H2 Agonist Research Articles

A qualitative model for the histamine H3 receptor explaining agonistic and antagonistic activity simultaneously.

A pharmacophore model for histamine H3 ligands is derived that reveals the putative interaction of both H3 agonists and antagonists with an aspartate residue of the receptor. This interaction is determined by applying the density functional theory implemented in a program package adapted for parallel computers. The model reveals a molecular determinant explaining efficacy as the conformation of the aspartic acid residue differs according to whether it is binding to agonists or antagonists. The differences in structure-activity relationships (SAR) observed for the lipophilic tails of different classes of H3 antagonists are now explained, since the model reveals two distinct lipophilic pockets available for antagonist binding.

Characterization of histamine H3 receptors in mouse brain using the H3 antagonist [125I]iodophenpropit.

We have characterized the binding of the histamine H3 receptor antagonist [125I]iodophenpropit to mouse brain. [125I]Iodophenpropit saturably bound to mouse brain membranes with a pKd-value of 9.31+/-0.04 nM and a receptor binding density of 290+/-8 fmol per mg protein. Saturation binding analysis revealed binding of [125I]iodophenpropit to a single class of sites, showing linear Scatchard plots and Hill coefficients not different from unity (nH=0.98+/-0.02). At a concentration of 0.25 nM [125I]iodophenpropit, specific binding represented about 75% of the total binding. Competition binding curves for H3 receptor antagonists were fitted best to a one-site model, showing pKi-values in general accordance with the pA2-values obtained in mouse cerebral cortex. Displacement of [125I]iodophenpropit by the H3 receptor agonists (R)-alpha-methylhistamine, immepip, imetit and histamine were fitted best to a two-site model. Competition binding curves of (R)-alpha-methylhistamine showed a rightward shift upon incubation with GTPgammaS (10 microM), indicating the involvement of G-proteins in H3 agonist binding. In contrast, competition binding curves of the antagonists iodophenpropit, thioperamide and burimamide were not affected by GTPgammaS (10 microM). Autoradiographic experiments showed that [125I]iodophenpropit binding sites were heterogeneously distributed, similarly to the distribution of histamine H3 receptors reported in rat brain. Highest densities were observed in the cerebral cortex, the striatum, the nucleus accumbens, the globus pallidus and the substantia nigra. In conclusion, we have demonstrated that in mouse brain, [125I]iodophenpropit selectively binds to histamine H3 receptors. We also observed that the mouse brain H3 receptors labelled by [125I]iodophenpropit displayed binding characteristics and a distribution similar to rat brain.

Histamine and H2 agonist amthamine increase oxidative burst activity of human leukocytes determined by flow cytometry.

Histamine and H2 agonist amthamine increase oxidative burst activity of human leukocytes determined by flow cytometry.

Histamine Induces Melanogenesis and Morphologic Changes by Protein Kinase A Activation via H2 Receptors in Human Normal Melanocytes

Hyperpigmentation frequently accompanies chronic or acute inflammation. A number of inflammatory mediators have been shown to stimulate melanin synthesis in human melanocytes. Although histamine is ubiquitous as an inflammatory factor, its involvement in pigmentation remains obscure. In this work, we examined the effects of histamine on cultured human melanocytes. Treatment of human melanocytes with 0.1-10 microM histamine evoked morphologic changes and increases in tyrosinase activity. The concomitant increases in melanin content of the histamine-treated melanocytes indicated an elevation of melanin synthesis by tyrosinase activation. These stimulatory effects of histamine were completely inhibited by an H2 antagonist, famotidine, whereas H1 and H3 antagonists had no inhibitory effect whatsoever. In addition, an H2 agonist, dimaprit, induced the same degree of melanogenesis as histamine at concentrations of 0.1-10 microM. We observed an increase in the intracellular cAMP contents of human melanocytes induced by histamine via the H2 receptors. We know that this cAMP accumulation and subsequent protein kinase A activation plays a critical role in histamine-induced melanogenesis, because a specific protein kinase A inhibitor, H-89, completely suppressed these stimulatory effects of histamine, and because dibutylic cAMP, a specific protein kinase A activator, stimulated human melanocytes as potently as histamine. Taken together, we show here that histamine induces melanogenesis of human cultured melanocytes by protein kinase A activation via H2 receptors.

