Role Of H1 Receptors Research Articles

H1 HISTAMINE RECEPTOR SPECIFIC AGONISTS DIFFERENTIALLY MODIFIES TH1/TH2 CYTOKINE SYNTHESIS BY MONONUCLEAR AND DENDRITIC CELLS

<h3>Introduction</h3> Histamine exhibits immunoregulatory effects via H1 -H4 receptors. Histamine can produce multiple effects on cytokine synthesis: inhibit the release of IL-1, IL-2, IFN-γ, and TNF and increase the release of IL-5, IL-6 and IL-8. The role of H1 receptors in the synthesis of Th1/Th2 regulatory cytokines was assessed. <h3>Methods</h3> The concentration of Th1/Th2 immunoregulatory cytokines were assessed in supernatants of peripheral blood mononuclear cells (PBMC) and dendritic cells (DC) derived from PBMC of 6 healthy donors. PBMC and DC were cultivated in the presence of specific H1 histamine receptor agonist 2-methyl-histamine (2-MH) during 48h by Luminex xMAP technology using 45-plex Human Cytokine/Chemokine/Growth Factor Elisa Kit (eBioscience, Procarta) (10 -5 M/ml). <h3>Results</h3> Activation of H1 histamine receptors by 2-MH differentially impacted synthesis of Th1/Th2 regulatory cytokines by PBMC and DC derived from the same population of PBMC healthy donors. Decreased synthesis of IL-4, IL-12 and IL-21 occurred by1.48, 1.23 and 2.89 fold, respectively (p<0.01) from PBMC and no effect on the synthesis of the same cytokines by DC. Opposite effects on production of IL-10, gIFN and IL-17A were seen, with a decrease after cultivation of PBMC by 1.19-2.64 fold (p<0.01) but increased after cultivation of DC in the presence of 2-MH. Synthesis of IL-13, IL-18 and IL-27 increased by both DC and PBMC. The most pronounced effect occurred in production of IL-27 by PBMC in more than 27 fold. <h3>Conclusion</h3> H1 receptors regulate Th1/Th2 cytokine synthesis by PBMC and DC.

RETRACTED: Activation of pallidal H2 receptors induces catalepsy in Wistar rats: A regulatory role of CRF1 receptors

An increased concentration of histamine was found in the globus pallidus of parkinsonian patients. The role of this abnormality in the development of parkinsonism is unclear. We examined cataleptogenic activity of histamine injected into the globus pallidus (GP); also, the role of H2 receptors in histamine effect was evaluated. Given a possible role of the GP in integration and processing of stress signals, we tested the involvement of CRF1 receptors in the regulation of histamine effect. The experiments were conducted with male Wistar rats, catalepsy was assessed using bar test. The entopeduncular nucleus (EPN) was used as a neuroanatomical control. Intrapallidal injections of histamine (1.0 and 10.0 µg) produced clear cataleptic response whereas intra-EPN injections were ineffective. Histamine-induced catalepsy was dose-dependently attenuated by H2 receptor antagonist ranitidine and CRF1 receptor antagonist NBI 35965. The results suggest the involvement of pallidal H2 and CRF1 receptors in the development of catalepsy in rats. These findings may provide novel insight into the mechanism of parkinsonian-like disorders. In light of the presented data, H2 and CRF1 receptors might be potential targets for therapy of parkinsonism.

Histamine H1 receptor on astrocytes and neurons controls distinct aspects of mouse behaviour

Histamine is an important neurotransmitter that contributes to various processes, including the sleep-wake cycle, learning, memory, and stress responses. Its actions are mediated through histamine H1–H4 receptors. Gene knockout and pharmacological studies have revealed the importance of H1 receptors in learning and memory, regulation of aggression, and wakefulness. H1 receptors are abundantly expressed on neurons and astrocytes. However, to date, studies selectively investigating the roles of neuronal and astrocytic H1 receptors in behaviour are lacking. We generated novel astrocyte- and neuron-specific conditional knockout (cKO) mice to address this gap in knowledge. cKO mice showed cell-specific reduction of H1 receptor gene expression. Behavioural assessment revealed significant changes and highlighted the importance of H1 receptors on both astrocytes and neurons. H1 receptors on both cell types played a significant role in anxiety. Astrocytic H1 receptors were involved in regulating aggressive behaviour, circadian rhythms, and quality of wakefulness, but not sleep behaviour. Our results emphasise the roles of neuronal H1 receptors in recognition memory. In conclusion, this study highlights the novel roles of H1 receptors on astrocytes and neurons in various brain functions.

