic electrical stimulation of the sciatic nerve in a dose-dependent manner at doses of 0.5-3 mg/kg (i.v.), and thioperamide (2 mg/kg i.p.), a specific histamine H3 receptor antagonist, prevented the inhibitory effect of R-(-)-alpha-methylhistamine. The antidromic stimulation also caused a significant increase in immunoreactive substance P release in the subcutaneous (s.c.) perfusate in the rat hindpaw. R-(-)-alpha-Methylhistamine (0.25-2 mg/kg) dose dependently inhibited the increase in release of immunoreactive substance P, and thioperamide (2 mg/mg i.p.) antagonized it. Perfusion of histamine (10(-3) M) elicited a significant increase of immunoreactive substance P release in the perfusate, which was reduced by R-(-)-alpha-methylhistamine and the antagonism of thioperamide was also observed. Histamine (in the presence of histamine H1 and H2 receptor antagonists) had an inhibitory effect on the electrically evoked release of immunoreactive substance P. These results strongly support the hypothesis that histamine regulates substance P release via prejunctional histamine H3 receptors that are located on peripheral endings of sensory nerves.

Topics: Animals; Capillary Permeability; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Nerve Endings; Neurons, Afferent; Perfusion; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Receptors, Presynaptic; Sciatic Nerve; Stimulation, Chemical; Substance P

We examined possible interactions between neuroleptics and the histamine H3 receptor and found an interaction of clozapine with this receptor. In competition binding experiments, using the H3 antagonist, [125I]-iodophenpropit, we observed a Ki of 236 +/- 87 nM. Functionally, clozapine was studied on the H3-mediated inhibition of [3H]-5-hydroxytryptamine ([3H]-5-HT) release from rat brain cortex slices. Clozapine acts as an antagonist with an apparent KB value of 79.5 nM.

Topics: Animals; Binding, Competitive; Cerebral Cortex; Clozapine; Haloperidol; Histamine Antagonists; Histamine Release; Imidazoles; Isothiuronium; Methylhistamines; Piperidines; Rats; Receptors, Histamine H3

1. The effect of central H3 histamine receptor activation on gastric acid and pepsin production has been investigated in pylorus-ligated rats. 2. Intracerebroventricular injections (i.c.v.) of the selective H3 agonist, R-alpha-methylhistamine (0.5-50 nmol per rat) caused a dose-dependent inhibition of gastric acid secretion while intravenous administration (5-500 nmol per rat) was completely ineffective. 3. I.c.v. microinjections of mepyramine, tiotidine and thioperamide (51 nmol per rat), selective antagonists at H1-, H2- and H3-sites respectively, failed to modify the acid secretory response to pylorus ligation. 4. The antisecretory effect of R-alpha-methylhistamine (5 nmol per rat, i.c.v.) was selectively prevented by the H3-blocker, thioperamide (51 nmol per rat, i.c.v.), mepyramine and tiotidine pretreatment being completely inactive. 5. Unlike acid secretion, pepsin production was not significantly affected by all the tested compounds. 6. These findings provide the first pharmacological evidence that the activation of central H3 histamine receptors exerts a negative control in the regulation of gastric acid secretion in conscious pylorus-ligated rats.

Topics: Animals; Cimetidine; Female; Gastric Acid; Gastric Mucosa; Histamine Agonists; Histamine Antagonists; Injections, Intraventricular; Methylhistamines; Piperidines; Pylorus; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H3

This study examined the gastroprotective effect of (R)-alpha-methylhistamine (MHA), a selective agonist of histamine H3 receptors. Gastric lesions were induced in the rat by administering absolute ethanol in a volume of 1 ml. Stomachs were removed 1 h later and lesions evaluated both macroscopically and histologically. MHA dose-dependently inhibited ethanol-induced lesions in the range 1-100 mg/kg both by the intragastric and intraperitoneal route. Histological findings indicated that the number of mucous granules in surface and neck cells was increased and the process of reepithelialization was rapidly promoted by MHA. Thioperamide, at 10 mg/kg, inhibited the protective effect of 10 but not of 100 mg/kg of MHA. Larger doses of thioperamide could not be tested because of an interaction with ethanol causing central nervous system effects. Famotidine and indomethacin pretreatment only partially counteracted the MHA effect. The results indicate that MHA is highly effective in preventing ethanol-induced lesions but the exact mechanism is still uncertain.

Topics: Animals; Ethanol; Famotidine; Gastric Mucosa; Male; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3

Norepinephrine release contributes to ischemic cardiac dysfunction and arrhythmias. Because activation of histamine H3-receptors inhibits norepinephrine release, we searched for the presence of H3-receptors directly in sympathetic nerve endings (cardiac synaptosomes) isolated from surgical specimens of human atria. Norepinephrine was released by depolarization with K+. The presence of H3-receptors was ascertained because the selective H3-receptor agonists (R) alpha-methylhistamine and imetit reduced norepinephrine release, and the specific H3-receptor antagonist thioperamide blocked this effect. Norepinephrine release was exocytotic, since it was inhibited by the N-type Ca(2+)-channel blocker omega-conotoxin and the protein kinase C inhibitor Ro31-8220. Functional relevance of these H3-receptors was obtained by showing that transmural electrical stimulation of sympathetic nerve endings in human atrial tissue increased contractility, an effect blocked by propranolol and attenuated in a concentration-dependent manner by (R) alpha-methylhistamine. Also, thioperamide antagonized the effect of (R) alpha-methylhistamine. Our findings are the first demonstration that H3-receptors are present in sympathetic nerve endings in the human heart, where they modulate adrenergic responses by inhibiting norepinephrine release. Since myocardial ischemia causes intracardiac histamine release, H3-receptor-induced attenuation of sympathetic neurotransmission may be clinically relevant.

Topics: Cell Separation; Electric Stimulation; Exocytosis; Heart; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; In Vitro Techniques; Indoles; Methylhistamines; Myocardial Ischemia; Myocardium; Norepinephrine; Piperidines; Protein Kinase C; Receptors, Histamine H3; Synaptosomes; Thiourea

Widespread clinical use of H2 antagonists for peptic ulcer disease has been associated with reports of impotence. Histamine is a vasoactive amine which is endogenously produced in many organs including the penis. To date, 3 histamine receptor subtypes (H1, H2 and H3) have been identified. However, the role and function of histamine in the corpus cavernosal physiology are poorly understood. This study evaluates the in vitro functional characteristics of the 3 histamine receptor subtypes in the isolated corpus cavernosal strips from New Zealand White rabbits. The isometric responses to histamine and specific histamine receptor subtype agonists were assessed, following cyclooxygenase (indomethacin, 10(-5) M.), adrenergic (guanethidine, 5 x 10(-6) M.) and cholinergic (atropine, 5 x 10(-6) M.) blockade, at resting tension and after submaximal precontraction with norepinephrine (NE, 2 x 10(-5) M.). Histamine (10(-8) M. to 10(-3) M.) produced concentration-dependent contraction from basal and precontracted states and did not relax precontracted tissue. The H1 agonist, 2-(2-thiazolyl)ethylamine (10(-8) M. to 10(-3) M.), produced a contractile response from both basal and precontracted states, while the corporal tissue did not respond to either dimaprit, an H2 agonist (10(-8) M. to 10(-5) M.) or R(-)-alpha-methyl-histamine, an H3 agonist (10(-8) M. to 10(-5) M.). The response to histamine was progressively attenuated by an H1 antagonist (mepyramine; 10(-8) M. to 10(-5) M.), while neither an H2 antagonist (cimetidine; 10(-4)M.) nor an H3 antagonist (thioperamide; 10(-4)M.) had any inhibitory effects. H1 antagonism enhanced relaxation induced by electrical field stimulation (neurally mediated). Such relaxation increased after preincubation with 10(-6) M. or greater of mepyramine (p < 0.05). This study suggests that the principal histamine receptor subtype that mediates smooth muscle cell contraction in the corpus cavernosum is the H1 subtype. Since histamine H1 receptor antagonism increased NANC neurally mediated corporal relaxation, it possesses potential as an intracavernosal pharmacotherapeutic agent for the treatment of erectile dysfunction. This study, therefore, strongly indicates that H2 receptor antagonists are unlikely to have direct effects on penile erection.

