Effects of impromidine- and arpromidine-derived guanidines on recombinant human and guinea pig histamine H1 and H2 receptors.

Imidazolylpropylguanidines derived from impromidine and arpromidine are more potent and efficacious agonists at the guinea pig histamine H2 receptor (gpH2R) than at the human H2R (hH2R) in the GTPase assay. Additionally, such guanidines are histamine H1 receptor (H1R) antagonists with preference for the human relative to the guinea pig receptor. The purpose of this study was to examine structure-activity relationships of guanidines at human and guinea pig H1R and H2R species isoforms expressed in Sf9 insect cells. Three impromidine analogues and six arpromidine analogues exhibited agonistic activity at H2R and antagonistic activity at H1R as assessed in the steady-state GTPase assay. Species selectivity of derivatives was similar as compared with the parent compounds. None of the structural modifications examined (different aromatic ring systems and different ring substituents) was superior in terms of H2R potency and efficacy relative to impromidine and arpromidine, respectively. These data point to substantial structural constraints at the agonist binding site of H2R. Guanidines exhibited distinct structure-activity relationships for H1R antagonism in a radioligand competition binding assay and the GTPase assay and for H1R inverse agonism. Our data indicate that it is difficult to obtain guanidine-type agonists with high potency and high efficacy for hH2R, but those compounds may be useful tools for exploring the antagonist binding site and constitutive activity of H1R.

Intraluminal acid and gastric mucosal integrity: the importance of blood-borne bicarbonate.

The acid-secreting gastric mucosa resists intraluminal acid better than the nonsecreting. Here we investigated pH at the epithelial cell surface, mucosal permeability, and blood flow during intraluminal administration of acid (100 mM) in acid-stimulated and nonstimulated gastric corpus mucosae. Surface pH (H(+)-selective microelectrodes), permeability (clearance of (51)Cr-EDTA), and mucosal blood flow (laser-Doppler flowmetry) were studied in Inactin-anesthetized rats. Acid secretion was stimulated with pentagastrin (40 microg. kg(-1). h(-1)) or impromidine (500 microg. kg(-1). h(-1)), or HCO(3)(-) (5 mmol. kg(-1). h(-1)) given intravenously. Surface pH was only slightly reduced by intraluminal acid in acid secretion-stimulated or HCO(3)(-)-treated rats but was substantially lowered in nonstimulated rats. Clearance increased threefold and blood flow increased by approximately 75% in nonstimulated rats. During stimulated acid secretion or intravenous infusion of HCO(3)(-), clearance was unchanged and blood flow increased by only approximately 30% during intraluminal acid. Increased epithelial transport of HCO(3)(-) buffering the mucus gel is most probably the explanation for the acid-secreting mucosa being less vulnerable to intraluminal acid than the nonsecreting.

Effects of histamine and related compounds on the differentiation of HL-60-Eo cells into eosinophils.

The effects of histamine and related compounds on the differentiation of HL-60-Eo cells into eosinophils were studied. The histamine and H2 agonists impromidine and 4-methylhistamine caused concentration-related increases in the number of differentiated cells. On the other hand, the H1 agonists 2-methylhistamine and 2-pyndylethylamine showed no such effect. Histamine-induced eosinophil differentiation was antagonized by the H2 antagonists cimetidine and ranitidine. Histamine and H2 agonists inhibited (3H)-thymidine uptake, suggesting that these compounds caused a decrease in proliferation. Histamine as well as the H2 agonists impromidine and 4-methythistamine caused increases in cAMP level, and this effect was antagonized by ranitidine. From these findings, we concluded that both the differentiation of HL-60-Eo cells into eosinophils and proliferation of HL-60-Eo cells were mediated via H2 receptors.

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.

Histamine receptor-independent muscle relaxation elicited by a series of histamine H2-receptor agonists on the isolated guinea pig duodenum: a study into the mechanism of action.

