Suppression of ischaemia-induced cytokine release by dimaprit and amelioration of liver injury in rats

Inflammatory reactions play an important role in ischaemia/reperfusion injury in various organs. Since histamine H(4) action has been shown to prevent the development of ischaemia/reperfusion liver injury, we examined the effects of dimaprit, a histamine H(2)/H(4) receptor agonist, on ischaemia-induced cytokine release and liver damage. Male Wistar rats (300 g) were subjected to warm ischaemia for 30 min. by occlusion of the left portal vein and hepatic artery under halothane anaesthesia. Saline or dimaprit (20 mg/kg, subcutaneously) was injected immediately after reperfusion of blood flow. Transient ischaemia provoked severe liver damage 24 hr after reperfusion, and the plasma concentrations of alanine transaminase and aspartate transaminase were 4600 IU/l and 13,200 IU/l, respectively. The values in the dimaprit group were 55% and 46% of those in control animals, respectively. Dimaprit also reduced the infarct size to 50%. Liver ischaemia markedly increased interleukin-12 levels 2-24 hr after reperfusion. The dimaprit treatment depressed the values to 40-64% of those in the corresponding control group 4-24 hr after reperfusion. Since interleukin-12 facilitates cell-mediated cytotoxicity, the protective effect of dimaprit may be attributed to regulation of cytokine release during reperfusion.     

Alleviation of ischemia-induced brain edema by activation of the central histaminergic system in rats

We have reported that facilitation of central histaminergic activity prevents the development of ischemia-induced brain injury. Since cerebral edema is a major cause of brain damage, we studied effects on brain edema of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H(3)-receptor antagonist, both of which enhance central histaminergic activity. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery in rats, and the water content and infarct size were determined 24 h after reperfusion. Changes in the extracellular concentration of histamine were examined in the striatum by a microdialysis procedure, and effects of these compounds were evaluated. Repeated administration of L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the increase in the water contents in ischemic regions. Simultaneous administration of thioperamide (5 mg/kg, s.c.) with L-histidine (1000 mg/kg, i.p.) completely prevented edema formation and alleviated brain infarction, although a single dose of L-histidine, immediately after reperfusion, showed no benefits. The striatal histamine level was gradually increased after reperfusion as well as during ischemia. Simultaneous administration of thioperamide with L-histidine markedly increased the brain histamine concentration, and the value increased up to 230% of that in the saline group 5 - 6 h after reperfusion. L-Histidine alone did not affect the increase in the histamine output after ischemia. These findings suggest that further activation of the central histaminergic system after initiation of cerebral ischemia prevents development of ischemia-induced brain edema.     

Suppression of inflammatory cell recruitment by histamine receptor stimulation in ischemic rat brains

Inflammation is a crucial factor in the development of ischemia-induced brain injury. Since facilitation of central histaminergic activity ameliorates reperfusion injury, effects of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H3 receptor antagonist, on inflammatory cell infiltration were evaluated in a rat model of transient occlusion of the middle cerebral artery. After reperfusion for 12, 24, or 72 h following 2 h of occlusion, brain slices were immunohistochemically stained with antibodies against myeloperoxidase and CD68, which were markers of polymorphonuclear leukocytes and macrophages/microglia, respectively. After reperfusion for 12-24 h, the number of neutrophils on the ischemic side increased markedly, whereas the increase was not observed on the contralateral side. Administration of L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the number of neutrophils to 52%. Simultaneous administration of thioperamide (5 mg/kg, s.c.) further decreased the number of neutrophils to 32%. Likewise, the ischemia induced increase in the number of CD68-positive cells after 24 h was suppressed by L-histidine injections. The L-histidine administration decreased the number of CD4+ T lymphocytes on both ischemic and contralateral sides after 12 h, and concurrent administration of thioperamide prolonged the effect. Although administration of mepyramine (3 nmol, i.c.v.) did not affect suppression of leukocyte infiltration, ranitidine tended to reverse the effect of L-histidine. These data suggest that enhancement of central histaminergic activity suppresses inflammatory cell recruitment after ischemic events through histamine H2 receptors, which may be a mechanism underlying the protective effect of L-histidine.     

Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists

The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.     