Topics: Acetylcholine; Animals; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Papaverine; Penis; Piperidines; Pyrilamine; Rabbits; Receptors, Histamine; Thiazoles

1. Conflicting reports in the literature over heterogeneity (West et al., 1990) or homogeneity (Arrange et al., 1990) of histamine H3-receptor binding sites may be attributed to the use of different incubation conditions. In the present study we have investigated the extent to which the binding of H3-receptor ligands to rat cerebral cortical membranes can be modified by both sodium ions and guanine nucleotides. 2. The H3-selective antagonist, thioperamide, discriminated between two specific binding sites for [3H]-N alpha-methylhistamine (IC50 1 = 2.75 +/- 0.87 nM, IC50 2 101.6 +/- 12.0 nM, % site 1 = 24 +/- 2%) in 50 mM Tris HCl buffer, but showed homogeneity of binding in 50 mM Na/K phosphate buffer. 3. Sodium ions markedly altered the binding characteristics of thioperamide (i.e. heterogeneity was lost and IC50 value shifted towards the high affinity site). The competition curves for a second H3-antagonist, clobenpropit and the H3-agonist N alpha-methylhistamine however, were unaltered in the presence of sodium ions. 4. Guanylnucleotides displaced only 60% of specific [3H]-N alpha- methylhistamine binding and modulated thioperamide binding in the same way as sodium ions. 5. These data suggest that the H3-receptor can exist in different conformations for which thioperamide, but not N alpha-methylhistamine and clobenpropit, show differential affinity. 6. The potential nature of these sites, and the implications of this apparent receptor heterogeneity for H3-receptor antagonism by thioperamide, are discussed.

Topics: Animals; Cerebral Cortex; Guanine Nucleotides; Histamine Agonists; Histamine Antagonists; Imidazoles; In Vitro Techniques; Male; Membranes; Methylhistamines; Piperidines; Rats; Receptors, Histamine H3; Sodium; Thiourea

We previously reported evidence for H3-receptor inhibition of cholinergic stimulation of acid secretion by isolated rabbit gastric glands. Because this inhibition was unsensitive to H2 antagonists, we postulated that the parietal cell should bear a H3-receptor. In the present study, we investigated the effects of M1-M3 muscarinic receptors antagonists on carbachol- and thioperamide-induced acid secretion (14CAP uptake) by isolated rabbit gastric glands. Furthermore, we examined whether H3-receptor ligands could affect [3H]-N-methylscopolamine binding to the isolated rabbit parietal cells. Both carbachol and thioperamide concentration-dependently stimulated 14CAP uptake in the glands with maximal responses being achieved for 100 microM and 0.1 microM, respectively. These stimulations were concentration-dependently inhibited by the H3-receptor agonists R(alpha)-methylhistamine and imetit. Maximal inhibitions did not exceed 60% for 1 microM. The muscarinic receptor antagonists, hexa-sila-difenidol p-fluoro analog (M3), pirenzepine (M1) and gallamine (M2) inhibited carbachol-induced 14CAP uptake with IC50 of 50 nM, 10 microM and >> 100 microM, respectively. Thioperamide-induced 14CAP uptake was also inhibited by hexa-sila-difenidol p-fluoro analog and pirenzepine with IC50 of 90 nM and 12 microM, respectively; whereas gallamine had no effect. [3H]-N-methylscopolamine binding to isolated parietal cells was inhibited by atropine and pFHHSiD with IC50 of 15 nM and 132 nM, respectively. Neither R(alpha)-MeHA nor thioperamide did affect this binding although a H3-receptor inhibitory effect was observed on carbachol-induced 14CAP uptake by the cells. These data support that H3-receptor activation inhibits M3-mediated cholinergic stimulation of acid secretion through mechanisms operating downstream to the receptors sites.

Topics: Animals; Carbachol; Cholinergic Antagonists; Gastric Acid; Gastric Fundus; Gastric Mucosa; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Methylhistamines; Muscarinic Antagonists; N-Methylscopolamine; Piperidines; Rabbits; Ranitidine; Receptors, Histamine H3; Receptors, Muscarinic; Scopolamine Derivatives

The effects of an H3 agonist, (R)-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in rat hypothalamus were studied in vitro. Thioperamide was more potent in inhibiting MAO-B than MAO-A activity; MAO-B activity in rat hypothalamic homogenates was competitively inhibited by thioperamide with a Ki value of 175 micronM. From this in vitro experiment, the conversion of N-telemethylhistamine to N-tele-methylimidazoleacetic acid may be inhibited by thioperamide, suggesting that thioperamide may affect the regulation of histamine metabolism within histaminergic neurons. In contrast with the results obtained with thioperamide, alpha-MeHA inhibited MAO-A more potently than MAO-B activity; the Ki values for MAO-A and -B of hypothalamic homogenates were estimated to be 1.1 and 3.3 mM, respectively. The weak inhibitory effect of alpha-MeHA for MAO-B does not seem to be a major cause of changes in N-tele-methylhistamine concentrations.

Topics: Animals; Brain; Histamine Agonists; Histamine Antagonists; Histamine Release; Male; Methylhistamines; Monoamine Oxidase; Piperidines; Rats; Rats, Sprague-Dawley

We characterized the histamine H3 receptors involved in the modulation of electrical field stimulated neurogenic contraction of guinea pig pulmonary artery sympathetic, and guinea pig ileum parasympathetic preparations. Simultaneous measures of electrical field stimulation-evoked 3H overflow and tension in [3H]norepinephrine-loaded pulmonary artery were sensitive to tetrodotoxin (300 nM) and insensitive to hexamethonium (100 microM). Only the contractile response was inhibited by prazosin (100 nM). (R)-alpha-Methylhistamine's inhibition of the pulmonary artery contraction and 3H overflow were dose-dependently antagonized by thioperamide (30-100 nM). (R)-alpha-Methylhistamine also inhibited the neurogenic contractions of the isolated ileum (pD2 = 8.2). In the pulmonary artery, the relative potency of the histamine H3 receptor antagonists vs. (R)-alpha-methylhistamine inhibition of neurogenic contractions (pD2 = 7.1) was thioperamide (pA2 = 8.6 +/- 0.1) > burimamide (pA2 = 7.6 +/- 0.2) > impromidine (pA2 = 6.9 +/- 0.02). Similarly, the relative potency of histamine H3 receptor antagonists in the isolated ileum was thioperamide > burimamide > or = impromidine, with pA2 estimates of 8.7 +/- 0.1, 7.3 +/- 0.1 and 7.1 +/- 0.1, respectively. Antagonist potencies suggest a predominant histamine H3A-like receptor population on postganglionic sympathetic neurons innervating the pulmonary artery and parasympathetic neurons innervating the ileum longitudinal muscle.

Topics: Animals; Brain Chemistry; Electric Stimulation; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Ileum; In Vitro Techniques; Methylhistamines; Muscle Contraction; Muscle, Smooth; Muscle, Smooth, Vascular; Norepinephrine; Piperidines; Pulmonary Artery; Receptors, Histamine H3; Vasoconstrictor Agents

To investigate the modulation of histamine release by autoreceptors and heteroreceptors, the rat anterior hypothalamus was superfused through a push-pull cannula with agonists or antagonists of histamine and acetylcholine muscarinic receptors. Superfusion with the H3 receptor agonist (R)-alpha-methylhistamine inhibited, while superfusion with thioperamide (H3 antagonist) enhanced histamine release. Superfusion with carbachol (a mixed M1, M2, M3 agonist) inhibited the release of histamine. The release of endogenous histamine was enhanced on superfusion with atropine (a mixed M1, M2, M3 antagonist). The M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine enhanced the release rate of histamine. It is concluded that in the anterior hypothalamus the release of endogenous histamine is modulated by H3 autoreceptors. Moreover, acetylcholine released from cholinergic neurons also modulates the release of histamine via M1 and/or M3 heteroreceptors.

Topics: Animals; Histamine Agonists; Histamine Antagonists; Histamine Release; Hypothalamus, Anterior; Male; Methylhistamines; Muscarinic Agonists; Muscarinic Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Receptors, Muscarinic

Anaphylactic histamine release from isolated rat peritoneal mast cells was concentration-dependently blocked by a 5-min treatment with exogenous histamine at 0.9 and 9 microM and enhanced by a 20- to 30-min treatment with thioperamide (H3-antagonist) at 3 microM with significance, but little affected by mepyramine (H1-antagonist) and cimetidine (H2-antagonist) at the cell concentration of 10(6) mast cells/ml. At a low concentration of mast cells (10(4) mast cells/ml), (R)-alpha-methylhistamine (alpha-MH), an H3-agonist, at 0.9-90 microM also inhibited the release in a concentration-dependent fashion. Thioperamide, but neither mepyramine nor cimetidine, significantly restored the decreased release by alpha-MH. However, the complete restoration by thioperamide could not be achieved because the drug itself slightly but concentration-dependently inhibited anaphylactic histamine release. On the other hand, not only betahistine and dimaprit but also alpha-MH did not suppress histamine release from the mast cells induced by compound 48/80. In rat plasma, considerable levels of histamine were detected. From these results, it is strongly suggested that histamine H3-like receptors are largely responsible for the negative feedback regulation of the anaphylactic histamine release from rat peritoneal mast cells.