1. The histamine H2 receptor agonists, dimaprit, impromidine, amthamine, and several dimaprit- and impromidine-analogues were investigated for their spasmolytic activity on the guinea pig duodenum, precontracted with acetylcholine or KCl. 2. Almost all the H2 receptor agonists exerted a histamine H2 receptor-independent muscle relaxation, which was more evident on acetylcholine- than on KCl-precontracted preparations. 3. The relaxing activity of these compounds was independent of inhibitory receptors, like beta-adrenergic, GABA-ergic, serotoninergic, etc. Similarly, modifications of cyclic nucleotide metabolism and nitric oxide production did not appear to be involved. 4. The behavior of histamine H2-receptor agonists was shared only by the Na+-blocker procaine, the intracellular Ca2+-antagonist ruthenium red and, at least in terms of efficacy, by the protein kinase C inhibitor, chelerithrine. 5. This spasmolytic effect is probably due to an impairment of receptor-mediated depolarization at the plasma membrane level and/or an inhibitory activity on the protein kinase C-dependent activation of the contractile machinery. 6. Finally, our findings suggest that the histamine H2 receptor-independent muscle relaxation is a general feature shown by H2 receptor agonists endowed with different chemical structure and the putative spasmolytic "receptor" prefers a (substituted) thiazole over a (substituted) imidazole.

Histamine affects interleukin-4, interleukin-5, and interferon-gamma production by human T cell clones from the airways and blood.

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.

Histamine increases the bursting activity of pyramidal cells in the CA3 region of mouse hippocampus.

An excitatory action of histamine was investigated by intracellular recording in the CA3 region of hippocampal slices. Bath application of histamine or impromidine, a H2 receptor agonist, had the following effects: (1) a depolarisation in 60% and no changes in membrane potential in 40% of the CA3 pyramids; (2) single cell firing and burst activity were evoked or more than doubled when spontaneously present; (3) the bursts were prolonged and often followed by afterdischarges instead of the normal afterhyperpolarisations (AHPs); (4) synaptic stimulation evoked large bursts instead of excitatory synaptic potentials (EPSPs) and primary burst responses became prolonged. CA3 bursts may play a decisive role in memory trace formation, their facilitation and potentiation is in keeping with a positive role of the histaminergic system in attention and learning.

Effects of different subtypes of histamine receptors on proliferation and differentiation of murine colony forming unit granulocyte-macrophage and colony forming unit megakaryocyte.

OBJECTIVE: To investigate the function and characteristics of histamine receptors on the hemopoietic progenitor cells. METHODS: BDF1 mice (both male and female), inbred at our university, aged 8-12 weeks, weighing 20-24 g, were used in this study. Bone marrow cells were incubated for 1 hour at 37 degrees C with 2-AT (H1 receptor agonist) or impromidine (H2 receptor agonist) alone, or in combination with the antagonists pyrilamine or cimetidine respectively. Control experiment was performed in Dulbecco's modified Eagle's Medium (DMEM) alone. Cells treated with different drugs were performed by colony forming unit-granulocyte-macrophage (CFU-GM) and colony forming unit-megakaryocyte (CFU-Meg) assay. RESULTS: When bone marrow cells were treated with 10(-8) mol/L to 10(-5) mol/L of 2-thiazolylethylamine (2-AT) which had no influence on CFU-GM and CFU-Meg proliferation, 10(-8) mol/L to 10(-5) mol/L of impromidine could increase the number of CFU-GM and CFU-Meg colonies. The effects of H2 receptor agonists on CFU-GM, CFU-Meg could be antagonized by H1 receptor agonist. CONCLUSIONS: Our findings suggest the existence of histamine H1 and H2 receptors on the hemopoietic progenitor cells and the antagonism between two different histamine receptor subtypes on the proliferation of CFU-GM and CFU-Meg.

Histamine H1 receptor activation blocks two classes of potassium current, IK(rest) and IAHP, to excite ferret vagal afferents.

