Humans ; Histamine ; Receptors, Histamine H2 ; Schizophrenia/drug therapy*

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (alpha-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with alpha-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, alpha-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.
Animals ; Blood Glucose* ; Cetirizine ; Dimaprit ; Down-Regulation ; Glucose ; Histamine* ; Mice* ; Mice, Inbred ICR ; Ranitidine ; Receptors, Histamine H2 ; Receptors, Histamine H3 ; Receptors, Histamine* ; Spinal Cord ; Up-Regulation

The present study was carried out to determine the role of histamine H(1) and H(2) receptors in the generation of basic respiratory rhythm. Neonatal (aged 0-3 d) Sprague-Dawley rats of either sex were used. The medulla oblongata slice containing the medial region of the nucleus retrofacialis (mNRF) and the hypoglossal nerve rootlets was prepared and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous carbogen (95% O(2) and 5% CO(2)), and ended in 3 min. Respiratory rhythmical discharge activity (RRDA) of the rootlets of hypoglossal nerve was recorded by suction electrode. Thirty medulla oblongata slice preparations were divided into 5 groups. In groups I, II and III, histamine (5 μmol/L), H(1) receptor specific antagonist pyrilamine (10 μmol/L) and H(2) receptor specific antagonist cimetidine (5 μmol/L) was added into the perfusion solution for 15 min separately. In group IV, after application of histamine for 15 min, additional pyrilamine was added into the perfusion for another 15 min. In group V, after application of histamine for 15 min, additional cimetidine was added into the perfusion for another 15 min. The discharges of the roots of hypoglossal nerve were recorded. Signals were amplified and band-pass filtered (100-3.3 kHz). Data were sampled (1-10 kHz) and stored in the computer via BL-420 biological signal processing system. Our results showed that histamine significantly decreased the respiratory cycle (RC) and expiratory time (TE), but changes of integral amplitude (IA) and inspiratory time (TI) were not statistically significant. Pyrilamine induced significant increases in RC and TE, but changes of TI and IA were not statistically significant. Cimetidine had no effects on RC, TE, TI and IA of RRDA. The effect of histamine on the respiratory rhythm was reversed by additional application of pyrilamine but not cimetidine. Taken together, with the results mentioned above, histamine H(1) receptors but not H(2) receptors may play an important role in the modulation of RRDA in the medulla oblongata slice preparation of neonatal rats.
Animals ; Animals, Newborn ; Cimetidine ; pharmacology ; Female ; Histamine ; pharmacology ; Histamine H1 Antagonists ; pharmacology ; Histamine H2 Antagonists ; pharmacology ; Hypoglossal Nerve ; physiology ; In Vitro Techniques ; Male ; Medulla Oblongata ; physiology ; Pyrilamine ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Histamine H1 ; physiology ; Receptors, Histamine H2 ; physiology ; Respiration

AIMTo explore the roles of H1 and H2 receptors in the locus ceruleus (LC) in the carotid baroreflex (CBR) resetting resulted from foot-shock stress.

METHODSMale SD rats were divided into two groups (n=18) at random: unstressed and stressed group. The latter were subjected to unavoidable electric foot-shock twice daily for a week and each session of foot-shock lasted 2 hours. The left and right carotid sinus regions were isolated from the systemic circulation in all animals anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner in vivo. ISP-mean arterial pressure (MAP), ISP-Gain relationship curves and reflex characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CBR performance induced by stress and the effects of microinjection with histaminergic receptors antagonists into the LC on the responses of CBR to stress were examined.

RESULTSStress significantly shifted the ISP-MAP relationship curve upwards (P < 0.05) and obviously moved the middle part of ISP-Gain relationship curve downwards (P < 0.05), and decreased the value of the MAP range and maximum gain (P < 0.05), but increased the threshold pressure, saturation pressure, set point and ISP at maximum gain (P < 0.05). Microinjection of selective H1 or H2 receptor antagonist, chlorpheniramine (CHL, 0.5 microg/microl) or cimetidine (CIM, 1.5 microg/microl) into the LC, significantly attenuated the above-mentioned changes in CBR performance induced by stress and the alleviate effect of CIM was less remarkable than that of CHL (P < 0.05). The responses of CBR under stress to H1 or H2 receptor antagonist generally occurred 20 min after the administration and lasted approximately for 16 min. Microinjection with the same dose of CHL or CIM into the LC in the unstressed group did not change CBR performance significantly (P > 0.05). However, microinjection of CHL or CIM into the LC could not completely abolish the stress-induced changes in CBR.