Role of H1 receptor in inflammatory response during ventilator-induced lung injury in rats

Objective To evaluate the role of H1 receptor in inflammatory responses during ventilator-induced lung injury (VILI) in rats. Methods Thirty clean-grade healthy male Sprague-Dawley rats, aged 9-10 weeks, weighing 250-300 g, were divided into 3 groups (n=10 each) using a random number table method: control group (group C), VILI group (group V) and H1 receptor antagonist clemastine group (group Cle). The animals were anesthetized and tracheostomized, and the rats in group C kept spontaneous breathing.The rats were mechanically ventilated for 4 h with the tidal volume of 40 ml/kg, respiratory rate 40 breaths/min, inspiratory/expiratory ratio 1∶1, and inspired oxygen fraction ratio 21% in group V. In group Cle, clemastine 0.9 mg/kg was intramuscularly injected at 30 min before anesthesia, the animals were tracheostomized after being anesthetized, and then the rats were mechanically ventilated with the same ventilator settings as group V. The animals were sacrificed at 4 h of ventilation, bronchoalveolar lavage fluid (BALF) was collected for determination of concentrations of total protein, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and the lung specimens were obtained for microscopic examination of pathologic changes and for determination of wet/dry weight ratio (W/D ratio). Results Compared with group C, the concentrations of total protein, IL-6 and TNF-α in BALF and W/D ratio were significantly increased in group V (P<0.05). Compared with group V, the concentrations of total protein, IL-6 and TNF-α in BALF and W/D ratio were significantly decreased in group Cle (P<0.05). The pathologic changes of lung tissues were significantly attenuated in group Cle as compared with group V. Conclusion H1 receptor is involved in the process of inflammatory responses during VILI in rats. Key words: Receptors, histamine H1; Ventilator-induced lung injury; Inflammation

The Systemic Administration of the Histamine H1 Receptor Antagonist/Inverse Agonist Chlorpheniramine to Pregnant Rats Impairs the Development of Nigro-Striatal Dopaminergic Neurons.

The dopaminergic and histaminergic systems are the first to appear during the development of the nervous system. Through the activation of H1 receptors (H1Rs), histamine increases neurogenesis of the cortical deep layers, while reducing the dopaminergic phenotype (cells immunoreactive to tyrosine hydroxylase, TH+) in embryo ventral mesencephalon. Although the function of histamine in neuronal differentiation has been studied, the role of H1Rs in neurogenesis has not been addressed. For this purpose, the H1R antagonist/inverse agonist chlorpheniramine was systemically administered (5 mg/kg, i.p.) to pregnant Wistar rats (gestational days 12–14, E12–14), and control and experimental embryos (E14 and E16) and pups (21-day-old) were evaluated for changes in nigro-striatal development. Western blot and immunohistochemistry determinations showed a significant increase in the dopaminergic markers’ TH and PITX3 in embryos from chlorpheniramine-treated rats at E16. Unexpectedly, 21-day-old pups from the chlorpheniramine-treated group, showed a significant reduction in TH immunoreactivity in the substantia nigra pars compacta and dorsal striatum. Furthermore, striatal dopamine content, evoked [3H]-dopamine release and methamphetamine-stimulated motor activity were significantly lower compared to the control group. These results indicate that H1R blockade at E14–E16 favors the differentiation of dopaminergic neurons, but hampers their migration, leading to a decrease in dopaminergic innervation of the striatum in post-natal life.