A comparison of protective effects between L-histidine and hypothermia against ischemia-induced neuronal damage in gerbil hippocampus

An increase in the histamine concentration in the brain has been demonstrated to provide protective effects against ischemia/reperfusion brain injury. Since hypothermia and barbiturates are also regarded to protect ischemic brains, effects of postischemic treatments were compared in gerbils between mild hypothermia and intraperitoneal administration of L-histidine, a precursor of histamine. Furthermore, effects of thioperamide, a histamine H(3) receptor antagonist, were evaluated in histidine-treated gerbils after 60 days. Transient forebrain ischemia for 4 min at 37 degrees C provoked severe neuronal damage in the hippocampal CA1 pyramidal cells after 7 days. Postischemic hypothermia (33 degrees C) for 3 h under pentobarbital anesthesia alleviated neuronal death, and the number of preserved neurons was 77+/-56/mm (mean+/-S.D., n=14). The effect of L-histidine injected three times, immediately, 6 h, and 24 h after reperfusion (1,000 mg/kg, i.p., each), was more prominent than that of hypothermia, and the number of preserved neurons was 142+/-55/mm (n=14). When the histologic outcome was evaluated after 60 days, most neurons were damaged in both the hypothermic and histidine groups. The improvement of the histologic outcome was observed even after 60 days in animals injected with thioperamide, immediately and 6 h after reperfusion (5 mg/kg, s.c., each), with three injections of l-histidine. The number of preserved neurons was 133+/-88/mm (n=10), while that in the hypothermic group was 7+/-15 (n=10). Activation of the central histaminergic system provides beneficial effects against cerebral ischemia.     

Modification of formalin-induced nociception by different histamine receptor agonists and antagonists.

The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20-40 microg/mouse i.c.v.) or subcutaneous (1-10 mg/kg s.c.) injection of HTMT (H(1) receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H(1) receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 mug/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H(2) receptor agonist, 30 mg/kg i.p.) and ranitidine (H(2) receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H(3) receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H(3) receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetit-induced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H(3) receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H(1) and H(3) receptor activations increase sensitivity to nociceptive stimulus in the formalin test.     

Influence of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rat

The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.     

Role of central histaminergic system in lorazepam withdrawal syndrome in rats.

Effects of histaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with the food in the following dose schedule (in mg/kg given daily x days): 10 x 4, 20 x 4, 40 x 4, 80 x 4, and 120 x 7. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA), and audiogenic seizures. During the withdrawal period, the rats were divided into groups of 10 each. Control-withdrawal group did not receive any drug. The drugs (in mg/kg administered intramuscularly)--L-histidine (50), histamine-N-methyl (2), promethazine (10), pheniramine (10), astemizole (10), and thioperamide (1)--were given separately in other groups daily during the withdrawal period. The withdrawal signs in control group were hyperkinesia, hyperaggression, and audiogenic seizures. L-Histidine, precursor of histamine, and thioperamide, antagonist of H3 receptor, potentiated hyperkinesia, hyperaggression, and audiogenic seizures. Histamine-N-methyl, agonist of H3 receptor, and H1 receptor antagonists, promethazine and pheniramine, blocked all the withdrawal signs. Astemizole, a peripheral antagonist of H1 receptor, could not affect any withdrawal sign. It may be concluded that histamine H1 receptors are facilitatory and H3 receptors are inhibitory for benzodiazepine (BZD) withdrawal syndrome.     

Histamine facilitates consolidation of fear extinction

Non-reinforced retrieval induces memory extinction, a phenomenon characterized by a decrease in the intensity of the learned response. This attribute has been used to develop extinction-based therapies to treat anxiety and post-traumatic stress disorders. Histamine modulates memory and anxiety but its role on fear extinction has not yet been evaluated. Therefore, using male Wistar rats, we determined the effect of the intra-hippocampal administration of different histaminergic agents on the extinction of step-down inhibitory avoidance (IA), a form of aversive learning. We found that intra-CA1 infusion of histamine immediately after non-reinforced retrieval facilitated consolidation of IA extinction in a dose-dependent manner. This facilitation was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrilamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-2-pyridylethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction while the H3 receptor agonist imetit hampered it. Extinction induced the phosphorylation of ERK1 in dorsal CA1 while intra-CA1 infusion of the MEK inhibitor U0126 blocked extinction of the avoidance response. The extinction-induced phosphorylation of ERK1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, our data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of ERK signalling.     

Histamine H3 receptor-mediated suppression of inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine

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.     