Topics: Anaphylaxis; Animals; Anticonvulsants; Chromatography, High Pressure Liquid; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Mast Cells; Methylhistamines; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Peritoneum; Piperidines; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H3

Bombesin (BN) and its mammalian homologue, gastrin-releasing peptide (GRP), are potent satiety agents and have been implicated in the physiological regulation of food intake. The mechanism(s) of action of this effect remains unclear. There is a functional and anatomic overlap between histamine and BN in relationship to feeding, which led us to hypothesize that BN may mediate its satiety effects through activation of the histaminergic system. To assess this contention, we examined the effects of R-alpha-methylhistamine (alpha-MH) and Imetit, selective H3-receptor agonists that inhibit the release and synthesis of histamine, on BN- or cholecystokinin (CCK)-induced satiety. In this report we present the first evidence for the role of histamine H3 receptors in the mediation of BN-elicited satiety. During the first hour of the 4-h daily feeding session, BN reduced food intake by > 50% relative to the control condition; this suppression was blocked by prior treatment with the H3-receptor agonist, alpha-MH. This blockade of BN-induced satiety was dose related and selective to BN as alpha-MH failed to attenuate sulfated CCK-8-induced satiety. When alpha-MH was administered alone, it failed to significantly affect food intake. The specificity of this effect was further supported by the demonstration that another H3 agonist, Imetit, was also able to block the feeding-suppressant effects of BN. Furthermore, thioperamide, an H3-receptor antagonist, blocked these effects of Imetit.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Bombesin; Eating; Gastrin-Releasing Peptide; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Methylhistamines; Motor Activity; Peptides; Piperidines; Rats; Rats, Sprague-Dawley; Satiation; Sincalide; Thiourea

1. The effect of (R)-alpha-methylhistamine (R-alpha-mHA), a selective histamine H3-receptor agonist, on increases in blood pressure and heart rate mediated by activation of the sympathetic nervous system induced by electrical stimulation of the spinal cord, was characterized in the vagotomized, pithed guinea-pig. 2. The frequency-dependent nature of (R)-alpha-mHA's effect on sympathetic cardiopressor responses was studied at frequencies between 1 and 20 Hz. (R)-alpha-mHA (10-100 micrograms kg-1, i.v.) produced a dose-dependent inhibition of the stimulated increase in both blood pressure (BP) and heart rate (HR). The inhibition was inversely related to frequency and maximum inhibition (BP, 61% at 1 Hz; HR, 50% at 1 Hz) was seen with 100 micrograms kg-1 of (R)-alpha-mHA. Treatment with the H3 receptor inactive stereoisomer, (S)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not inhibit the neurogenic sympathetic cardiopressor responses. 3. Pretreatment with thioperamide (1 mg kg-1, i.v.), a histamine H3 receptor antagonist, blocked (R)-alpha-mHA's inhibitory effect on stimulation-induced sympathetic cardiopressor responses. 4. Combined pretreatment with the H2-receptor antagonist cimetidine (3 mg kg-1, i.v.) and the H1-receptor antagonist chlorpheniramine (0.3 mg kg-1, i.v.) did not attenuate (R)-alpha-mHA's inhibitory effects. 5. (R)-alpha-mHA (100 micrograms kg-1) had no effect on the hypertensive or tachycardia effects induced by adrenaline (1 and 3 micrograms kg-1, i.v.). 6. Treatment with a combination of prazosin (1 mg kg-1, i.v.) and yohimbine (1.5 mg kg-1, i.v.) to block alpha 1- and alpha 2-adrenoceptors, abolished the sympathetic hypertension without affecting the inhibition of sympathetic tachycardia induced by (R)-alpha-mHA. Conversely, pretreatment with the beta-adrenoceptor antagonist propranolol (1 mg kg-1, i.v.), which blocked the sympathetic tachycardia, did not block (R)-alpha-mHA's inhibition of sympathetic hypertensive responses. 7. In adrenalectomized guinea-pigs, (R)-alpha-mHA (100 micrograms kg-1, i.v.) also produced a frequency-dependent inhibition of sympathetic hypertensive cardiopressor responses that was not significantly different from intact animals. 8. These results demonstrate that (R)-alpha-mHA produces a frequency-dependent inhibition of the cardiopressor responses due to activation of the sympathetic innervation to the resistance vessels and the heart.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adrenalectomy; Animals; Blood Pressure; Chlorpheniramine; Cimetidine; Drug Interactions; Electric Stimulation; Epinephrine; Guinea Pigs; Heart; Heart Rate; Histamine Agonists; Male; Methylhistamines; Piperidines; Prazosin; Spinal Cord; Sympathetic Nervous System; Vagotomy; Yohimbine

The effects of the selective histamine H3 receptor agonist (R)-alpha-methylhistamine and antagonist thioperamide on stimulant-induced locomotor activity in the mouse were examined. Amphetamine (1 mg.kg-1 s.c.), apomorphine (2 mg.kg-1 s.c.) or cocaine (5 mg.kg-1 s.c.) increased locomotor activity. Neither thioperamide (10 mg.kg-1 i.p.) nor (R)-alpha-methylhistamine (20 mg.kg-1 i.p.) affected spontaneous locomotor activity in their own right. (R)-alpha-Methylhistamine (0.3, 3 or 20 mg.kg-1 i.p.) also had no effect on amphetamine (1 mg.kg-1 s.c.)-induced locomotor activity. In contrast, thioperamide (0.2-10 mg.kg-1 i.p. or 0.3-20 micrograms i.c.v.) inhibited, in a dose-dependent manner, the hyperactivity response induced by amphetamine (1 mg.kg-1 s.c.). (R)-alpha-Methylhistamine (20 mg.kg-1 i.p.) completely reversed the inhibitory response to thioperamide (2 mg.kg-1 i.p.). Thioperamide (2 or 10 mg.kg-1 i.p.) also inhibited apomorphine (2 mg.kg-1 s.c.)- and, to a lesser extent, cocaine (5 mg.kg-1 s.c.)-induced hyperactivity. We therefore conclude that antagonism of the central histamine H3 receptor inhibits, to a varying degree, the effects of locomotor stimulants.

Topics: Amphetamine; Animals; Apomorphine; Central Nervous System Stimulants; Cocaine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Mice; Motor Activity; Piperidines

Potential species differences in cardiovascular responses to histamine H3 receptor activation were studied in the conscious guinea pig, rabbit, normotensive rat and the spontaneously hypertensive rat. R-alpha-Methylhistamine (100 micrograms/kg i.v.) decreased blood pressure in both the guinea pig and the rabbit. In the guinea pig, R-alpha-methylhistamine decreased heart rate, whereas in the rabbit it produced a tachycardia. In the normotensive rat and spontaneously hypertensive rat, R-alpha-methylhistamine (100 micrograms/kg i.v.) had no effect on blood pressure and heart rate. The cardiovascular action of R-alpha-methylhistamine in the guinea pig and rabbit was blocked by pretreatment with thioperamide (1.0 mg/kg i.v.) but not by chlorpheniramine (0.3 mg/kg i.v.) or cimetidine (3.0 mg/kg i.v.), respectively. These results indicate species differences in cardiovascular responses to histamine H3 receptor activation.

Topics: Animals; Blood Pressure; Cimetidine; Guinea Pigs; Heart Rate; Hemodynamics; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Piperidines; Rabbits; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Histamine H3; Species Specificity

To investigate whether histamine receptor ligands influence the in vivo-release of acetylcholine in the ventral striatum, this brain region was superfused with histamine receptor agonists or antagonists through a push-pull cannula and drug effects on the release of acetylcholine were investigated. Histamine, the H1 receptor agonist 2-thiazolyl-ethylamine and the H3 receptor antagonist thioperamide enhanced acetylcholine release, while the H3 receptor agonist (R)-alpha-methylhistamine was ineffective. The results indicate that H1 receptors and H3 receptors modulate acetylcholine release. The thioperamide-induced increase of acetylcholine release might be exerted via H3-receptors located on cholinergic terminals. Alternatively, thioperamide might enhance acetylcholine release by increasing endogenous histamine release via H3 autoreceptors. It is concluded that, via stimulation of striatal H1- and H3 receptors, histaminergic neurons are involved in the regulation of cholinergic neuronal activity in the ventral striatum.