Involvement of histamine receptors in SAPK/JNK phosphorylation

Histamine is a mediator of inflammation in allergic disease and asthma. Stress activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) are involved in asthma. This study examined the role of histamine receptors on the phosphorylation of SAPK/JNK in splenocytes. C57BL/6 mice splenocytes were treated with histamine (10−4M to 10−11M), and its selective receptor agonists, phorbol 12 myristate 13-acetate (PMA) was used as a positive control, and phosphorylation of SAPK/JNK was determined. Histamine (10−4M–10−8M) inhibited phosphorylation of SAPK/JNK. H1R agonist betahistine (10−5M) decreased SAPK/JNK phosphorylation and H2R agonist amthamine (10−5M) did not show any significant effect. However, H3R agonist methimepip (10−6M) and H4R agonist 4-methyl histamine (10−6M), increased SAPK/JNK phosphorylation.We used TNFα knockout mice to determine if histamine regulated SAPK/JNK phosphorylation via TNFα. While the effects of histamine and H1 agonists were similar to that of wild type mice in inhibiting the phosphorylation of SAPK/JNK, the effects of H3 and H4 agonists differed in TNFα knockout mice splenocytes. Activation of H3 receptors decreased SAPK/JNK phosphorylation in TNFα knockout mice, as opposed to an increase in wild type mice, whereas H4 agonist did not show any significant effect on the phosphorylation of SAPK/JNK. This data showed that histamine acting through H4 receptors caused the phosphorylation of SAPK/JNK via TNFα. The role of H4 receptors in pro-inflammatory response is intriguing.

In response to “The effect of agomelatine on 5HT2C receptors in humans: a clinically relevant mechanism?” by Trevor Norman

We thank Dr. Norman for his interesting comments about the role of H1 receptors in the regulation of slow wave sleep. It is of course quite plausible that H1-receptor blockade could modify slow wave sleep (SWS) in humans; however, in a study with the selective H1 receptor antagonist, mepyramine, we saw no such effect (Solomon et al. 1989). Regardless of whether or not H1-receptors play a role in SWS regulation in humans, the key issue in the case of agomelatine is whether selective 5-HT2C receptor blockade is able by itself to increase SWS. In animals, there is good evidence that this is the case, and indeed, agomelatine, given in acute doses of 10 and 40 mg/kg, also increases SWS in rats, an effect mimicked by the selective 5-HT2C receptor antagonist, S32006 (Descamps et al. 2009). This suggests that a dose of agomelatine sufficient to block 5-HT2C receptors in humans should also increase SWS. However, we agree with Dr. Norman that to resolve the question of whether agomelatine does block 5-HT2C receptors in the human brain at clinically relevant doses, other models of 5-HT2C receptor activity will be needed.

H4 receptors in mast cells and basophils: a new therapeutic target for allergy?

It has long been recognised that mast cells and basophils are prominent sources of preformed histamine in humans and that this biogenic amine serves as one of the most important inflammatory mediators. In allergic diseases, histamine has previously been shown to partially modulate symptoms such as airway obstruction, mucus secretion, reddening of the skin and itch, all of which were attributed to engagement of H₁-receptors with the amine. However, more recently it has been shown that certain key biological functions of histamine, such as itch, are also crucially controlled by H₄-receptor stimulation, resulting in a growing interest in combinational anti-H1 and -H₄ therapeutic approaches. Moreover, research is beginning to shed light on a role of H₄-receptors in mast cell precursor trafficking to various tissues commonly affected by allergic inflammation. Furthermore, H₄-receptors are also expressed on mature basophils and other effector cells of allergic reactions, such as eosinophils. This presents exciting possibilities in terms of potentially modulating the pro-allergic function of these cells as well as.

Effects of the histamine (H)3 receptor antagonist ABT-239 on acute and repeated nicotine locomotor responses in rats

AbstractThe addictive potential of nicotine is linked to psychomotor and cognition-enhancing effects. Histamine (H)3 receptor antagonism has similarly received attention for a role in cognition, however, the role of H3 receptors are far less studied for affects on nicotine-induced locomotor responses. In the present study we tested whether the H3 receptor antagonist 4-(2-{2-[(2R)-2methylpyrrolidinyl]ethyl}-benzofuran-5-yl) benzonitrile (ABT-239) influenced the psychomotor responses to acute and repeated nicotine, including sensitization and conditioned locomotion. ABT-239 (0.3–3mg/kg) did not alter basal, nicotine-evoked (0.4mg/kg) locomotor responses, the expression of sensitization, or cue-conditioned locomotion. However, in combination studies rats pretreated with a separate dose of ABT-239 (1mg/kg) prior to nicotine (0.4mg/kg) for 5 days and then challenged with nicotine (0.4mg/kg) after a 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in nicotine-pretreated and challenged rats. Our findings implicate a limited role for H3 receptors in locomotor responses to nicotine.