1. Intracellular recordings were made in intact and acutely dissociated vagal afferent neurones (nodose ganglion cells) of the ferret to investigate the membrane effects of histamine. 2. In current-clamp or voltage-clamp recordings, histamine (10 microM) depolarized the membrane potential (10 +/- 0.8 mV; mean +/- S.E.M.; n = 27) or produced an inward current of 1.6 +/- 0.35 nA (n = 27) in approximately 80% of the neurones. 3. Histamine (10 microM) also blocked the post-spike slow after-hyperpolarization (AHP slow) present in 80% of these neurones (95 +/- 3.2%; n = 5). All neurones possessing AHPslow in ferret nodose were C fibre neurones; all AHPslow neurones had conduction velocities < or = 1 m s-1 (n = 7). 4. Both the histamine-induced inward current and the block of AHPslow were concentration dependent and each had an estimated EC50 value of 2 microM. These histamine-induced effects were mimicked by the histamine H1 receptor agonist 2-(2-aminoethyl) thiazole dihydrochloride (10 microM) and blocked by the H1 antagonists pyrilamine (100 nM) or diphenhydramine (100 nM). Schild plot analysis of the effect of pyrilamine on the histamine-induced inward current revealed a pA2 value of 9.7, consistent with that expected for an H1 receptor. Neither impromidine (10 microM) nor R(-)-alpha-methylhistamine (10 microM), selective H2 or H3 agonists, respectively, significantly affected the membrane potential, input resistance or AHPslow. 5. The reversal potential (Vrev) for the histamine-induced inward current was -84 +/- 2.1 mV (n = 4). The Vrev for the histamine response shifted in a Nernstian manner with changes in the extracellular potassium concentration. Alterations in the extracellular chloride concentration had no significant effect on the Vrev of the histamine response (n = 3). The Vrev for the AHPslow was -85 +/- 1.7 mV (n = 4). 6. These results indicate that histamine increases the excitability of ferret vagal afferent somata by interfering with two classes of potassium current: the resting or 'leak' potassium current (IK(rest)) and the potassium current underlying a post-spike slow after-hyperpolarization (IAHP). Both these effects can occur in the same neurone and involve activation of the same histamine receptor subtype, the histamine H1 receptor.

Characterization of histamine receptors in the ureter of the dog.

We investigated the effects of histamine on the motility of isolated segments from canine ureters and characterized pharmacologically the histamine receptors involved. We also evaluated the effects of various autacoids (5-HT, carbachol, noradrenaline, thromboxane, prostaglandin F2alpha) on the motility of canine ureters. Histamine as well as the H1 receptor agonist 2-(2-pyridyl)ethylamine elicited a concentration-dependent contraction. This contractile response was antagonized by dimethindene, causing a rightward shift (pA2 8.30) and a reduction of the slope and the maximal effect (pD'2 6.01) of the concentration-response curve. The histamine H2 receptor antagonist cimetidine in a concentration of 10(-5) mol/l was ineffective concerning the concentration-response curve for histamine. After precontraction of the ureter segments (5-HT, carbachol, prostaglandin F2alpha), a concentration-dependent relaxant effect was evaluated in the presence of histamine or the histamine H2 receptor agonist impromidine. The histamine H2 receptor antagonist cimetidine attenuated the relaxant response, causing a rightward shift of the concentration-response curve. All autacoids except thromboxane were capable of increasing contractility in canine ureters. Comparing the absolute contractile force in the presence of prostaglandin F2alpha, 5-HT, carbachol, noradrenaline and potassium, we found that histamine exhibits the most marked effect on this parameter in the canine ureter. It is concluded that there are two types of histamine receptors modulating contractile activity in the canine ureter: histamine H1 receptors, which mediate contraction, and histamine H2 receptors, which mediate relaxation (in the precontracted tissue).

Changes in cardiovascular responsiveness to dopexamine and beta 1- and beta 2-adrenoceptor function after the chronic treatment of beta-adrenoceptor antagonists and agonists in anaesthetized dogs.

1. The studies were designed to investigate the changes in responsiveness to beta-adrenoceptor agonists induced by chronic administration of beta-adrenoceptor antagonists and agonists. 2. Dose-response curves for dopexamine, isoprenaline, noradrenaline and impromidine on heart rate, blood pressure and myocardial contractility (dP/dt:integrated isometric tension) were obtained in untreated dogs and compared to those measured in dogs which had been pretreated with propranolol (8 mg kg-1 day-1), atenolol (6 mg kg-1 day-1), isoprenaline (0.5 microgram kg-1 min-1) or noradrenaline (0.5 microgram kg-1 min-1) for 14 days. 3. Propranolol pretreatment significantly enhanced the inotropic and chronotropic responses to isoprenaline. There were noticeable, but non-significant increases in inotropic sensitivity to noradrenaline and dopexamine, especially at higher dose levels. In the atenolol treatment group, there were significant increases in inotropic responses to dopexamine and isoprenaline and in depressor responses to isoprenaline. 4. Thus, chronic administration of propranolol increased responses mediated by both beta 1- and beta 2-adrenoceptors, whereas, atenolol selectively enhanced the inotropic responsiveness to dopexamine, which is mediated mainly by beta 2-adrenoceptors. 5. Isoprenaline pretreatment caused a significant decrease in inotropic sensitivity to dopexamine, isoprenaline and noradrenaline and a significant reduction in chronotropic responses to dopexamine. The tendency to reduced depressor responses to isoprenaline and dopexamine failed to reach significance. Pretreatment with noradrenaline decreased only the inotropic response to noradrenaline. 6. Thus, chronic isoprenaline treatment reduced the responsiveness of both beta 1- and beta 2-adrenoceptors, while chronic noradrenaline infusion only reduced beta 1-adrenoceptor-mediated responses. 7. There was no significant change in any of the dose-response curves to impromidine after any beta-adrenoceptor antagonist or agonist treatment. This indicates that there was no non-specific alteration in responsiveness and that the observed changes were likely to be associated with specific alterations in beta-adrenoceptor number or function.