Topics: Acetylcholine; Animals; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Neostriatum; Piperidines; Rats; Receptors, Histamine

There is increased recognition that lung mast cell mediators not only produce the symptoms of acute asthma, but also result in the recruitment and activation of additional proinflammatory cells, such as eosinophils. Histamine, one of the major mast cell mediators, is known to have numerous effects on eosinophil function. These effects of histamine are mediated by distinct receptors on the surface of eosinophils, only some of which have been characterized. Prior studies have suggested that eosinophils have non-H1, non-H2 histamine receptors which mediate the chemotactic effects of histamine. We observed previously that the histamine-induced increase in cytosolic calcium in human eosinophils could not be blocked by classic H1 or H2 antagonists, but could be inhibited by the H3 antagonist thioperamide. The purpose of this study was to further characterize the pharmacologic properties of this calcium-linked histamine receptor. Using Fura-2 loaded eosinophils to measure the concentration of cytosolic calcium, we examined the effect of additional histamine receptor antagonists and agonists. We found that the pKb for the H3 antagonists thioperamide, impromidine, and burimamide (8.1, 7.6, and 7.2, respectively), were similar to those reported for H3 receptors in the central nervous system, suggesting that the eosinophil histamine receptor was similar to H3 receptors. However, when the known H3 agonists were tested for activity ([R]-alpha-methylhistamine, N alpha-methylhistamine), the potencies of these compounds were much less than the potency of histamine itself, indicating a significant difference between H3 receptors and this eosinophil histamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Anticonvulsants; Asthma; Burimamide; Calcium; Eosinophils; Fura-2; Histamine Agonists; Histamine Antagonists; Humans; Impromidine; Inflammation; Intracellular Fluid; Mast Cells; Methylhistamines; Phosphatidylethanolamines; Piperidines; Platelet Aggregation Inhibitors; Receptors, Histamine

The action of (R)-alpha-methylhistamine (alpha-MeHA), a selective H3-receptor agonist, on field stimulation induced contraction of guinea pig vas deferens was composed of 2 components: the "inhibition" (0.1-100 nmon.L-1) and the "enhancement" (1-10 mumol.L-1). In the presence of histamine H1 antagonist, chlorpheniramine (1 mumol.L-1), alpha-MeHA (0.1 nmol.L-1-10 mumol.L-1) showed only a concentration-dependent inhibition. Selective histamine H3-receptor antagonist, thioperamide (1 nmol.L-1-10 mumol.L-1) antagonized the inhibitory effect of alpha-MeHA and increased the contractile amplitude of vas deferens elicited by field pulses when thioperamide was used alone. alpha-MeHA 10 mumol.L-1 enhanced the contractile amplitude, which was reversed by chlorpheniramine 1 mumol.L-1, but not by ranitidine (1 mumol.L-1). Pyridelethylamine, an H1-receptor agonist, facilitated concentration-dependently the contractile response of vas deferens. The effect was antagonized by chlorpheniramine, but not by ranitidine. Dimaprit, an H2-receptor agonist had no effect on the field stimulation induced sympathetic response. Both alpha-MeHA and pyridelethylamine failed to influence the contraction of vas deferens elicited by direct field stimulation in smooth muscle or by exogenously applied norepinephrine. It was concluded that histamine H1- and H3-receptors existed in sympathetic terminals of guinea pig vas deferens and facilitated or inhibited the sympathetic neurotransmission.

Topics: Animals; Chlorpheniramine; Dimaprit; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Piperidines; Ranitidine; Sympathetic Nervous System; Synaptic Transmission; Vas Deferens

Histamine H3 antagonists have been reported to discriminate subclasses of histamine H3 agonist binding in rat cortical membranes. This phenomenon was investigated by autoradiography of cryostat sections of rat forebrain labelled with [3H]N alpha-methylhistamine ([3H]NAMH, 4 nM). Displacement curves with thioperamide detected a single site in cortex and striatum (pIC50 = 8.18 +/- 0.03). However, Hill coefficients (nH = 0.51 +/- 0.12) suggested the possible presence of multiple binding sites. Displacement with burimamide was consistent with two site models in all brain regions examined (pIC50(A) = 7.9 +/- 1.5; pIC50(B) = 5.6 +/- 0.7), except for the medial septum where a single site was detected. Elsewhere, the relative abundance of the two sites displaced by burimamide (H3A:H3B) appeared to be 1:2. Thioperamide may have failed to discriminate two sites because the IC50s were too similar to be distinguished in the present autoradiographic study.

Topics: Animals; Autoradiography; Binding Sites; Binding, Competitive; Brain; Burimamide; Cerebral Cortex; Corpus Striatum; Histamine Antagonists; Male; Methylhistamines; Organ Specificity; Piperidines; Prosencephalon; Rats; Rats, Wistar; Receptors, Histamine H3; Tritium

1. Effects of substances which are able to alter brain histamine levels on the nociceptive threshold were investigated in mice and rats by means of tests inducing three different kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). 2. A wide range of i.c.v. doses of histamine 2HCl was studied. Relatively high dose were dose-dependently antinociceptive in all three tests: 5-100 micrograms per rat in the paw pressure test, 5-50 micrograms per mouse in the abdominal constriction test and 50-100 micrograms per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 microgram per rat in the paw pressure test and 0.1-1 microgram per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed. 3. The histamine H3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose-dependent antinociceptive effect by both parenteral (10-40 mg kg-1) and i.c.v. (1.1-10 micrograms per rat and 3.4-10 micrograms per mouse) routes. 4. The histamine H3 agonist, (R)-alpha-methylhistamine dihydrogenomaleate was hyperalgesic, with a rapid effect (15 min after treatment) following i.c.v. administration of 1 microgram per rat and 3 microgram per mouse, or i.p. administration of 100 mg kg-1 in mice. In rats 20 mg kg-1, i.p. elicited hyperalgesia only 4 h after treatment. 5. Thioperamide-induced antinociception was completely prevented by pretreatment with a non-hyperalgesic i.p. dose of (R)-alpha-methylhistamine in the mouse hot plate and abdominal constriction tests. Antagonism was also observed when both substances were administered i.c.v. in rats. 6. L-Histidine HCl dose-dependently induced a slowly occurring antinociception in all three tests. The doses of 250 and 500 mg kg-1, i.p. were effective in the rat paw pressure test, and those of 500 and 1500 mg kg-1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000 mg kg-1, i.p. showed their maximum effect 2 h after treatment. 7. The histamine N-methyltransferase inhibitor, metoprine, elicited a long-lasting, dose-dependent antinociception in all three tests by both i.p. (10-30 mg kg-1) and i.c.v. (50-100 micrograms per rat) routes. 8. To ascertain the mechanism of action of the antinociceptive effect of L-histidine and metoprine, the two substances were also studied in combination with the histamine synthesis inhibitor (S)-alpha-fluoromethylhistidine and

Topics: Analgesics; Animals; Histamine; Histidine; Hyperalgesia; Male; Methylhistamines; Methylhistidines; Mice; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Sensory Thresholds

The influence of N-ethylmaleimide (NEM) on sympathetic neurotransmission induced by field stimulation on the isolated guinea pig vas deferens was studied. Application of (R)-alpha-methylhistamine (0.1 mcmol/l) significantly inhibited the sympathetic response by 26.0%, while thioperamide facilitated the sympathetic contraction of vas deferens evoked by field pulses by 221.1%. Pretreatment of vas deferens with NEM (60 mcmol/l) for 15 min abolished both the inhibitory and facilitatory effects. Attenuation of thioperamide facilitatory effect by NEM was not significantly altered when the H3-receptors were occupied by thioperamide prior to and during NEM treatment. The results suggest that effects mediated by H3-receptors in the guinea pig vas deferens were NEM-sensitive and possibly transmitted by Gi or Go proteins.