Pharmacology and quantitative structure-activity relationships of imidazolylpropylguanidines with mepyramine-like substructures as non-peptide neuropeptide Y Y<sub>1</sub> receptor antagonists

The design of non-peptide, Y1-selective antagonists of neuropeptide Y (NPY) as pharmacological tools is in progress and is increasingly important as therapeutic applications are expected. Starting from the potent histamine H2 agonist and weak NPY Y1 antagonist arpromidine, 16 imidazolylpropylguanidine derivatives were synthesized and tested for Y1 antagonistic activity (inhibition of NPY-stimulated Ca2+ increase in human erythroleukemic cells), where the pheniramine-like moiety of arpromidine was replaced with 2-pyridylaminoalkyl, benzyl-(2-pyridyl)aminoalkyl, and phenyl-(2-pyridyl)alkylaminoalkyl partial structures derived from mepyramine. The pA2 values of the most active compounds are in the range of 6.2-6.5. Quantitative structure-activity relationships (QSAR) were investigated by fragment regression analysis. Results indicate that a tetramethylene spacer between the guanidino group and the amino nitrogen is optimal. For an at least moderate degree of Y1 antagonistic activity, a second benzyl or phenyl group must be present in addition to the 2-pyridyl ring. At this second group, hydrophobic substituents such as 3,4-di-CI and 4-Br further enhance Y1 antagonism. The most active derivative additionally bears a 5-Br substituent at the 2-pyridyl moiety. Structure-activity relationships suggest that the compounds might be able to partially imitate the role of NPY when interacting with Y1 receptors and thus behave as moderate non-peptide NPY Y1 antagonists.

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H3 histamine receptors

To investigate whether histaminergic neurons influence the activity of cholinergic neurons, the ventral striatum was superfused through a push-pull cannula and the release of endogenous acetylcholine was determined in the superfusate. Local inhibition of histamine synthesis by superfusion with alpha-fluoromethylhistidine (FMH) gradually decreased the release rate of acetylcholine. Superfusion with histamine increased the release of acetylcholine. The releasing effect of histamine was greatly inhibited when the striatum was simultaneously superfused with the D2/D3 agonist quinpirole and the D1 antagonist (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-3-benzapine (SKF 83566). The effect of histamine on acetylcholine release was abolished by the GABA(A) receptor antagonist bicuculline. Superfusion with the H3 receptor agonists imetit or immepip increased acetylcholine release rate in the striatum. The releasing effects of the two H3 agonists were FMH resistant, while superfusion with quinpirole and SKF 83566 abolished the H3 receptor agonist-induced acetylcholine release. Superfusion with the H3 receptor antagonist thioperamide enhanced acetylcholine release rate. The releasing effect of thioperamide was abolished after inhibition of histamine synthesis by FMH. The release of acetylcholine by thioperamide was also abolished on simultaneous superfusion with quinpirole and SKF 83566. The findings show that, in the striatum, the activity of cholinergic neurons is permanently modulated by neighbouring histaminergic nerve terminals and axons. The release of acetylcholine is also permanently inhibited by neighbouring GABAergic neurons. The enhanced release of acetylcholine by the H3 receptor agonists imetit and immepip is due to stimulation of H3 heteroreceptors, while the increase of acetylcholine release by the H3 receptor antagonist thioperamide is elicited via blockade of H3 autoreceptors. Histamine released from histaminergic nerve terminals increases the release of acetylcholine in part by inhibition of dopamine release which, in turn, decreases GABAergic transmission. A dopamine-independent way seems also to be involved in the histamine-evoked acetylcholine release.

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H1 and H2 histamine receptors.