CONCLUSIONThe stress results in a resetting of CBR and a decrease in reflex sensitivity. The stress-induced changes in CBR may be mediated, at least in part, by activating the brain histaminergic system. The H1 and H2 receptors in the LC, especially, Hi receptors may play an important role in the resetting of CBR under stress. The descending histaminergic pathway from the hypothalamus to LC may be involved in these effects. Moreover, the effects of stress on CBR also have other mechanisms.

Animals ; Baroreflex ; Carotid Sinus ; physiology ; Locus Coeruleus ; physiology ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Histamine H1 ; physiology ; Receptors, Histamine H2 ; physiology ; Stress, Physiological

Spinal α-motoneurons directly innervate skeletal muscles and function as the final common path for movement and behavior. The processes that determine the excitability of motoneurons are critical for the execution of motor behavior. In fact, it has been noted that spinal motoneurons receive various neuromodulatory inputs, especially monoaminergic one. However, the roles of histamine and hypothalamic histaminergic innervation on spinal motoneurons and the underlying ionic mechanisms are still largely unknown. In the present study, by using the method of intracellular recording on rat spinal slices, we found that activation of either H or H receptor potentiated repetitive firing behavior and increased the excitability of spinal α-motoneurons. Both of blockage of K channels and activation of Na-Ca exchangers were involved in the H receptor-mediated excitation on spinal motoneurons, whereas the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels were responsible for the H receptor-mediated excitation. The results suggest that, through switching functional status of ion channels and exchangers coupled to histamine receptors, histamine effectively biases the excitability of the spinal α-motoneurons. In this way, the hypothalamospinal histaminergic innervation may directly modulate final motor outputs and actively regulate spinal motor reflexes and motor execution.
Animals ; Histamine ; pharmacology ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; metabolism ; Motor Neurons ; drug effects ; physiology ; Rats ; Receptors, Histamine H2 ; metabolism ; Sodium-Calcium Exchanger ; metabolism

This study was designed to examine the effects of histamine on gastric motility and its specific receptor in the circular smooth muscle of the human gastric corpus. Histamine mainly produced tonic relaxation in a concentration-dependent and reversible manner, although histamine enhanced contractility in a minor portion of tissues tested. Histamine-induced tonic relaxation was nerve-insensitive because pretreatment with nerve blockers cocktail (NBC) did not inhibit relaxation. Additionally, K+ channel blockers, such as tetraethylammonium (TEA), apamin (APA), and glibenclamide (Glib), had no effect. However, N(G)-nitro-L-arginine methyl ester (L-NAME) and 1H-(1,2,4)oxadiazolo (4,3-A) quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), did inhibit histamine-induced tonic relaxation. In particular, histamine-induced tonic relaxation was converted to tonic contraction by pretreatment with L-NAME. Ranitidine, the H2 receptor blocker, inhibited histamine-induced tonic relaxation. These findings suggest that histamine produced relaxation in circular smooth muscle of human gastric smooth muscle through H2 receptor and NO/sGC pathways.
Apamin ; Glyburide ; Guanylate Cyclase ; Histamine ; Humans ; Muscle, Smooth* ; Nerve Block ; NG-Nitroarginine Methyl Ester ; Nitric Oxide* ; Ranitidine ; Receptors, Histamine H2 ; Relaxation* ; Tetraethylammonium

OBJECTIVETo investigate histamine-induced changes of the intracortical vessels in the cortical slice of rat brain.

METHODSImmunohistochemistry was employed to detect the expression of H1 and H2 receptors in the intracortical blood vessels of rats. Histamine-induced constriction of the intracortical blood vessels of the brain slices was observed with differential interference contrast microscope. Measurements of the luminal diameter were made on-line during the course of the experiment and confirmed off-line from the stored images. In order to observe whether histamine H1 and H2 receptors affected histamine-induced constriction, the intracortical blood vessels in the brain slices were pre-treated with H1 receptor antagonist diphenhydramine and H2 receptor antagonist cimetidine.

RESULTSExpression of H1 and H2 receptors was detected in the intracortical blood vessels of the rat brain. Histamine (1-100 micromol/L) induced a concentration-dependent constriction from (1.48-/+0.67)% to (32.91-/+7.91)%. The reactions to each histamine concentration were significantly (P<0.01) different from each other, with the exception of the highest histamine concentrations (30 and 100 micromol/L) when maximal constriction due to histamine were observed (P>0.05). With pre-treatment of the slice with 10 micromol/L diphenhydramine, application of histamine did not elicit constriction. Pre-treatment of the slice with 10 micromol/L cimetidine did not completely inhibit but somehow significantly weakened vascular constriction in response to histamine treatment at 10 and 30 micromol/L (P<0.05).