Topics: Animals; Electric Stimulation; Ethylmaleimide; GTP-Binding Proteins; Guinea Pigs; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Piperidines; Receptors, Histamine H3; Receptors, Presynaptic; Signal Transduction; Sympathetic Nervous System; Synaptic Transmission; Vas Deferens

Experiments were undertaken to determine the effect of the selective histamine H3 receptor agonist (R)-alpha-methylhistamine on the amplitude of neurally evoked electrodermal (sudomotor) responses in anesthetized cats. (R)-alpha-Methylhistamine produced comparable dose-related depressions of these evoked sympathetic-cholinergic electrodermal responses elicited by either pre- or postganglionic nerve stimulation. Responses evoked by i.a. methacholine were not depressed by pretreatment with (R)-alpha-methylhistamine. (R)-alpha-Methylhistamine inhibition of preganglionic evoked responses was antagonized by pretreatment with the histamine H3 receptor antagonist thioperamide, but not by pretreatment with selective blockers of histamine H1 or histamine H2 receptors (chlorpheniramine or cimetidine). Pretreatment with thioperamide did not antagonize presynaptic inhibition produced by i.v. (-)-epinephrine, nor did rauwolscine block the inhibition produced by (R)-alpha-methylhistamine. These results suggest that (R)-alpha-methylhistamine stimulates presynaptic histamine H3 receptors located on sudomotor postganglionic nerve endings to depress neurally evoked release of acetylcholine. (R)-alpha-Methylhistamine does not appear to act at an autonomic ganglionic site in this system.

Topics: Animals; Cats; Chlorpheniramine; Cimetidine; Electric Stimulation; Female; Histamine Agonists; Male; Methacholine Chloride; Methylhistamines; Parasympathetic Nervous System; Piperidines; Receptors, Histamine H3; Skin; Sympathetic Nervous System

1. The effect of the selective histamine H3 receptor agonist, R-alpha-methylhistamine given intravenously (10-100 micrograms kg-1) was examined on baseline total peripheral resistance (TPR), and cardiovascular haemodynamics in bilaterally vagotomized, anaesthetized guinea-pigs. 2. R-alpha-methylhistamine produced a dose-dependent hypotension and fall in TPR at 30 and 100 micrograms kg-1. A decrease in heart rate (HR) was observed at a dose of 100 micrograms kg-1. R-alpha-methylhistamine (10-100 micrograms kg-1) also produced a dose-dependent fall in rate pressure product (RPP). There was no effect on cardiac output (CO) or stroke volume (SV) at these doses. 3. Histamine H1 and H2 blockade in animals pretreated with a combination of chlorpheniramine (0.3 mg kg-1) and cimetidine (3.0 mg kg-1) did not alter the haemodynamic actions of R-alpha-methyl-histamine (100 micrograms kg-1, i.v.). Pretreatment with the selective H3 antagonist, thioperamide (1 mg kg-1), completely blocked the action of R-alpha-methylhistamine on haemodynamic parameters. 4. To study the mechanism of action of R-alpha-methylhistamine, the vasodilator hydralazine (1 mg kg-1, i.v.) was used. Hydralazine lowered BP, TRP and RPP in guinea-pigs pretreated with ipratropium (50 micrograms kg-1, i.v.). Hydralazine had no effect on HR, SV or CO. 5. R-alpha-methylhistamine (100 micrograms kg-1) did not affect the vasopressor action and increases in TPR produced by adrenaline (1 and 3 micrograms kg-1). On the other hand, the vasodilator hydralazine (1 mg kg-1, i.v.) inhibited the effects of adrenaline (3 micrograms kg-1) on TPR and RPP. The effect of both doses of adrenaline on BP were attenuated by hydralazine. Therefore, the inhibitory effects of R-alpha-methylhistamine are not mediated through a direct action on vascular smooth muscle.6. In adrenalectomized guinea-pigs, R-alpha-methylhistamine (100 microg kg-1) produced a drop in BP and HR.There was no difference between the effects of R-alpha-methylhistamine on blood pressure and heart rate in adrenalectomized and non-adrenalectomized guinea-pigs.7. These results show that activation of peripheral H3 receptors lowers basal BP, HR and TPR, most likely by a peripheral prejunctional mechanism. The fall in BP and TPR is probably due to a decrease in noradrenaline release from sympathetic effector nerves innervating the resistance blood vessels.

Topics: Adrenalectomy; Anesthesia; Animals; Cardiac Output; Dose-Response Relationship, Drug; Guinea Pigs; Hemodynamics; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Hydralazine; Male; Methylhistamines; Muscle, Smooth, Vascular; Piperidines; Receptors, Histamine H3; Vascular Resistance

The pharmacological activity of the histamine H3 receptor antagonist VUF 9153 (S-[3-(4(5)-imidazolyl)]propyl-N-(4-chlorobenzyl)isothiourea) has been investigated in vitro and in vivo. VUF 9153 displaced [3H]N alpha-methylhistamine binding to rat cortex/hippocampal membranes (pKi = 9.77 +/- 0.03) and antagonised the inhibitory responses to (R)-alpha-methylhistamine against electrical field stimulation in the isolated longitudinal smooth muscle preparation of guinea-pig ileum (pKB = 9.95 +/- 0.07). In these assays, VUF 9153 was 10-50-fold more potent than the prototype H3 receptor antagonist thioperamide. VUF 9153 showed no or very weak activity in in vitro functional assays for histamine H1 or H2 receptors. Systemic administration of VUF 9153 (s.c. or p.o.) dose-dependently inhibited the ex vivo binding of [3H]N alpha-methylhistamine to rat cortex/hippocampal membranes and dipsogenic responses induced by (R)-alpha-methylhistamine. Calculation of ED50 values, at the 1 h pretreatment time used, revealed that VUF 9153 administered s.c. or p.o., was approximately 2-fold weaker than thioperamide. These data indicate that, like thioperamide, VUF 9153 is a potent and selective antagonist for histamine H3 receptors in vitro, possesses the ability to penetrate the blood-brain barrier to access central H3 receptors and can inhibit H3 receptor-mediated functional responses in vivo.

Topics: Animals; Cerebral Cortex; Dose-Response Relationship, Drug; Drinking; Electric Stimulation; Guinea Pigs; Hippocampus; Histamine Agonists; Histamine Antagonists; Ileum; Imidazoles; In Vitro Techniques; Male; Methylhistamines; Muscle, Smooth; Piperidines; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Thiourea

Frequency-dependent pupillary dilations were evoked by electrical stimulation of the pre- or post-ganglionic cervical sympathetic nerve (sympatho-excitation) or the hypothalamus (parasympatho-inhibition) in sympathectomized anesthetized cats. Systemic administration of the selective histamine H3 receptor agonist (R)-alpha-methylhistamine (R alpha MeHA) produced a dose-dependent depression of mydriasis due to direct neural sympathetic activation but had no effect on responses elicited by parasympathetic withdrawal. The histamine H2 receptor agonist, dimaprit, was inactive. R alpha MeHA was much more effective in depressing sympathetic responses obtained at lower frequencies when compared to higher frequencies of stimulation. Responses evoked both pre- and postganglionically were inhibited by R alpha MeHA. This peripheral sympatho-inhibitory action of R alpha MeHA was antagonized by the histamine H3 receptor blocker thioperamide but not by intravenous pretreatment with the histamine H1 receptor antagonist chlorpheniramine. Histamine H2 receptor blockers cimetidine and ranitidine were also without effect. R alpha MeHA did not depress pupillary responses elicited by i.v. (-)-adrenaline. The results demonstrate that histamine H3 receptors modulate sympathetic activation of the iris at a site proximal to the iris dilator muscle. The predominant mechanism of action appears to the prejunctional inhibition of noradrenaline release from postganglionic sympathetic nerve endings. However, a concomitant ganglionic inhibitory action cannot be excluded.

Topics: Animals; Cats; Dose-Response Relationship, Drug; Electric Stimulation; Female; Histamine Agonists; Histamine Antagonists; Iris; Male; Methylhistamines; Neuromuscular Junction; Piperidines; Pupil; Receptors, Histamine H3; Receptors, Presynaptic; Sympathetic Nervous System

Effects of intracerebroventricular (i.c.v) injection of histamine (Hi) and its related compounds on prolongation of the response latency ensuing after a long interruption of learning were studied by testing the active avoidance response in old rats. After Hi application at doses of 50 and 100 ng, the response latency became significantly shorter than that determined in the pre-injection periods, suggesting that Hi facilitates memory retrieval in old rats. H1-agonists, 2-methylHi and 2-thiazolylethylamine, effected a dose-related shortening of response latency as seen after Hi application, whereas H2-agonists, 4-methylHi and impromidine, failed to prompt the response latency. Simultaneous i.c.v. injection of pyrilamine, a H1-antagonist and Hi abolished the Hi-induced shortening of response latency. Furthermore, intraperitoneal administration of histidine at doses of 200 and 500 mg/kg significantly shortened the response latency. Neither (R)-alpha-methylHi nor thioperamide caused a significant effect indicating that H3-receptor may not be involved in Hi-induced facilitation of memory retrieval. Based on these findings, it may be concluded that Hi takes an active part in facilitating memory recall via H1-receptor in old rats.