Role of H4 receptor in histamine-mediated responses in human melanoma

We have previously reported that histamine at micromolar concentrations reduces the proliferation of melanoma cell lines. It is also known that melanoma cells express histamine H1, H2, and H3 receptors. The aim of this study was to investigate the presence of histamine H4 receptor (H4R) in human melanoma cells and its associated biological processes. To better understand the importance of histamine in tumor development, we explored the expression of H4R in human melanoma tissue biopsies. The expression of H4R in WM35 and M1/15 cells was analyzed by reverse-transcription-PCR, western blot, and immunocytochemistry. To characterize the biological responses we evaluated cell proliferation by clonogenic assay and 5-bromo-2'-deoxyuridine incorporation. In addition, cell senescence and differentiation were determined by β-galactosidase enzyme assay and dopa oxidase activity, respectively. The expression levels of H4R were determined by immunohistochemistry in 19 samples of human malignant lesions. Results indicate that melanoma cells express H4R at the messenger RNA and protein levels. By using histamine agonists, antagonists, and H4R small-interfering RNA we showed that the inhibitory effect of histamine on proliferation was in part mediated through the stimulation of the H4R. The decrease in proliferation was associated with an induction of cell senescence and an increase in melanogenesis, which is a differentiation marker of these cells. Furthermore, H4R was expressed in 42% of human melanoma biopsies. To our knowledge, this is the first report that describes the presence of the H4R in melanoma cells and tissue, suggesting a potential therapeutic application of H4R ligands.

Enhanced morphine-induced antinociception in histamine H3 receptor gene knockout mice

Previous studies have implicated a potential role for histamine H3 receptor in pain processing. There have been conflicting data, however, on the roles of H3 receptors in pain perception, and little information is available about the role of spinal histamine H3 receptors in morphine-induced antinociception. In the present study we examined the role of histamine H3 receptor in morphine-induced antinociception using histamine H3 receptor knockout mice and a histamine H3 receptor antagonist. Anitinociception was evaluated by assays for four nociceptive stimuli: hot-plate, tail-flick, paw-withdrawal, and formalin tests. Antinociception induced by morphine (0.125 nmol/5 μl, i.t.) was significantly augmented in histamine H3 receptor knockout (−/−) mice compared to the wild-type (+/+) mice in all four assays of pain. Furthermore, the effect of intrathecally administered morphine with thioperamide, a histamine H3 antagonist, was examined in C57BL/6J mice. A low dose of i.t. administered thioperamide (0.125 nmol/5 μl) alone had no significant effect on the nociceptive response. In contrast, the combination of morphine (0.125 nmol/5 μl, i.t.) with the same dose of thioperamide resulted in a significant reduction in the pain-related behaviors in all four nociceptive tests. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H3 receptors at the spinal level.

Characterization of histamine-induced relaxation in pre-contracted rat aorta

Histamine is one of many neurotransmitters that have been implicated in cardiovascular functioning. Three subtypes of histamine receptors (H1, H2 and H3) have been identified in the different blood vessels of some animal species [1]. Accordingly, several studies showed in vitro differences of histamine vasomotor effects depending on the animal species, vessel type or vascular bed used in the experiments [2]. In the rat isolated aorta the involvement of H1 and H2 receptors in the vasorelaxation response have been shown [1, 3, 4]. However, the role of H3 receptors in the vasomotor responsiveness remains to be elucidated [5]. Thus, the complexity of vascular responses to histamine, based on its action on histaminergic receptor subtypes, was re-evaluated using similar experimental protocols. The aim of the study was to evaluate the effect of selective histamine H1, H2 and H3 receptor antagonists [6] on histamine induced relaxation of noradrenaline pre-contracted rat isolated aortic rings.

