突触前组胺H_1和H_3受体对豚鼠输精管交感神经冲动传递的影响(英文)

(R)-α-甲基组胺(α-MeHA)低浓度抑制,高浓度增强电场刺激诱发的离体输精管收缩。上述效应可分别被thioperamide和氯苯那敏拮抗,Pyridelethyl-amine(Pyr)能增强电场刺激诱发的输精管收缩,α-MeHA和Pyr对于直接电刺激或去甲肾上腺素(NE)诱发的输精管收缩均无影响,以上表明,豚鼠输精管交感神经末稍分布有组胺H_3和H_1两种受体,它们分别介导抑制和促进NE的释放。     

突触前组胺H1和H3受体对豚鼠输精管交感神经冲动传递的影响

（Ｒ）－α－甲基组胺低浓度抑制，高浓度增强电场刺激诱发的离体输精管收缩。上述效应可分别被ｔｈｉｏｐｅｒａｍｉｄｅ和氯苯那敏拮抗。Ｐｙｒｉｄｅｌｅｔｈｙｌａｍｉｎｅ（Ｐｙｒ）能增强电场刺激诱发的输精管收缩，α－ＭｅＨＡ和Ｐｙｒ对于直接电刺激或去甲肾上腺素诱发的输精管收缩均无影响。以上表明，豚鼠输精管交感神经末稍分布有组胺Ｈ３和Ｈ１两种受体，它们分别介导抑制和促进ＮＥ的释放。     

组胺H_3受体介导抑制豚鼠心交感神经释放去甲肾上腺素的直接依据

组胺Ｈ３受体介导抑制豚鼠心交感神经释放去甲肾上腺素的直接依据罗晓星，文爱东１，郭治安２，谭月华（第四军医大学药理教研室，１西京医院临床药理室；２西北大学化学系，西安７１００３２，中国）关键词心房；电刺激；甲基组胺；组胺拮抗剂；去甲肾上腺素；节后交感神...     

组胺H3受体介导抑制豚鼠心交感神经释放去甲肾上腺素的直接依据

观察组胺Ｈ３受体介质抑制心交感神经末稍释放去甲肾上腺素。     

The effect of intracerebroventricular injection of histamine in visceral nociception induced by acetic acid in rats

Objective:

This study was designed to investigate the role of brain histamine and H1 and H2 receptors in mediating the central perception of visceral pain in rats.

Materials and Methods:

In conscious rats implanted with a lateral brain ventricle cannula, the effect of intracerebroventricular (i.c.v.) injection of histamine (2.5, 10, and 40 μg), and chlorpheniramine and ranitidine at the same doses of 5, 20, and 80 μg were investigated on visceral pain. Visceral nociception induced by intraperitoneal (i.p.) injection of acetic acid (1 mL, 1%), and the number of complete abdominal wall muscle contractions accompanied with stretching of hind limbs (writhes) were counted for 1 h.

Results:

Histamine at doses of 10 and 40 μg and chlorpheniramine and ranitidine at the same doses of 20 and 80 μg, significantly decreased the numbers of writhes (P < 0.05). Pretreatment with chlorpheniramine and ranitidine at the same dose of 80 μg, significantly prevented histamine (40 μg)-induced antinociception (P < 0.05).

Conclusion:

The results of this study suggest that brain histamine may be involved in modulation of visceral antinociception through both central H₁and H₂receptors.     

维生素C对氟化钠和化合物48-80诱导大鼠肥大细胞释放组胺的影响

氟化钠(NaF)和化合物48-80均可诱发大鼠胸腔，腹腔肥大细胞释放组胺，前者依赖细胞外钙参与，后者与细胞外钙关系不大，二者的最适诱导浓度分别为10 mmol·L^-1和0.2 mg·L^-1. 维生素C可促进NaF诱导的组胺释放，但对化合物48-80所诱导的组胺释放无明显影响. 将肥大细胞置于37 ℃，2 h，NaF或化合物48-80诱导的组胺释放率均下降.预先加入维生素C 1 mmol·L^-1，此现象显著减弱.由此提示：NaF激发肥大细胞，增敏其对Ca²⁺分泌作用不是由自由基引发的，另一方面也不排除37 ℃长时间温育细胞产生自由基可能与降低细胞对NaF-Ca²⁺系统和化合物48-80的敏感性有关.     