Investigation into the role of histamine receptors in rodent antinociception.

The aim of the present study is to the elucidate the confusion that exists in the literature concerning which receptor subtype is involved in mediating histamine antinociception. To this purpose impromidine 3HCl and burimamide were used. Because both substances have been described to block histamine H3-receptor, and, at higher doses, also to act on the postsynaptic site as agonist and antagonist, respectively, they were administered in a wide range of ICV doses, to distinguish the effects due to action on different receptors. Experiments were performed 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). Both substances showed, at the lowest doses tested, antinociception, which was antagonized by the selective H3-receptor agonist, (R)-alpha-methylhistamine 2HCl (RAMH) (10 mg/kg SC in mice or 0.5 microgram per rat ICV). At higher doses impromidine was antinociceptive while burimamide was hypernociceptive, in accordance with their opposite action on the H2-receptor. It is suggested that the histaminergic system modulates nociception via activation of the H2-receptor.

[The relationship between H2 receptor and the pathogenesis of bronchial asthma in guinea-pigs].

UNLABELLED: H2 receptor (H2R) is one of the three histamine receptor subtypes. In order to explore the relationship between H2R and the pathogenesis of bronchial asthma, we investigated the effects of H2R agonist impromidine on guinea-pig isolated tracheal smooth muscle and the effects of dimaprit on the lung function of guinea-pigs provoked by antigen. RESULTS: (1) Impromidine (10(6) mol/L) relaxed partly the guinea-pig isolated tracheal spirals contricted by histamine challenge. After pretreating the spirals with impromidine, the maximum response to histamine was reduced in a dose-dependent manner and the cumulative dose-response curve to histamine was shifted to right. (2) Dimaprit (3mg/kg) given by intravenous injection protected the lung function from damage caused by antigen. These results suggest that H2R agonist produces relaxation of guinea-pig tracheal smooth muscle and inhibits the release of inflammatory mediators in anaphylactic reaction. We concluded that H2R plays some protective roles in the pathogenesis of bronchial asthma.

[The relationship between H2 receptor of airways and the pathogenesis of bronchial asthma].

In order to explore the relationship between H2 R and the pathogenesis of asthma, we treated 19 stable asthmatic patients with H2-receptor agonist impromidine and observed its effect on bronchial hyperresponsiveness (BHR). The results showed that single dose inhalation of impromidine (2.5mg, in 13 cases) had no effect on the starting respiratory resistance (Rrs) and the minimum amount of cumulative dose (Dmin) to asthmatic airways, while repetitive inhalation of impromidine for 10 days (2. 5mg a day, in 6 cases) decreased the Rrs (P = 0.059) and increased the Dmin significantly (P < 0.05); and that H2R agonist impromidine could reduce the sensitivity of airway to methacholine and improve the BHR of asthmatic patients. The results suggest that H2R agonist may be used as anti-inflammatory drug to treat asthma and H2R may have protective role in the inflammatory reaction of asthmatic airways.

Effect of the histamine-2 agonist impromidine on stem cell proliferation of rat oxyntic mucosa.