To investigate whether H1 and H2 histamine receptors are implicated in the modulation of acetylcholine release by endogenous histamine, the ventral striatum of the conscious, freely moving rat was superfused by the push-pull superfusion technique with drugs and the release of acetylcholine was determined in the superfusate. Superfusion with the H1 receptor agonist 2-thiazolylethylamine (TEA, 50 micromol/l) enhanced the release of acetylcholine, while the H1 receptor antagonist triprolidine (50 micromol/l) reduced acetylcholine outflow and abolished the TEA-evoked release of the neurotransmitter. The inhibitory effect of triprolidine was not influenced either on simultaneous superfusion with 10 micromol/l (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-benzazepine (SKF-83566, D1 dopamine receptor antagonist) and 50 micromol/l quinpirole (D2/D3 dopamine receptor agonist) or on superfusion with the GABAA receptor antagonist bicuculline (50 micromol/l). The H2 receptor antagonists ranitidine or famotidine (50 micromol/l each) greatly enhanced acetylcholine release rate in the ventral striatum. Presuperfusion with alpha-fluoromethylhistidine (FMH, 1 mmol/l), which inhibits neuronal synthesis of histamine, abolished the famotidine-induced release of acetylcholine. The releasing effect of famotidine was also abolished on simultaneous superfusion with 10 micromol/l SKF-83566 and 50 micromol/l quinpirole. The release of acetylcholine elicited by famotidine was reversed to a decreased acetylcholine outflow when the striatum was superfused with the GABA(A) receptor antagonist bicuculline (50 micromol/l) prior to famotidine. Superfusion with the H2 receptor agonist impromidine (1 micromol/l) decreased acetylcholine outflow, while the H2 agonist dimaprit (50 micromol/l) exerted the opposite effect. The releasing effect of dimaprit was not influenced by FMH (1 mmol/l), but it was abolished in the presence of SKF-83566 (10 micromol/l) and quinpirole (50 micromol/l). In the presence of bicuculline the release of acetylcholine by dimaprit was enhanced and prolonged. It seems possible that dimaprit and impromidine stimulate different subtypes of H2 receptors. The findings suggest that the release of acetylcholine in the striatum is modulated by neighbouring histaminergic neurons in a complex way. Stimulation of H1 histamine receptors, probably located on cholinergic neurons, enhances acetylcholine release. Stimulation by histamine of H2 receptors located on cholinergic or GABAergic neurons enhances the release of acetylcholine, while stimulation of H2 receptors located on dopaminergic neurons exerts the opposite effect.

Binding ability of impromidine, a potent H2 agonist of histamine

Impromidine (fig.1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. The present work deals with the study of coordination equilibria between impromidine and Cu(II) and Ni(II) in aqueous solution at 25 ○C. Potentiometric, UV-Visible and EPR studies on Cu(II) complexes with impromidine have shown that this anti-ulcerogenic drug is a very potent chelating agent. This drug is found to be a very effective ligand for Ni(II) ions also. The effective coordination of impromidine to metal ions may have significant biological implications.

Betahistine increases vestibular blood flow

Betahistine is used for treatment of several vestibular disorders. Despite the accepted use of this histamine-like substance, its mechanism of action is not well understood. The purpose of this study was to assess the possibility that one of the activities of betahistine is increasing blood flow in the peripheral vestibular end organs. Using a novel surgical approach, we identified the posterior semicircular canal ampulla of guinea pigs and placed a laser Doppler probe in position to obtain blood flow measurements from the posterior semicircular canal ampulla. Blood pressure, heart rate, and vestibular blood flow were continuously recorded. Concentration-response curves were obtained for betahistine (2.5, 5, 7.5, and 10 mg/kg) and control-vehicle (0.15 mol/L NaCl) infusions. A separate group of subjects was pretreated with the competitive selective H3 agonist, thioperimide maleate, before betahistine treatment. Increases in vestibular blood flow and decreases in blood pressure were observed in response to betahistine infusions. Pretreatment with thioperamide maleate abolished these changes at low doses of betahistine and attenuated the responses at higher doses of betahistine. These results show that betahistine administration induces increases in vestibular blood flow. These findings support the potential use of betahistine for treatment of vestibular disorders, which may be caused by compromised circulation. (Otolaryngol Head Neck Surg 1999;120:400-5.)

Effects of histamine and related compounds on regional cerebral blood flow in rats

The effects of histamine and related compounds on regional cerebral blood flow (rCBF) in the hippocampus of conscious rats were studied. Intracerebroventricular injection of histamine caused a dose-dependent increase in rCBF in the hippocampus, and similar findings were observed with not only the H1 agonist, 2-thiazolylethylamine, but also the H2 agonist, dimaprit. Intraperitoneal injection of L-histidine also resulted in an increase in rCBF in the hippocampus, in parallel with elevation of histamine content in the brain. The increase in rCBF in the hippocampus induced by L-histidine was antagonized by both H1 and H2 antagonists (diphenhydramine, pyrilamine and zolantidine). In addition, when both antagonists were injected simultaneously, an additive effect was observed in antagonism of the L-histidine-induced increase in rCBF. L-Histidine caused no marked changes in blood pressure even at a dose of 1,500 mg/kg, which showed an increase in rCBF in the hippocampus. These results indicate that histamine elicited an increase in rCBF via both H1 and H2 receptors.