Influence of estrogen in the acquisition of intravenously self-administered heroin in female rats

Effects of substances that are able to alter the histamine level, a histamine H(1)-receptor agonist and antagonist, and a histamine H(2)-receptor agonist were investigated in an anxiety-like state in mice by means of the light/dark box test. Diazepam was used as positive control. The histamine H(3)-receptor antagonist, thioperamide (2, 5, and 20 mg/kg s.c.), showed an anxiogenic-like effect that reached a maximum with the dosage of 5 mg/kg. The histamine-N-methyltransferase (HMT) inhibitor, metoprine (5 and 20 mg/kg s.c.), also decreased the time in the light at the highest dose used and, likewise, the highly selective histamine H(1)-receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 microg/mouse, i.c.v.). On the contrary, the histamine H(2)-receptor agonist, impromidine (3, 10, 20, and 30 microg/mouse, i.c.v.), dose-dependently showed an anxiolytic-like effect. The selective histamine H(1) antagonist, pyrilamine (20 mg/kg i.p.) was able to prevent the anxiogenic-like effect of FMPH significantly, and that of thioperamide partially, while the effect caused by metoprine remained unvaried. It is suggested that the histaminergic system modulates anxiety-like states via the activation of both postsynaptic receptors in a contrasting manner: activation of the H(1) receptor causes an anxiogenic-like effect, while that of the H(2) receptors reduces anxiousness. However, on the basis of effects observed with the substances capable of releasing endogenous histamine, it seems likely that the anxiogenic-like effect is prevalent.     

Modulation of the discriminative stimulus effects of cocaine and methamphetamine by the histaminergic system.

The role of the histaminergic system in the discriminative stimulus effects of cocaine and methamphetamine was examined in rats trained to discriminate between saline and cocaine (10 mg/kg) or methamphetamine (1.0 mg/kg). L-histidine (400 mg/kg), a precursor of histamine, significantly enhanced the discriminative stimulus effects of cocaine and methamphetamine. Previous studies have revealed the existence of several histamine receptor types, H1-, H2-, and H3-receptors. These enhancing effects of L-histidine on the discriminative stimulus effects of cocaine and methamphetamine were attenuated by 5.0 mg/kg of pyrilamine (an H1-receptor antagonist), but not by 1.0 mg/kg of zolantidine (an H2-receptor antagonist), suggesting that these enhancing effects of L-histidine were mediated through the activation of H1-receptors. Thioperamide (7.5 mg/kg), an H3-receptor antagonist, also significantly enhanced the discriminative stimulus effects of cocaine and methamphetamine. However, neither pyrilamine nor zolantidine affected the enhancing effects of thioperamide, unlike the results attained with L-histidine. Therefore our findings suggest that the histaminergic system may modify the discriminative stimulus effects of cocaine and methamphetamine mediated through H1- and H3-receptors.     

Histamine at low concentrations aggravates rat liver BRL-3A cell injury induced by hypoxia/reoxygenation through histamine H2 receptor in vitro

AimHistamine released from mast cell degranulation participates in the pathogenesis of ischemia/reperfusion injury. The purpose of our study was to define the role of histamine in hypoxia/reoxygenation mediated liver cell injury and to elucidate the underlying mechanism in vitro.MethodsHistamine alone or in combination with H1 receptor antagonist (pyrilamine), H2 receptor antagonist (cimetidine) or H3/4 receptor antagonist (thioperamide) at different concentrations before hypoxia was added to rat liver BRL-3A cell which was subjected to 24 h hypoxia followed by 4 h reoxygenation. Cell proliferation, apoptosis and the changes of ultrastructure were assessed, and MDA contents, SOD activities and ALT levels were quantified as well.ResultsHistamine (from 10^?3 to 10^?9 M) did not affect the growth of BRL-3A cells without hypoxia treatment. However, histamine 10^?8 M significantly lowered the growth of BRL-3A cells challenged by hypoxia/reoxygenation, accompanied with concomitant elevations in MDA contents and decreases in SOD activities, all these changes were blocked by cimetidine, not by pyrilamine or thioperamide. However, histamine (above 10^?6 M) did not show exacerbating effects in BRL-3A cell subjected to hypoxia/reoxygenation.ConclusionHistamine at low concentrations (10^?7–10^?9 M) aggravates hypoxia/reoxygenation mediated BRL-3A damage through histamine H2 receptor.     