Topics: Acetylcholine; Aging; Animals; Anticonvulsants; Avoidance Learning; Cerebrovascular Circulation; Cimetidine; Dose-Response Relationship, Drug; Exploratory Behavior; Histamine; Histamine Agonists; Injections, Intraventricular; Male; Memory; Methylhistamines; Motor Activity; Piperidines; Pyrilamine; Rats; Rats, Wistar

Histamine (HA) stimulates prolactin secretion via H1 and H2 receptors. In the present study, we examined the role of a third subtype of receptor recently described in brain, the H3-HA receptor, on prolactin secretion in male rats. R(-)alpha-methyl-HA (alpha-MHA), a selective H3 receptor agonist, was injected into the lateral ventricle of the brain in freely moving rats. alpha-MHA produced a dose-dependent (1-5 micrograms) and long-lasting increase in plasma prolactin levels. This increase was observed from 15 to 60 min after injection of alpha-MHA. Its stimulatory action was prevented by thioperamide (20 micrograms i.v.t), a selective H3 antagonist. This compound, injected intraventricularly, lacked effect by itself on basal plasma prolactin levels. Neither pyrilamine (H1 antagonist; 60 micrograms i.v.t.) nor ranitidine (H2 antagonist; 60 micrograms i.v.t.) affected alpha-MHA-induced prolactin release. The stimulatory effect was still present when brain HA was depleted by alpha-fluoromethylhistidine (30 mg/kg i.p.). Our findings suggest that alpha-MHA evokes prolactin release by activation of postsynaptic H3 receptors.

Topics: Animals; Brain; Injections, Intraventricular; Kinetics; Male; Methylhistamines; Methylhistidines; Piperidines; Prolactin; Rats; Rats, Sprague-Dawley; Receptors, Histamine

The effect of (R)alpha-methylhistamine (MH) and thioperamide (selective agonist and antagonist respectively of histamine H3 receptors) was examined in conscious gastric fistula dogs to investigate the role of histamine H3 receptors in the control of basal and stimulated gastric acid secretion. Intravenous infusion of MH at 0.3 and 0.6 mumol/kg/h caused a significant reduction of the 2-deoxy-D-glucose (2-DG)-stimulated acid output, maximal inhibition being 60%. The inhibitory effect of MH was counteracted by thioperamide (0.1 mumol/kg/h), which, by itself, did not modify the 2-DG-induced acid secretion. The increase in plasma gastrin levels induced by 2-DG was not significantly affected either by MH or by thioperamide. Under basal conditions MH (0.3 mumol/kg/h) did not induce any significant change in acid secretion and in plasma gastrin levels; by contrast, thioperamide (0.1 mumol/kg/h) produced a significant increase both in acid output and in plasma gastrin. These results suggest that activation of H3 receptors can exert a negative control in stimulated acid secretion in conscious dogs, when cholinergic pathways to acid secretion are activated by 2-DG; moreover, the slight, but significant, stimulatory effect of thioperamide on basal acid output and basal plasma gastrin may be suggestive for a tonic inhibitory role of H3 receptors in the regulation of basal acid secretion, however, a nonspecific effect of this drug cannot be excluded.

Topics: Animals; Deoxyglucose; Dogs; Female; Gastric Acid; Gastric Fistula; Gastrins; Male; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3

The effect of the selective H3 receptor agonist (R)-alpha-methylhistamine and antagonist thioperamide on water consumption in the rat were examined. (R)-alpha-Methylhistamine (0.1-20 mg.kg-1 i.p.) evoked a dose-dependent increase in water consumption the maximum effect being 310 +/- 23% (n = 67) above the vehicle control response. Thioperamide (0.2,2 and 10 mg.kg-1 i.p.) alone had no effect on water consumption. However, the stimulatory effect of (R)-alpha-methylhistamine on water consumption was antagonised by thioperamide in a dose-dependent manner, whereas the H1 receptor antagonist mepyramine and the H2 receptor antagonist loxtidine were without effect. It is therefore concluded that the H3 receptor may play a role in the regulation of water consumption in the rat.

Topics: Animals; Drinking; Histamine; Histamine Antagonists; Male; Methylhistamines; Nicotinic Acids; Piperidines; Pyrilamine; Rats; Receptors, Histamine; Receptors, Histamine H3; Tetrazoles; Triazoles

The stress-induced release of anterior pituitary hormones and changes in hypothalamic content of histamine (HA) and its metabolite tele-methylHA (t-meHA) were studied in male rats during inhibition of HA synthesis or activation or blockade of HA H3 receptors. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha-FMH; 200 micrograms intracerebroventricularly (icv) at -120 min) or the specific H3 receptor agonist R(alpha)methylhistamine (RmHA; 10 mg/kg intraperitoneally (ip) at -180 and -60 min) inhibited by 30-80% the responses of prolactin (PRL), corticotropin (ACTH) and beta-endorphin (beta-END) immunoreactivity to 1, 2.5 or 5 min of restraint stress (p < 0.05-0.01), but had no effect on basal secretion of the hormones. The inhibitory effect of the H3 receptor agonist RmHA (10 mg/kg x 2) on the hormone response to 5 min of restraint stress was prevented by simultaneous ip administration of the H3 receptor antagonist thioperamide. alpha-FMH reduced the hypothalamic content of HA 60% and that of t-meHA 30%, while RmHA had no effect on the HA content. Restraint stress for 5 min did not affect the HA and t-meHA contents, which may be due to the short duration of stress exposure. Pretreatment with the H3 receptor antagonist thioperamide (5 or 10 mg/kg ip at -120 min) had no effect on basal or restraint stress-induced release of PRL, ACTH or beta-END, although the compound increased the hypothalamic content of t-meHA 2-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Histamine; Histamine Antagonists; Hypoglycemia; Hypothalamus; Insulin; Kinetics; Male; Methylhistamines; Methylhistidines; Piperidines; Pituitary Hormones, Anterior; Prolactin; Rats; Rats, Wistar; Receptors, Histamine; Receptors, Histamine H3; Restraint, Physical; Stress, Physiological

In superfused mouse striatal slices preincubated with [3H]dopamine 25 nmol/l, the electrically (3 Hz) evoked tritium overflow was inhibited by histamine 10 mumol/l by 18%. The degree of inhibition was increased to 38% by haloperidol but not affected by (1) atropine, (2) reducing the stimulation frequency to 0.3 Hz or (3) increasing the concentration of [3H]dopamine (used for preincubation) to 100 nmol/l. The effect of histamine was mimicked by the H3 agonist R-(-)-alpha-methylhistamine; it was not affected by the H1 antagonist dimetindene and the H2 antagonist ranitidine but abolished by the H3 antagonist thioperamide. Tritium overflow evoked by Ca2+ ions (introduced into Ca(2+)-free, K(+)-rich medium containing tetrodotoxin) was not affected by histamine 10 mumol/l in the absence, but inhibited (by 30%) in the presence of haloperidol; the effect of histamine was abolished by thioperamide. In conclusion, the dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H3 receptors. Simultaneous blockade of dopamine autoreceptors increases the extent of the H3 receptor-mediated inhibition of dopamine release.

Topics: Animals; Calcium; Corpus Striatum; Dopamine; Electric Stimulation; Histamine; Histamine Agonists; In Vitro Techniques; Male; Methylhistamines; Mice; Mice, Inbred Strains; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Stereoisomerism; Synapses; Tritium

1. The influence of epithelium on the effects of H3-histamine receptor agonist (R)alpha-methylhistamine [(R)alpha-MeHist] on airways was investigated on the guinea-pig perfused bronchioles. 2. In preparations under resting tone, removal of the bronchiolar epithelium or treatment with the cyclo-oxygenase inhibitor indomethacin (10(-5) M) increased the constriction induced by histamine and acetylcholine in a concentration-dependent manner without an alteration of the K(+)-induced contraction. 3. In this preparation (R)alpha-MeHist induced a concentration-dependent bronchodilatation which was antagonized in a competitive manner by thioperamide (an H3-antagonist) with a pA2 value of 8.6. 4. This bronchodilatation was reversed to a low concentration-dependent constriction after either removal of the epithelium or treatment with indomethacin (10(-5) M) but was unaffected by both 10(-5) M tranylcypromine (an inhibitor of PGI2 synthesis) and 5 x 10(-5) M NG-nitro-L-arginine methyl ester (an inhibitor of NO synthesis). 5. It is suggested that, in guinea-pig perfused bronchioles (R)alpha-MeHist induces an epithelium-dependent relaxation via the release of metabolite(s) of arachidonic acid.