P–56 - Imifuramine; a novel histamine H3 agonist based on imidazole C-nucIeoside.

P–56 - Imifuramine; a novel histamine H3 agonist based on imidazole C-nucIeoside.

Effect of histamine H2 and H3 receptor modulation in the septum on post-training memory processing.

We compared the effects of modulating the postsynaptic histamine receptor subtype 2 (H2) and inhibitory presynaptic autoreceptor subtype 3 (H3) on memory processing in the septum. Mice were partially trained on footshock avoidance in a T-maze. Immediately after training, saline or a drug solution was infused into the septum. One week later, retention was tested by continuing training until the mice made five avoidance responses in six consecutive trials. The results indicate that dimaprit, an H2 agonist, facilitated retention (25 and 50 pg) with a U-shaped dose-response curve typical of drugs acting at postsynaptic receptors. Cimetidine, an H2 antagonist, impaired retention (15-50 ng). The H3 agonist. imetit, impaired retention (25-200 ng), while the H3 antagonist, thioperamide, facilitated retention (10-400 ng). An unusual feature of the dose-response curve for thioperamide was that it did not appeal to yield a U-shaped curve as occurs with drugs acting postsynaptically, but facilitated retention to approximately the same degree from 50 to 400 ng. As histamine neurons project to various limbic system structures involved in memory processing, it may play an important role in regulating the activity of structures such as the septum, hippocampus and amygdala.

Histamine stimulates ion transport by dog pancreatic duct epithelial cells through H1 receptors.

Histamine affects pancreatic secretion, but its direct action on ion transport by pancreatic duct epithelial cells (PDEC) has not been defined. We now characterize the secretory effects of histamine on cultured, well-differentiated, and nontransformed dog PDEC. Histamine stimulated, in a concentration-dependent manner (1-100 microM), a cellular 125I- efflux that was inhibited by 500 microM 5-nitro-2-(3-phenylpropylamino)benzoic acid, 2.5 mM diphenylamine-2-carboxylate, and 500 microM DIDS and thus mediated through Ca2+-activated Cl- channels. Histamine-stimulated 125I- efflux was 1) inhibited by 100 microM diphenhydramine, an H1 receptor antagonist, 2) resistant to 1 mM cimetidine, an H2 receptor antagonist, 3) not reproduced by 1 mM dimaprit, an H2 agonist, and 4) inhibited by 50 microM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM, a Ca2+ chelator, suggesting that it was mediated through H1 receptors acting via increased cytosolic Ca2+. Histamine also stimulated a 86Rb+ efflux that was sensitive to 100 nM charybdotoxin and thus mediated through Ca2+-activated K+ channels. When PDEC monolayers were studied in Ussing chambers, a short-circuit current of 21.7 +/- 3.1 microA/cm2 was stimulated by 100 microM histamine. This effect was inhibited by diphenhydramine but not cimetidine, was not reproduced with dimaprit, and was observed only after serosal addition of histamine, suggesting that it was mediated by basolateral H1 receptors on PDEC. In conclusion, histamine, acting through basolateral H1 receptors, activates both Ca2+-activated Cl- and K+ channels; in this manner, it may regulate PDEC secretion in normal or inflamed pancreas.

Neutrophil adhesion to histamine stimulated cultured endothelial cells is primarily mediated via activation of phospholipase C and nitric oxide synthase isozymes.