CONCLUSIONHistamine can induce constriction of the intracortical blood vessels, which is mediated by H1 receptor.

Animals ; Blood Vessels ; drug effects ; metabolism ; physiology ; Cerebral Cortex ; blood supply ; Cimetidine ; pharmacology ; Diphenhydramine ; pharmacology ; Histamine ; pharmacology ; Histamine H1 Antagonists ; pharmacology ; Histamine H2 Antagonists ; pharmacology ; In Vitro Techniques ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Histamine H1 ; metabolism ; physiology ; Receptors, Histamine H2 ; metabolism ; physiology ; Vasoconstriction ; drug effects

OBJECTIVETo investigate the effects of histamine on the neurotoxicity induced by beta-amyloid(1-42)(Abeta42) in rat phaeochromocytoma (PC12) cells.

METHODSThe in vitro model of Alzheimer's disease was constructed with A beta42-treated PC12 cells. Cell morphology and MTT assay were used to evaluate the cell toxicity and histamine effects. The different histamine antagonists were applied to investigate the involvement of receptor subtypes.

RESULTThe neurotoxicity was induced by A beta42 in a concentration-dependent manner, which was reversed by histamine at concentration of 10(-7), 10(-6) mol/L. The effect was reversed by H(2) antagonist zolantidine and H(3)antagonist clobenpropit, but not by H(1) antagonist diphenhydramine.

CONCLUSIONHistamine reduces neurotoxicity induced by beta-amyloid(1-42), which may be mediated by H(2) and H(3)receptors.

Alzheimer Disease ; chemically induced ; metabolism ; prevention & control ; Amyloid beta-Peptides ; toxicity ; Animals ; Benzothiazoles ; pharmacology ; Diphenhydramine ; pharmacology ; Dose-Response Relationship, Drug ; Histamine ; pharmacology ; Histamine H2 Antagonists ; pharmacology ; Histamine H3 Antagonists ; pharmacology ; Imidazoles ; pharmacology ; Neuroprotective Agents ; metabolism ; pharmacology ; PC12 Cells ; Phenoxypropanolamines ; pharmacology ; Piperidines ; pharmacology ; Rats ; Receptors, Histamine H2 ; metabolism ; Receptors, Histamine H3 ; metabolism ; Thiourea ; analogs & derivatives ; pharmacology

OBJECTIVETo determine the effect of histamine on N-methyl-D-aspartate (NMDA) induced neuron death and to elucidate its mechanism.

METHODSThe primary cortical cell culture was adopted. Neuron morphology and MTT assay were used to evaluate the drugs effects.

RESULTHistamine at doses of 10(-4) 10(-6) 10(-7) 10(-8) mol/L reversed the neuron death induced by NMDA (50 micromol/L) for 3 h. The protection of histamine peaked at doses of 10(-4) mol/L and 10(-7)mol/L. The effect of histamine of 10(-7) mol/L was reversed only by cimetidine an H(2)receptor antagonist. However, the effect of histamine of 10(-4) mol/L was reversed only by pyrilamine but not cimetidine.

CONCLUSIONHistamine could reduce neuron death induced by NMDA; its protection at a low dose might be mediated by H(2)receptor, and at a high dose by H(1)receptor.

Animals ; Cell Death ; drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Histamine ; pharmacology ; N-Methylaspartate ; toxicity ; Neurons ; drug effects ; Neuroprotective Agents ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Histamine H1 ; physiology ; Receptors, Histamine H2 ; physiology

Contribution of histamine H1- and H2-receptors to the effect of compound 48/80, a potent histamine releaser, upon asphyxiation and body temperature in mice was investigated in the present experiments. Compound 48/80 showed an apparent protective potency against hypoxia and significantly prolonged the latencies for convulsions and death in a dose-dependent manner. Compound 48/80 also decreased the body temperature, which was in relation with the antihypoxic effect. Both the H1-receptor antagonist, dimethindene, and the H2-receptor antagonist, ranitidine, attenuated the hypothermic effect of compound 48/80, indicating the involvement of central histamine through both the H1- and H2-receptors. Ranitidine had no effect on the protective effect of compound 48/80 against hypoxia-induced lethality, whereas dimethindene completely antagonized it. These results suggest that the protective effect of compound 48/80 against hypoxia is mediated through histamine H1-receptors and is not related to its ability to induce hypothermia.
Animal ; Anoxia/*drug therapy/physiopathology ; Body Temperature/*drug effects ; Convulsions/prevention & control ; Male ; Mice ; Mice, Inbred BALB C ; Receptors, Histamine H1/*physiology ; Receptors, Histamine H2/*physiology ; p-Methoxy-N-methylphenethylamine/*pharmacology