维生素C对氟化钠和化合物48-80诱导大鼠肥大细胞释放组胺的影响

氟化钠（ＮａＦ）和化合物４８－８０均可诱发大鼠胸腔，腹腔肥大细胞释放组胺，前者依赖细胞外钙参与，后者与细胞外钙关系不大，二者的最适诱导浓度分别为１０ｍｍｏｌＬ－１和０．２ｍｇＬ－１．维生素Ｃ可促进ＮａＦ诱导的组胺释放，但对化合物４８－８０所诱导的组胺释放无明显影响．将肥大细胞置于３７℃，２ｈ，ＮａＦ或化合物４８－８０诱导的组胺释放率均下降．预先加入维生素Ｃ１ｍｍｏｌＬ－１，此现象显著减弱．由此提示：ＮａＦ激发肥大细胞，增敏其对Ｃａ２＋分泌作用不是由自由基引发的，另一方面也不排除３７℃长时间温育细胞产生自由基可能与降低细胞对ＮａＦ－Ｃａ２＋系统和化合物４８－８０的敏感性有关．     

N-methyl-d-aspartate (NMDA)-stimulated noradrenaline (NA) release in rat brain cortex is modulated by presynaptic H3-receptors

In superfused rat brain cortex slices and synaptosomes preincubated with [³H]noradrenaline the effect of agonists or antagonists at presynaptic H₃ receptors on NMDA-evoked [³H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H₃ receptor agonist R-(–)--methylhistamine inhibited NMDA-evoked tritium overflow (IC₂₀ values 0.27 mol/l or 0.032 mol/l, respectively); S-(+)--methylhistamine (up to 10 mol/l) as well as the selective H₁ receptor agonist (2-(2-thiazolyl)ethylamine) and the selective H₂ receptor agonist dimaprit (each up to 10 mol/l) were ineffective. The H₃ receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H₁ receptor antagonist dimetindene and the preferential H₂ receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(–)--methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of -conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(–)--methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H₃ receptors. NMDA receptors and H₃ receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H₃ receptor stimulation. Correspondence to: M. Göthert at the above address     

Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein by presynaptic histamine H3 receptors

Summary The human saphenous vein was used to examine whether presynaptic histamine receptors can modulate noradrenaline release and, if so, to determine their pharmacological characteristics. Strips of this blood vessel were incubated with [³H]noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. Electrically (2 Hz) evoked ³H overflow was inhibited by histamine and the H₃ receptor agonist R-(–)--methylhistamine. Histamine-induced inhibition of electrically evoked tritium overflow was not affected by ₂-adrenoceptor blockade by rauwolscine. S-(+)--methylhistamine (up to 10 mol/l) as well as the histamine H₁ and H₂ receptor agonists 2-(2-thiazolyl)ethylamine (up to 3 mol/l) and dimaprit (up to 30 mol/l), respectively, were ineffective. The selective histamine H₃ receptor antagonist thioperamide abolished the inhibitory effect of histamine. The histamine H₂ and H₁ receptor antagonists ranitidine and pheniramine, respectively, did not affect the histamine-induced inhibition of evoked tritium overflow. The present results are compatible with the suggestion that the sympathetic nerves of the human saphenous vein are endowed with inhibitory presynaptic histamine receptors of the H₃ class. Send offprint requests to M. Gothert at the above address     

Involvement of presynaptic H3 receptors in the inhibitory effect of histamine on serotonin release in the rat brain cortex