In order to understand the underlying mechanism of histamine stimulated inflammatory responses, histamine receptor subtypes and signal transduction pathways by which histamine mediates the stimulation of neutrophil adhesion to endothelial cells has been studied in vitro. Human neutrophils and human umbilical vein endothelial cells. Confluent human endothelial cell layer were incubated with histamine (1 mM), H1, H2 or H3 receptor agonists: fluorophenylhistamine (10 microM), amthamine (10 microm), methylhistamine (10 microM), respectively. Ten minutes prior to histamine (1 mM) stimulation H1, H2 or H3 receptor antagonists (dimethindene, 100 microM; famotidine, 1OO microM, thioperamid 100 microM, respectively) were added. Histamine stimulated signal transduction pathways were inhibited by adding phospholipase C inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamat (200 microM), adenylate cyclase inhibitor 9-(2 tetrahydrofuryl)adenine (80 microM), nitric oxide synthase isozymes inhibitor S-ethylisothiourea (1 microM) or guanylate cyclase inhibitor (LY 83583; 10 microM). Neutrophil adhesion was monitored at 30, 60, 90, 120, 150, 180 and 210 min. Neutrophil adhesion to endothelial cells was quantified by analysing alkaline phosphatase activity. Histamine stimulation of endothelial cells resulted in a biphasic time and concentration dependent pattern of neutrophil adhesion. This pattern of neutrophil adhesion was mimicked by stimulation of endothelial cells with H1 or H2 agonists. Stimulation of endothelial cells with an H3 agonist had no effect on neutrophil binding. Inhibition of phospholipase C (PLC), nitric oxide synthase isozymes (NOS) or guanylate cyclase (GC) resulted in a significant decrease of neutrophil binding to histamine or agonist stimulated endothelial cells. An increase of neutrophil binding to unstimulated or to agonist stimulated endothelial cells was observed during inhibition of adenylate cyclase. Our results suggest that histamine stimulated neutrophil adhesion is due to H1 and H2 receptor mediated activation of PLC, NOS and GC. Increase of cAMP concentration seems to mediate an inhibitory effect on PMN adhesion to endothelial cells.

Regulation of interleukin-6, and macrophage colony-stimulating factor mRNA levels by histamine in stromal cell line (MC3T3-G2/PA6).

The aim of this study was to examine the role of histamine in regulation of IL-6 and M-CSF gene expression in bone marrow stromal cells. Total cellular synthesis was also estimated for IL-6. The effects of the amine were evaluated using the stromal cell line, MC3T3-G2/PA6 (PA6). Histamine caused a distinct accumulation of IL-6 mRNA in the cells, whereas it decreased M-CSF transcripts. Both pyridylethylamine, a H1 agonist, and dimaprit, a H2 agonist, caused a large increase in the level of IL-6 mRNA in PA6 cells. The histamine-induced expression of IL-6 mRNA was associated with enhanced secretion of IL-6, as determined by ELISA. These results, together with the results of our previous studies, suggest that histamine produced by stromal macrophages differentially regulates the production of IL-6 and M-CSF in other kinds of stromal cells and hence promotes differentiation and/or proliferation of hematopoietic progenitor cells.

Antidepressant-like effects of endogenous histamine and of two histamine H1 receptor agonists in the mouse forced swim test.

1. Effects of substances which are able to alter brain histamine levels and two histamine H1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test. 2. Imipramine (10 and 30 mg kg(-1), i.p.) and amitriptyline (5 and 15 mg kg(-1), i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H3 receptor agonist, (R)-alpha-methylhistamine, at a dose (10 mg kg(-1), i.p.) which did not modify the cumulative time of immobility. 3. The histamine H3 receptor antagonist, thioperamide (2-20 mg kg(-1), s.c.), showed an antidepressant-like effect, with a maximum at the dose of 5 mg kg(-1), which was completely prevented by (R)-alpha-methylhistamine. 4. The histamine-N-methyltransferase inhibitor, metoprine (2-20 mg kg(-1), s.c.), was effective with an ED50 of 4.02 (2.71-5.96) mg kg(-1); its effect was prevented by (R)-alpha-methylhistamine. 5. The histamine precursor, L-histidine (100-1000 mg kg(-1), i.p.), dose-dependently decreased the time of immobility [ED30 587 (499-712) mg kg(-1)]. The effect of 500 mg kg(-1) L-histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)-alpha-fluoromethylhistidine (50 mg kg(-1), i.p.), administered 15 h before. 6. The highly selective histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl)histamine (0.3-6.5 microg per mouse, i.c.v.), and the better known H1 agonist, 2-thiazolylethylamine (0.1-1 microg per mouse, i.c.v.), were both dose-dependently effective in decreasing the time of immobility [ED50 3.6 (1.53-8.48) and 1.34 (0.084-21.5) microg per mouse, respectively]. 7. None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test. 8. It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant-like effect, via activation of H1 receptors.

The vascular mechanism of action of betahistine in the inner ear of the guinea pig.