Topics: Acetylcholine; Animals; Anticonvulsants; Arginine; Bronchi; Bronchodilator Agents; Epithelium; Female; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Indomethacin; Male; Methylhistamines; Muscle Relaxation; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Papaverine; Perfusion; Piperidines; Prostaglandins; Receptors, Histamine H3; Tranylcypromine

In the brain, the H3 type of histamine receptor has a pre-synaptic autoreceptor inhibitory role which regulates neuronal release and synthesis of histamine. To examine the interaction of the selective H3 receptor antagonist thioperamide with H3 receptors in the brain in vivo, we have used a functional and non-functional measurement of H3 receptor occupancy. In three species (rat, guinea-pig and mouse) peripheral administration of thioperamide caused dose-related increases in histamine turnover in the cerebral cortex (whole brain was examined in the mouse) and, in the same tissues, inhibited the ex vivo binding of the selective H3 receptor agonist [3H](R)-alpha-methylhistamine ([3H]-RAMH). The peak effect of thioperamide to inhibit ex vivo binding of [3H]RAMH was observed approximately 30 min after i.p. administration, whilst the maximum increase in histamine turnover did not occur until after at least 100 min. At a pretreatment time of 30 min, the ED50 of thioperamide to inhibit ex vivo binding of [3H]RAMH binding in the rat, guinea-pig and mouse brain was found to be 2.0 +/- 0.2, 4.8 +/- 0.6 and 2.6 +/- 0.3 mg/kg (mean +/- SEM, N = 4), respectively. We have also examined the effect of peripheral administration of RAMH on ex vivo binding of [3H]RAMH in rat cortex. Qualitatively and quantitatively similar results to those of thioperamide were observed following i.p. administration of RAMH to rats (ED50 = 3.9 +/- 0.4 mg/kg, mean +/- SEM, N = 4). An effect of RAMH on histamine turnover in rat cortex could not be determined as this compound displayed significant cross-reactivity with the antibodies used in the radioimmunoassay to measure histamine and telemethylhistamine. These data indicate that, following peripheral administration, both thioperamide and RAMH penetrate the brain where they can subsequently interact with H3 receptors. It would appear that binding of thioperamide to H3 receptors is linked with a concomitant increase in histamine turnover in the brain. In conclusion, the ex vivo binding technique, particularly when coupled with measurement of histamine turnover, should provide a valuable means for investigating the ability of any peripherally administered compound to cross the blood-brain barrier and subsequently interact with histamine H3 receptors.

Topics: Animals; Brain Chemistry; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Male; Methylhistamines; Mice; Piperidines; Rats; Receptors, Histamine; Receptors, Histamine H3

1. The effect of (R)-alpha-methylhistamine, a selective H3-histamine receptor agonist, was examined on the neurogenic hypertension and tachycardia that is induced by stimulation of areas in the medulla oblongata of guinea-pigs. Electrical medullary stimulation (32 Hz, 3-5 s trains, 0.5-1.0 ms square pulse, 25-400 microA) produced intensity-dependent increases in blood pressure and a more variable tachycardia. 2. (R)-alpha-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-alpha-methylhistamine was dose-dependent (10-300 micrograms kg-1, i.v.) and was not seen at high intensities of stimulation. 3. (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not attenuate the pressor response to adrenaline (1 and 3 micrograms kg-1, i.v.), indicating that the effect of (R)-alpha-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4. The inhibition of CNS-induced hypertension by (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg-1, i.v.), impromidine (ID50 = 0.22 mg kg-1, i.v.) and burimamide (ID50 = 6 mg kg-1, i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 micrograms kg-1, i.v.) and cimetidine (3 mg kg-1, i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-alpha-methylhistamine. 5. These results suggest that (R)-alpha-methylhistamine inhibits sympathetic hypertensive responses in guinea-pigs by activation of prejunctional H3-receptors, possibly located on postganglionic nerve terminals. Furthermore, on the basis of the rank order potency to different H3-antagonists, it appears that the H3B-receptor subtype is involved with H3-receptor responses on vascular sympathetic nerves.

Topics: Animals; Blood Pressure; Burimamide; Dose-Response Relationship, Drug; Electric Stimulation; Epinephrine; Guinea Pigs; Heart Rate; Histamine Agonists; Histamine Antagonists; Impromidine; Male; Medulla Oblongata; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Sympathetic Nervous System

1. The effect of agents which interact with the histamine H3 receptor on potassium-stimulated tritium release from slices of rat entorhinal cortex preloaded with [3H]-choline is described. We have examined the effects of the selective H3 receptor agonist, (R)-alpha-methylhistamine (RAMH), and a number of H3 receptor antagonists, including the selective compound thioperamide, on the potassium-stimulated release of tritium. 2. In the presence of mepyramine and ranitidine, RAMH (0.01-10 microM) inhibited potassium-stimulated tritium release in a concentration-dependent manner, EC50 = 0.11 microM. The maximum inhibition was approximately 50%. 3. Thioperamide displaced the RAMH concentration-response curve to the right yielding a pKB value of 8.4. There was no change in the maximum response to RAMH. 4. Other H3 receptor antagonists, including impromidine and burimamide, also caused rightwards displacement of the linear portion of the RAMH concentration-response curve. However, phenylbutanoylhistamine and betahistine, which are reported to be relatively potent H3 receptor antagonists, showed very low affinity. 5. Thioperamide (0.001-1 microM) alone enhanced the potassium-stimulated release of tritium in a concentration-dependent manner. Maximum effects were observed at 0.1-1 microM thioperamide, enhancing release by approximately 20%. 6. Results are discussed in terms of the regulatory role of H3 receptors on acetylcholine release and the possible existence of H3 receptor subtypes.

Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Hippocampus; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Piperidines; Potassium; Pyrilamine; Ranitidine; Rats; Receptors, Histamine; Receptors, Histamine H3

A simple and rapid functional test system for the screening of histamine H3 ligands is described. It is based on the inhibitory effect of histamine H3 agonists on electrically-evoked contractile response of isolated guinea pig intestine. Whole jejunum segments are continuously stimulated maximally (15 V) by electrical pulses with a frequency of 0.1 Hz and a duration of 0.5 msec. The resulting twitches are recorded isotonically (1.0 g) and can be completely abolished by atropine (0.1 mcM).

Topics: Acetylcholine; Animals; Atropine; Drug Evaluation, Preclinical; Electric Stimulation; Guinea Pigs; Histamine Agonists; In Vitro Techniques; Isotonic Contraction; Jejunum; Ligands; Male; Methylhistamines; Muscle Contraction; Piperidines; Receptors, Histamine; Receptors, Histamine H3

The effects of the specific H3 agonist (R)-alpha-methylhistamine (alpha-MeHA) and the specific H3 antagonist thioperamide were examined on histamine release and acid secretion [( 14C]-aminopyrine (AP) accumulation) by isolated rabbit gastric glands. Thioperamide significantly enhanced basal histamine release from the glands (+50% at 30 min for 10(-7) M thioperamide; P less than 0.01), and this increase was prevented by alpha-MeHA. Histamine-elicited AP accumulation was increased by 18% (P less than 0.05) by 10(-7) M thioperamide and decreased by 70% (P less than 0.01) by 10(-6) M of the H2 antagonist ranitidine. Thioperamide alone significantly enhanced AP accumulation in a dose-dependent manner, whereas alpha-MeHA had no effect of its own on this accumulation. Thioperamide stimulation of basal AP accumulation was not modified by ranitidine but was 50% decreased by alpha-MeHA. Furthermore, carbachol-induced AP accumulation was decreased by alpha-MeHA and increased by thioperamide; the latter effect was not blocked by ranitidine. These findings support that H3 receptors pharmacologically distinct from H2 receptors are involved in the regulation of histamine-stimulated acid secretion. They further suggest that these gastric H3 receptors occur in the gastric glands as 1) H3 autoreceptors located on the histamine-secreting cells and acting to downregulate histamine release from these cells and 2) H3 (or H3-like) receptors located on the parietal cell and regulating in a negative manner the acid secretory process.