BACKGROUND: The trophic effect of gastrin on the histamine-containing enterochromaffin-like cell is pronounced but on the stem cell of the oxyntic mucosa it is only modest. In the rat, gastrin stimulates acid secretion mainly by releasing histamine from enterochromaffin-like cells. This study was designed to test the hypothesis that the trophic effect of gastrin on stem cells is also mediated by histamine released from the enterochromaffin-like cell. METHODS: We stimulated rats with the histamine-2 agonist impromidine. Impromidine, 0.2 mg/h, was given for 2 days by subcutaneously implanted osmotic minipumps, and the trophic effect on stem cells was assessed by incorporation of tritiated thymidine. RESULTS: The plasma gastrin concentrations were 33.9 (9.4) pM and 27.3 (6.0) pM, and the stem cell labelling index values were 5.92 (1.94) and 8.09 (3.78) in the controls and impromidine-stimulated animals, respectively (mean value (SD)). These differences were not statistically significant. CONCLUSION: The present study provides no evidence that histamine-2 receptors mediate a trophic effect on the stem cell of the rat oxyntic mucosa.

Regulation of K+ conductance by histamine H1 and H2 receptors in neurones dissociated from rat neostriatum.

1. The effects of histamine on dissociated neostriatal neurones of the rat were investigated in the whole-cell mode using the nystatin-perforated patch recording technique. 2. Histamine evoked a net inward current accompanied by a decrease in the membrane conductance at a holding potential (Vh) of -44 mV. This response was observed in neurones considered to be interneurones based on morphology, membrane properties and the responsiveness to acetylcholine. 3. A net inward current evoked by 10(-8) to 10(-6) M histamine was inhibited in a concentration-dependent manner by the H1 receptor antagonists, pyrilamine and triprolidine. The H1 receptor agonists, 2-methylhistamine and 2-thiazolylethylamine, mimicked the histamine response, indicating that this response was mediated by the H1 receptor. 4. Histamine, at high concentrations between 10(-6) and 10(-5) M, evoked an additional net inward current with a decrease in the membrane conductance, which was inhibited by the H2 receptor antagonists, cimetidine, ranitidine and famotidine. The H2 receptor agonist, impromidine, partially mimicked the response. Thus, this additional current was considered to be mediated by the H2 receptor. 5. The reversal potentials for H1 and H2 receptor-operated currents shifted 56.9 and 59.3 mV for a 10-fold change in [K+]o, respectively, suggesting that these currents were carried by K+. 6. An analysis of change in current fluctuations mediated by H1 and H2 receptors suggested that the unitary current amplitudes of K+ channels linked to H1 and H2 receptors were 0.29 +/- 0.06 (n = 4) and 0.27 +/- 0.07 pA (n = 4), respectively. There was no significant difference between these values. The estimated mean life times (tau) for both channels were also identical (1.1 ms). 7. It was concluded that histamine reduces K+ currents in neostriatal interneurones and that both H1 and H2 receptors are involved in the response.

Opening of the blood-brain barrier during cortical superfusion with histamine.

Histamine may influence cerebral microcirculation from the intravascular and parenchymal side. The latter route can be simulated by cortical superfusion. The effect of cortical superfusion with histamine (10(-9)-10(-3) M) on blood-brain barrier (BBB) permeability was studied in the cat by measuring extravasation of the tracers Na(+)-fluorescein (MW 376) or fluorescein isothiocyanate (FITC) labelled dextran (MW 62,000 or 145,000) by intravital fluorescence microscopy. Histamine induced an opening of BBB resulting in extravasation of small and large molecular weight tracers with threshold concentrations of 10(-9), 10(-8) and 10(-6) M for Na(+)-fluorescein, FITC-dextran 62,000 and 145,000, respectively. Once tracer extravasation had started the degree of extravasation increased with increasing concentrations of histamine in the superfusion fluid. Similar to histamine the H2 agonist impromidine (3 x 10(-12)-3 x 10(-9) M) induced a concentration dependent extravasation of Na(+)-fluorescein. 2-Pyridylethylamine which is 3-4 times more selective for H1 than for H2 receptors also induced an extravasation of Na(+)-fluorescein. Cortical superfusion with mepyramine (10(-7) M) or cimetidine (10(-4) M), which block the H1 and H2 receptors, respectively, already induced significant extravasation of Na(+)-fluorescein by themselves. These compounds could thus not be used as competitive antagonists to block histamine-induced extravasation. However, our data are in accord with data obtained during intravascular and topical application of histamine and support the hypothesis that H2 receptors at the luminal and abluminal membrane of the endothelium mediate the opening of the BBB.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacologic characterization of a novel histamine receptor on human eosinophils.

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)