The aim of this study was to investigate the mechanism and site of action of betahistine dihydrochloride in the inner ear of the guinea pig. Betahistine-evoked increases in cochlear blood flow (CBF) have been presumed to be due to the drug effect on the later wall capillary bed or larger feeding vessels in the cochlea vascular system. As such, the mechanism of action could be due to inhibition of H3 receptors. Betahistine may also have a direct effect on postsynaptic H1/H2 receptors and/or an effect modulated by other autonomic receptors. Betahistine-evoked CBF responses were assessed by laser Doppler flowmetry in the presence of an H3 agonist (alpha N-methyl-histamine dihydrochloride), an H3 antagonist (thioperamide), an H2 antagonist (cimetidine) or an alpha 2 antagonist (idazoxan). The effects of betahistine on circulation in the anterior inferior cerebellar artery (AICA) and ipsilateral stria vascularis (SV) were assessed using intravital microscopy (IVM). Findings showed that betahistine increased CBF and reduced systemic blood pressure (BP). In contrast, alpha N-methylhistamine dihydrochloride had no effect on baseline CBF or BP and did not influence betahistine-induced increases in CBF. Thioperamide reversed the effects of betahistine on CBF, but had no effect on baseline CBF or BP. Cimetidine had no marked effect on baseline CBF or betahistine-induced increases in CBF Idazoxan had no consistent effects on baseline CBF, but abolished the effect of betahistine on CBF. The mean increase of red blood cell velocity in SV capillaries was 15% and occurred without a demonstrable change in capillary diameters. In contrast, the diameter of the AICA increased by 17-20%, indicating that betahistine-evoked increases in CBF resulted primarily from vasodilatation of the AICA. We suggest that this effect may be mediated via presynaptic H3 heteroreceptors and autonomic alpha 2 receptors.

Trans-4-methyl-3-imidazoyl pyrrolidine as a potent, highly selective histamine H3 receptor agonist in vivo.

Extensive structural modification of immepyr (+)-2 led to the discovery of trans-4-methyl-3-imidazoyl pyrrolidine (+/-)-3a as a potent and highly selective H3 agonist. The pyrroline (+/-)-3a was resolved, and its (+) enantiomer, Sch 50971 [(+)-3a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 330) than (R)-alpha-methylhistamine (+)-1 (H3/H1 ratio = 17), the standard H3 agonist.

Effects of newly synthesized amino acids containing thiazole residues on electrically evoked smooth muscle contractions

New amino acids containing thiazole residues have been synthesized and in vitro experiments were performed to study their action on neurotransmission in target tissues with adrenergic and cholinergic neurotransmission. Acetaminothiazoles, structurally related to the novel class, are known to act as H1 agonists, therefore, the effects of the newly synthesized Ala- and Pro-thiazole derivatives on smooth muscle contractile activity were compared to those of histamine (HA). The experiments were carried out on electrically stimulated prostatic part of rat and rabbit vasa deferentia and proximal guinea pig ileum. HA had biphasic effect on electrically evoked neurogenic contractions of guinea pig ileum, Pro(Thz) had a stimulating effect, while Ala(Thz) had no effect. The histamine H1-receptor antagonist diphenhydramine inhibited the Pro(Thz)-induced spontaneous contractile activity in the longitudinal layer of guinea pig ileum. HA had a biphasic effect on electrically induced neurogenic contractions of rat and rabbit vasa deferentia while Pro(Thz) and Ala(Thz) inhibited the ES-contractions. The present results show that the newly synthesized compounds might affect the electrically evoked smooth muscle contractions. Some similarity in the effects of HA and of the new substances was observed.

Histaminergic ligands attenuate barrel rotation in rats following unilateral labyrinthectomy

In this paper we present a unilateral labyrinthectomy (UL) surgical procedure in rats that was derived from previous techniques. The utility of this model to assess vestibular dysfunction was evaluated by examining the ability of clinically used histaminergic agents and more selective H3 receptor antagonists to attenuate of UL-induced body rotations. Unilateral labyrinthectomy was performed by injection of ethanol into the rat right inner ear. An elevated body rotation test (EBRT) was used to assess the abnormal rotational behavior induced by UL. Scores of "3" to "0" were used to characterize the degree of abnormal behavior according to the latency of body rotations to begin. Our results demonstrate that: i) 100 microliters ethanol induced robust behavioral changes, which was used in further experiments; ii) the clinically used antivertigo agent, astemizole, significantly reduced the rotational behavior in UL rats; iii) the more potent H3 antagonists, thioperamide and GT-2016, were more efficacious than betahistine, a mixed H3 antagonist and H1 agonist. These results indicate that this model may be a potential tool for testing novel drugs for antivertigo effects and provide better support to the role of the histaminergic system in the control of vestibular function.