Topics: Aminopyrine; Animals; Carbachol; Gastric Mucosa; Histamine; Histamine Release; In Vitro Techniques; Male; Methylhistamines; Piperidines; Rabbits; Ranitidine; Receptors, Histamine H1

Topics: Animals; Brain Stem; Cimetidine; Electric Stimulation; Eye Movements; Guanidines; Guinea Pigs; Head; Imidazoles; Impromidine; In Vitro Techniques; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H2; Reflex, Vestibulo-Ocular; Rotation; Vestibular Nuclei

The effects of the histamine H3 receptor ligands thioperamide and (R)-alpha-methylhistamine on the histidine decarboxylase (HDC) activity and histamine content of mouse brain were examined. Thioperamide, a histamine H3 antagonist, significantly increased the HDC activity in the brain of ddY, W/Wv and ICR mice 2-6 hr after its intraperitoneal (i.p.) injection. On the other hand, (R)-alpha-methylhistamine, a histamine H3-receptor agonist, caused no significant change in the HDC activity. The whole brain histamine content of ddY mice decreased significantly to 60-70% of the control level 2-8 hr after injection of thioperamide (25 mg/kg, i.p.), but then increased to 90% of the control level 10 hr after the injection. These in vivo results showed that blockade of the presynaptic histamine H3-receptor, which causes release of presynaptic histamine, increased the HDC activity.

Topics: Animals; Brain; Histamine; Histamine Antagonists; Histidine Decarboxylase; Injections, Intraperitoneal; Male; Methylhistamines; Mice; Mice, Inbred Strains; Piperidines; Time Factors

In an attempt to assess the role of histamine H3 receptors in the control of gastric acid secretion, the effects of the selective histamine H3 receptor agonist, (R) alpha-methylhistamine and antagonist, thioperamide were evaluated in the conscious gastric fistula cat under basal conditions and against different stimuli. (R) alpha-methylhistamine (0.05-0.2 mumol/kg/h) was ineffective against spontaneous and dimaprit-induced acid secretion; it also did not reduce significantly pentagastrin-induced acid output, but caused a dose-dependent (0.05-0.1 mumol/kg/h) and significant inhibition of the acid response to 2-deoxy-D-glucose. Thioperamide (0.02-0.04 mumol/kg/h) did not modify spontaneous acid secretion, whereas it evoked a significant enhancement of the acid response to submaximal doses (50 mg/kg i.v.) of 2-deoxy-D-glucose. Thioperamide completely reversed the inhibitory effect of (R) alpha-methylhistamine against 2-deoxy-D-glucose-induced secretion, while leaving unaffected the inhibition induced by somatostatin. These data suggest that histamine H3 receptors may be involved in the control of acid secretion stimulated by indirectly acting secretagogues.

Topics: Animals; Cats; Female; Gastric Acid; Gastric Fistula; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3

The effects of intracarotid (i.a.) administration of the histamine (HA) H3-receptor agonist (R)-alpha-methyl-histamine (alpha MeHA) and of the H3-antagonist thioperamide, (THIO) on basal or morphine (M)-induced prolactin (PRL) and growth hormone (GH) secretion were studied in male rats. M was administered 3 h after the H3-drugs. Neither THIO (2.5 mg/kg) nor alpha MeHA (10 mg/kg) changed basal PRL levels and only THIO enhanced the PRL-releasing effect of M (6 mg/kg). Basal GH secretion was not modified by THIO. alpha MeHA slightly increased GH secretion. THIO significantly decreased M-stimulated GH secretion (1 mg/kg, i.a.) and alpha MeHA slightly increased it. These results, in agreement with previous evidence obtained after central HA administration, indicated that endogenous brain HA facilitates PRL and inhibits GH secretion.

Topics: Animals; Growth Hormone; Histamine Antagonists; Kinetics; Male; Methylhistamines; Morphine; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3

The role of histamine H3-receptors in the control of acetylcholine release from peripheral cholinergic neurons was evaluated in the isolated guinea pig ileum, previously loaded with 3H-choline. When tested in the presence of H1- and H2-blockade, histamine (0.1-100 mumol/l) and (R) alpha-methylhistamine (0.01-1 mumol/l) dose-dependently reduced the electrically-evoked choline outflow, with (R) alpha-methylhistamine being a partial agonist. Selective H3-receptor blocking drugs, thioperamide (0.1 mumol/l) and impromidine (0.1 mumol/l) reversed the histamine-induced inhibitory effect. These data suggest that intestinal cholinergic nerves are endowed with histamine H3-receptors whose activation produces an inhibitory effect upon acetylcholine release. The practical implications of these findings are obvious.

Topics: Acetylcholine; Animals; Electric Stimulation; Guanidines; Guinea Pigs; Histamine; Histamine Antagonists; Ileum; Imidazoles; Impromidine; Methylhistamines; Myenteric Plexus; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Tritium

The effects of the H3-agonist R-alpha-methylhistamine (R-alpha-MeHA) and the H3-antagonist thioperamide on the spontaneous and concanavalin A (ConA) induced histamine release from human mast cells were tested and compared with the effect of some H1- and H2-receptor active substances. R-alpha-MeHA (10(-9)-10(-7) M) exerted no effect on histamine release whereas thioperamide increased the spontaneous release at 10(-6)-10(-4) M but inhibited the ConA induced release in a narrow concentration range (10(-6)-10(-5) M). This enhancement might be taken as an indication of the existence of H3-receptor dependent autoregulation although presently other mechanism cannot be excluded.

Topics: Adenoids; Cimetidine; Concanavalin A; Guanidines; Histamine Antagonists; Humans; Hydroxyzine; Imidazoles; Impromidine; Mast Cells; Meclizine; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3

The histamine H3 agonist, (R)-alpha-methylhistamine (alpha-MeHA, 10(-10) to 10(-5) M), caused a concentration-dependent inhibition of the sympathetic contractile response to electrical field stimulation of guinea pig isolated atria, but alpha-MeHA did not alter the basal tension or the contraction induced by exogenously applied norepinephrine. Blockade of H1 and H2 histamine receptors, and alpha- and beta-adrenoceptors failed to prevent the inhibitory effect of alpha-MeHA, whereas the specific H3 receptor antagonist, thioperamide, concentration dependently reversed the inhibitory effect of alpha-MeHA. At the concentration of 10(-7) M, which was effective for antagonizing the action of alpha-MeHA, thioperamide did not modify the sympathetic responses facilitated by the beta 2-adrenoceptor agonist, clenbuterol, or attenuated by the alpha 2-adrenoceptor agonist, clonidine. Our results suggest that H3 receptors exist on the cardiac sympathetic terminals, which may modulate adrenergic neurotransmission in guinea pig myocardium.

Topics: Animals; Chlorpheniramine; Clenbuterol; Clonidine; Dose-Response Relationship, Drug; Electric Stimulation; Evoked Potentials; Guinea Pigs; Heart; Heart Atria; In Vitro Techniques; Methylhistamines; Nerve Endings; Norepinephrine; Phentolamine; Piperidines; Propranolol; Ranitidine; Receptors, Histamine; Receptors, Histamine H3; Sympathetic Nervous System; Synaptic Transmission

Topics: Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Cardiovascular System; Consciousness; Guinea Pigs; Heart Rate; Histamine Antagonists; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3

The effects of the histamine H3 receptor agonist, (R)-alpha-methylhistamine were compared with those of the histamine H3 antagonist, thioperamide, in rats implanted with electrodes for chronic sleep recordings. (R)-alpha-Methylhistamine (1.0-4.0 micrograms) injected bilaterally into the premammillary area where histamine immunoreactive neurons have been detected increased slow wave sleep, whereas wakefulness and REM sleep were decreased. No significant effects were observed when (R)-alpha-methylhistamine (1.0-8.0 mg/kg) was administered i.p. Thioperamide (1.0-4.0 mg/kg i.p.) increased wakefulness and decreased slow wave sleep and REM sleep. Pretreatment with thioperamide (4.0 mg/kg) prevented the effects of (R)-alpha-methylhistamine (2.0 micrograms) on slow wave sleep and wakefulness. Our results further support an active role for histamine in the control of the waking state.

Topics: Animals; Drug Interactions; Histamine Antagonists; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mammillary Bodies; Methylhistamines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3; Sleep; Wakefulness