Role of H1 receptors in the regulation of IL-4 production (37.16)

Abstract Histamine alters the Th1/Th2 cytokine balance towards the Th2 cytokine profile and consequently play a role in allergic disease and asthma. This study was designed to determine if the effects of histamine on Signal Transducer and Activator of Transcription(STAT)-6 were direct or mediated via release of IL-4 production.The splenocytes from IL-4 knockout C57Bl/6 mice were pretreated with antibody to IL-13 for 30 minutes followed by treatment with histamine. The cells were then stimulated with PMA + ininomycin for 6 hours under standard cell culture conditions. For the control experiments splenocytes from the wild type C57BL/6 mice were used. The cells were lyzed and the total basal and phosphorylated STAT6 were analyzed using the Western Blot Analysis. Furthermore, splenocytes from C57Bl/6 mice were pretreated with antibodies to IL-4 and IL-13 followed by treatment with histamine and PMA + ionomycin and Western blot analysis were performed to determine the phosphorylated Stat6 levels.In the control group histamine caused hyper-phosphorylation of Y641 tyrosine residues of STAT6. These effects were not observed when splenocytes from the IL-4 knockout mice were used or the wildtype splenocytes were pretreated with antibodies to IL-4 and IL-13. These observations suggest that histamine indirectly affected the heper-phosphorylation of STAT6 via its effects on the secretion of IL-4 and H1 receptors played a role in this process, since H1 receptor antagonists blocked these effects. The clinical significance of STAT6 hyper-phosphorylation in the exacerbation of asthma symptoms has not yet been determined.

Histamine affects STAT6 phosphorylation via its effects on IL-4 secretion: Role of H1 receptors in the regulation of IL-4 production

Signal Transducer and Activator of Transcription (STAT)-6 is a transcriptional factor activated mainly through the cytokines IL-4 and IL-13 leading to the Th2 cell differentiation. Th2 cells play a role in the etiology and pathogenesis of allergic disease.Histamine alters the Th1/Th2 cytokine balance towards the Th2 cytokine profile and consequently plays a role in allergic diseases and asthma. This study was designed to investigate the effects of histamine on the STAT6 phosphorylation. C57/BL6 splenocytes were pretreated with different concentrations of histamine (10−4 M to 10−13 M) followed by stimulation with PMA+ionomycin or IL-4. The phosphorylated and total basal STAT6 levels were assessed by employing the immunoblotting technique. Histamine caused the hyper-phosphorylation of STAT6. H1 receptor antagonist pyrilamine reversed the effect of histamine on STAT6 phosphorylation. However, H2 receptor antagonist ranitidine and H3/H4 receptor antagonist thioperamide did not affect the histamine mediated hyper-phosphorylation of STAT6. Furthermore, H1 receptor agonist betahistine enhanced the phosphorylation of STAT6 whereas H2 receptor agonist amthamine did not affect the phosphorylation STAT6. Furthermore, tyrosine kinase inhibitor, tyrphostin, inhibited the histamine mediated phosphorylation of STAT6 when stimulated with PMA+ionomycin. The effects of histamine on the STAT6 phosphorylation were indirect since they were blocked either by the antibodies to IL-4 and IL-13 or in IL-4 knock out mice in the presence of IL-13 antibody. These observations suggest that histamine indirectly affected the STAT6 phosphorylation via its effects on the secretion of cytokines (IL-4) and H1 receptor played a role in this process.

Role of H1 receptors in histamine-mediated up-regulation of STAT4 phosphorylation

Histamine shifts TH1/TH2 cytokine balance from TH1 to TH2 cytokines and regulates the function of lymphocytes after binding to histamine receptors. The phosphorylation of STAT factors and the translocation to the nucleus are important steps in the regulation of TH1/TH2 cytokine balance. This study was designed to investigate the effects of histamine on the phosphorylation of STAT4. C57BL/6 splenocytes were isolated and treated with histamine (10−4 to 10−9 M) after activation with either PMA (phorbol 12 myristate 13-acetate) plus ionomycin or IL-12. The phosphorylated STAT4 levels were analyzed by Western Blot Analysis. Unstimulated splenocytes expressed both STAT4 and phosphorylated STAT4. However, phosphorylated STAT4 gradually declined within 24 h. Histamine increased the phosphorylation of STAT4 at lower concentrations (10−6 to 10−9 M), and had no effect at higher concentrations (10−4 and 10−5 M) after the cells were stimulated with PMA+ionomycin. Histamine did not affect IL-12-induced phosphorylation of STAT4. To characterize the histamine receptor subtypes involved in the up-regulation of STAT4 phosphorylation, various H1, H2 and H3/H4 receptor antagonists and/or agonists were employed. H1 receptor agonist (betahistine), but not H2 receptor agonist (amthamine), induced phosphorylation of STAT4. H1 receptor antagonist (pyrilamine) inhibited histamine-mediated phosphorylation of STAT4. However, H2 receptor antagonist (ranitidine) and H3/H4 receptor antagonist (thioperamide) did not alter this effect. Tyrosine kinase inhibitor (tyrphostin) failed to block histamine-mediated phosphorylation of STAT4. These observations suggest that histamine up-regulated the phosphorylation of STAT4 via H1 receptors, and that the Ca2+-PKC pathway, but not the tyrosine kinase pathway, was involved in this effect.