Histamine H3 receptor-mediated inhibition of sympathetically evoked mydriasis in rats

This study was designed to determine if the histamine H3 receptor agonist R-alpha-methylhistamine would play a role in modulation of sympathetically evoked mydriasis in anesthetized rats, and if so, to ascertain the specific receptor subtype(s) involved. Reproducible frequency-response curves of pupillary dilation were generated by stimulation of the cervical preganglionic sympathetic nerve (1-32 Hz). Systemic administration of R-alpha-methylhistamine (0.3-3.0 mg kg(-1)) produced a dose-related inhibition of the evoked mydriasis. The greatest inhibition was seen at lower frequency levels, with about 43% depression observed at 2 Hz. The specific histamine H3 receptor antagonist, clobenpropit (3.0 mg kg(-1), i.v.), blocked the inhibitory effect of R-alpha-methylhistamine, whereas neither the histamine H2 receptor antagonist, cimetidine (5.0 mg kg(-1), i.v.), nor the histamine H1 receptor antagonist, chlorpheniramine (0.5 mg kg(-1), i.v.), was effective. The histamine H2 receptor agonist, dimaprit (10 mg kg(-1), i.v.), was also without effect on the evoked mydriasis. R-alpha-methylhistamine (3.0 mg kg(-1)) did not inhibit phenylephrine-induced mydriasis. These results support the conclusion that R-alpha-methylhistamine produces inhibition of sympathetically evoked mydriasis via histamine H3 receptor stimulation, presumably by an action on presynaptic histamine H3 receptors.     

L-arginine protects from pringle manoeuvere of ischemia-reperfusion induced liver injury

Pringle described a new technique to reduce blood loss during liver surgery. Adult Wistar rats were subjected to 1 h of partial liver ischemia and followed by 3 h reperfusion. Eighteen Wistar rats were divided into sham-operated control group (I) (n=6), ischemia and reperfusion (I/R) group (II) (n=6), L-arginine treated group (100 mg/kg body weight/daily by oral route for 7 d before induced ischemia reperfusion maneuver) (III) (n=6). Ischemic and reperfusion hepatocellular injury occurred as indicated by increased-alanine transaminase (ALT), aspartate transaminase (AST). Pre-treatment with L-arginine significantly decreased serum-ALT, AST after 1 h ischemia followed by 3 h of reperfusion. Nitric oxide production, in hepatocytes was increased 2 fold and MDA levels significantly decreased by L-arginine treatment as compared to I/R rat. Histopathology and TEM studies showed markedly diminished hepatocellular injury in L-arginine pretreated rats during the hepatic I/R, which reached a level comparable to saline-treated rat of sham operated group. Thus, findings it may be concluded that L-arginine afforded significant protection from hepatobiliary function from I/R injury by nitric oxide production.     

Identification of two H3-histamine receptor subtypes

The H3-histamine receptor provides feedback inhibition of histamine synthesis and release as well as inhibition of other neurotransmitter release. We have characterized this receptor by radioligand binding studies with the H3 agonist N alpha-[3H]methylhistamine ([3H]NAMHA). The results of [3H]NAMHA saturation binding and NAMHA inhibition of [3H]NAMHA binding were consistent with an apparently single class of receptors (KD = 0.37 nM, Bmax = 73 fmol/mg of protein) and competition assays with other agonists and the antagonists impromidine and dimaprit disclosed only a single class of sites. In contrast, inhibition of [3H]NAMHA binding by the specific high affinity H3 antagonist thioperamide revealed two classes of sites (KiA = 5 nM, BmaxA = 30 fmol/mg of protein; KiB = 68 nM, BmaxB = 48 fmol/mg of protein). Burimamide, another antagonist that, like thioperamide, contains a thiourea group, likewise discriminated between two classes of sites. In addition to differences between some antagonist potencies for the two receptors, there is a differential guanine nucleotide sensitivity of the two. The affinity of the H3A receptor for [3H] NAMHA was reduced less than 2-fold, whereas [3H]NAMHA binding to the H3B receptor was undetectable in the presence of guanosine 5'-O-(3-thiotriphosphate). The distinction between H3A and H3B receptor subtypes, the former a high affinity and the latter a low affinity thioperamide site, draws support from published in vitro data.     