Summary Rat brain cortex slices or synaptosomes preincubated with ³H-serotonin were superfused with physiological salt solution (which, in the case of slices, contained citalopram, an inhibitor of serotonin uptake), and the effects of histamine and related drugs on the evoked tritium overflow were studied.The electrically (3 Hz) evoked tritium overflow from slices was inhibited by histamine and the H₃ receptor agonists R-(–)--methylhistamine and N-methylhistamine (pIC_12.5 values: 6.41, 7.28 and 6.12, respectively), but not affected by the H₁ receptor agonist 2-(2-thiazolyl)ethylamine and the H₂ receptor agonist dimaprit (each at 10 mol/l). The concentration-response curve for histamine was shifted to the right by the H₃ receptor antagonists impromidine, burimamide and thioperamide (apparent pA₂ values: 7.45, 5.97 and 7.88, respectively); the concentration-response curve of serotonin for its inhibitory effect on the electrically evoked overflow was not affected by the three drugs (apparent pA₂ values: < 5.5, < 5.5 and < 6.5). Given alone, impromidine, thioperamide and a low concentration of burimamide facilitated the electrically evoked overflow. In slices superfused with K⁺-rich, Ca²⁺-free solution containing tetrodotoxin throughout and in synaptosomes superfused with Ca²⁺-free solution, histamine inhibited the overflow evoked by introduction of Ca²⁺ (in synaptosomes, simultaneously with an increased amount of K⁺). In either tissue, the effect of histamine was counteracted by thioperamide.The results provide evidence that exogenous and probably also endogenous histamine inhibits serotonin release in the rat brain cortex via presynaptic histamine H₃ receptors.Send offprint requests to E. Schlicker at the above address     

Brain histamine H3 receptors in rats with portacaval anastomosis: in vitro and in vivo studies

The long-term effects of portacaval anastomosis (PCA) on histamine H₃ receptors in rat brain were studied by in vitro and in vivo methods. The overflow of histamine from the anterior hypothalamus and from cortex after long-term PCA was determined by in vivo microdialysis. The binding properties of [³H]-R-α-methylhistamine in membranes from cortex, cerebellum, and rest of brain (ROB) were examined with saturation binding experiments. The regional distribution of [³H]-R-α-methylhistamine binding sites in the brain of sham- and PCA-operated rats was assessed also with autoradiography. The tissue levels of histamine were significantly elevated in cortex and ROB of PCA-operated rats. In addition, the spontaneous and K⁺-evoked overflow of histamine from anterior hypothalamus, and the thioperamide-induced overflow from both anterior hypothalamus and cortex were increased after chronic PCA. In spite of the significantly elevated tissue concentrations and the moderate increase in histamine release, the binding properties of [³H]-R-α-methylhistamine to cortical membranes were not significantly changed. However, the autoradiography study did reveal a decrease in [³H]-R-α-methylhistamine binding density, particularly in striatum and cortex, where H₃ receptors are located mainly at non-histaminergic neurons. In conclusion, we suggest that there is a region-selective increase in the histaminergic activity in chronic PCA, which leads to the down-regulation of somadendritic and pre-synaptic H₃ receptors located at non-histaminergic neurons. At the same time, the autoreceptor mediated control of histamine neuronal activity via pre-synaptic H₃ receptors located at histaminergic neurons is preserved after long-term PCA. Received: 11 May 1998 / Accepted: 10 August 1998     

Recent advances in histamine H3/H4 receptor ligands

Advances in molecular biology have brought fresh impetus to the field of research into histamine receptor ligands with the recent cloning of human histamine H₃ and H₄ receptors. Numerous promising potential therapeutic targets have been suggested for H₃ receptor ligands based on various pharmacological investigations, e.g., Alzheimer’s disease, schizophrenia, obesity, epilepsy, inflammatory diseases, sleep disorders and attention-deficit hyperactivity disorder. Concurrent to the availability of the receptors, the number of leads has also largely increased in the last few years, with some hybrid compounds acting simultaneously at two targets. In particular, the large number of different non-imidazole H₃ receptor antagonists possessing high affinities and selectivities and the first compound in clinical testing raise the hope for having a drug available in the market in the near future. The first studies with H₄ receptor ligands show promising anti-inflammatory and immunomodulatory properties.     

Brain histamine and schizophrenia: potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

BF2.649, a high affinity and selective non-imidazole histamine H(3)-receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either C(max) or AUC values. At low oral doses (2.5-20mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation. DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons. BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition. These observations suggest that H(3)-receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.