P1160 Mammary artery and saphenous vein, but not radial artery release nitric oxide in response to histamine: role of H2 receptor

P1160 Mammary artery and saphenous vein, but not radial artery release nitric oxide in response to histamine: role of H2 receptor

The role of H1 receptors in the anticonvulsive effect of morphine against maximal electroconvulsive shock in mice

The role of H1 receptors in the anticonvulsive effect of morphine against maximal electroconvulsive shock in mice

The role of H2 receptors in the nociceptive effect of compound 48/80 in mice

The role of H2 receptors in the nociceptive effect of compound 48/80 in mice

Presynaptic histamine H2 receptors modulate the sympathetic nerve transmission in the isolated rat vas deferens; no role for H3-receptors

The modulatory activity mediated by histamine receptors on the sympathetic nerve transmission was investigated in the rat vas deferens. Agonists and antagonists acting at the different histamine receptor subtypes (H1, H2 and H3) were tested on electrically-driven preparations in vitro. Low-frequency stimulation (0.1 Hz) evoked muscle contractions almost completely-sustained by ATP release, while at high-frequency stimulation (5-10 Hz) norepinephrine was mainly involved. The H1 receptor agonists, pyridilethylamine and 2-(2 aminoethyl)thiazole, enhanced the electrically evoked twitch responses, but not contractions induced by exogenously-applied norepinephrine and ATP. These effects were prevented by the H1-blocking drugs, mepyramine and phenyramine, but only at high concentrations (10 mumol/l). All these H1-antagonists strongly enhanced muscle response to electrical stimulation. The H2 receptor agonists, dimaprit, amthamine and impromidine, reduced the contractions evoked by field stimulation, but not by exogenously applied norepinephrine and ATP, the effect being antagonised by H2-blocking drugs, ranitidine and famotidine. The H3 receptor agonist, R(alpha)-methylhistamine, reduced the electrically evoked muscle contractions, the effect being not modified by the selective H3-blocking drug, thioperamide, but prevented by famotidine. These data suggest that rat vas deferens contains presynaptic histamine H2 receptors, able to mediate inhibitory effects on the sympathetic transmission, while histamine H3 receptors are apparently not involved. On the contrary, the role of H1 is still unclear, since both agonists and antagonists may have the same effects.

Role of H1 receptors and P-selectin in histamine-induced leukocyte rolling and adhesion in postcapillary venules.

The objective of this study was to define the nature, magnitude, and mechanisms of histamine-induced leukocyte-endothelial cell interactions in postcapillary venules of the rat mesentery using intravital microscopic techniques. Superfusion of the mesentery with histamine (10(-7)-10(-5) M) resulted in a dose-related increase in the number of rolling leukocytes, a reduction in rolling velocity, and an increased clearance of FITC-labeled rat albumin from blood to superfusate. The histamine-induced recruitment of rolling leukocytes and increased albumin clearance were prevented by histamine H1 (hydroxyzine, diphenhydramine) but not H2 (cimetidine) receptor antagonists. Because histamine induces expression of the adhesion molecule P-selectin in cultured endothelial cells, a monoclonal antibody directed against rat P-selectin and soluble sialyl-LewisX oligosaccharide (the carbohydrate ligand to P-selectin) were also tested as inhibitors. Both were effective in preventing the histamine-induced recruitment of rolling leukocytes, but neither agent attenuated the increased albumin clearance. These observations suggest that (a) histamine recruits rolling leukocytes and increases albumin leakage in postcapillary venules via H1 receptor activation, (b) histamine-induced recruitment of rolling leukocytes is mediated in part by P-selectin expressed on the endothelial cell surface, and (c) the histamine-induced vascular albumin leakage is unrelated to leukocyte-endothelial cell adhesion. Our results are consistent with the view that histamine may act as a mediator of acute inflammatory reactions.