Effects of histamine H3-receptor ligands on various biochemical indices of histaminergic neuron activity in rat brain

The interaction of the potent histamine H3-receptor ligands i.e. (R)alpha-methylhistamine, an agonist, and thioperamide, an antagonist, with the three classes of cerebral histamine receptors was studied in vitro and in vivo. The histamine-induced stimulation of 3',5'-cyclic AMP accumulation in slices of guinea-pig hippocampus was not modified by thioperamide (up to 0.1 mM) and (R)alpha-methylhistamine stimulated cyclic AMP accumulation only at millimolar concentrations. Hence, both (R)alpha-methylhistamine and thioperamide were at least 100,000-fold more potent at H3- than at H1- or H2-receptors in brain. In vivo, the turnover of histamine in rat cerebral cortex, as determined from its depletion elicited by alpha-fluoromethylhistidine in a synaptosomal fraction was not modified by mepyramine and zolantidine but was markedly enhanced by thioperamide at a low dose (ED50 = 2 mg/kg). Thioperamide also elicited a long-lasting decrease in synaptosomal histamine and increase in radioimmunoassayable N tau-methylhistamine. In contrast, (R)alpha-methylhistamine markedly reduced cortical [3H]histamine synthesis (ED50 = 5 mg/kg). This long-lasting action was accompanied by an increase in synaptosomal histamine and a decrease in N tau-methylhistamine levels. These changes were compared with those in plasma drug levels. Hence the two H3-receptor ligands appear to modify the activity of cerebral histamine neurons markedly and in a long-lasting and opposite manner.     

组氨酸，一种组胺的前体对戊四唑诱发大鼠癫痫的作用

目的:研究和阐明中枢组胺对戊四唑(PTZ诱发大鼠点燃癫痫的作用机制.方法:隔日腹腔内注射亚惊厥剂量的PTZ 35 mg/kg诱发化学点燃癫痫,直至癫痫发作级别为4—5级.观察每次PTZ注射后30分钟内大鼠的行为变化.结果:在癫痫形成过程中,腹腔内注射组氨酸(200,500mg/kg),一种组胺的前体,剂量依赖性地延缓出现肌性痉挛和阵挛性癫痫全身性发作的反应潜时和抑制癫痫发作的级别.在癫痫模型形成后点燃激发过程中,组氨酸(500,1000mg/kg)和组胺H_3受体阻断剂4-[4′-(环己氨基硫代甲酰基哌啶)]-4H-咪唑(10,20μg)也分别表现出了明显的抗癫痫作用(2.6±0.4,2.2±0.3),(2.8±0.6,2.1±0.5).组氨酸的作用可被4-[4′-(环已氨基硫代甲酰基哌啶)]-4H-咪唑(5μg)显著性增强,却被选择性组氨酸脱羧酶抑制剂α-氟甲基组胺酸(20μg)和H_1受体拮抗剂美吡拉敏(2,5mg/kg)剂量依赖性、显著性地抑制.另外,H_2受体拮抗剂卓兰替丁即使在10mg/kg剂量下也无明显的对抗作用.结论:内源性组胺在对抗阵挛性癫痫全身性发作中起到了较重要的作用,其作用主要与突触前膜H_3受体与突触后膜H_1受体相关.     

Effects of selective activation or blockade of the histamine H3 receptor on sleep and wakefulness.

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.     

Constitutive activity of H3 autoreceptors modulates histamine synthesis in rat brain through the cAMP/PKA pathway

We previously described that agonist-activated histamine H3 autoreceptors inhibit the stimulation of histamine synthesis mediated by calcium/calmodulin- and cAMP-dependent protein kinases (CaMKII and PKA respectively) in histaminergic nerve endings. In the absence of an agonist H3 receptors show partial constitutive activity, so we hypothesized that suppression of constitutive activity by an inverse agonist could stimulate these transduction pathways. We show here that the H3 inverse agonist thioperamide increases histamine synthesis in rat brain cortical slices independently from the amounts of extracellular histamine. Thioperamide effects were mimicked by the inverse agonists clobenpropit and A-331440, but not by the neutral antagonist VUF-5681. In contrast, coincubation with VUF-5681 suppressed thioperamide effects. The effects of thioperamide were completely blocked by the PKA inhibitor peptide myristoyl-PKI14-22, a peptide that did not block depolarization stimulation of histamine synthesis. In addition, thioperamide effects required depolarization and were impaired by blockade of N-type calcium channels (mediating depolarization), but not by CaMKII inhibition. These results indicate that constitutive activity of H3 receptors in rat brain cortex inhibits the adenylate cyclase/PKA pathway, and perhaps also the opening of N-type voltage sensitive calcium channels, but apparently not CaMKII.