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PubMed1999

Histamine effects on conjunctival fibroblasts from patients with vernal conjunctivitis.

Histamine, an important mast cell mediator in allergic disorders, may affect extracellular matrix production and cell growth in vernal keratoconjunctivitis (VKC). In the present study, the histamine reactivity of conjunctival fibroblasts derived from VKC patients was investigated in vitro. Conjunctival fibroblast cultures were derived from biopses of 8 tarsal VKC patients and 5 normal subjects. These cells were maintained in vitro and stimulated with different concentrations of histamine with and without H1 (clorpheniramine) and H2 (cimetidine) receptor antagonists. Comparisons were made to fibroblasts grown in the same media without histamine and to fibroblasts stimulated with just antihistamine. The effects of histamine were evaluated by: (1) the MTT test to assess cell proliferation; (2) an in vitro wound model for cell migration and (3) the measurement of procollagen I (PIP) and procollagen III (PIIIP) in supernatants for collagen production. Results showed: (1) While VKC-derived fibroblasts proliferated at a faster rate than normal cells in unstimulated media, after histamine stimulation, VKC and normal cells grew at a similar rate. Both H1 and H2 antagonists significantly inhibited (P<0.05) histamine-induced cell proliferation. (2) Histamine enhanced cell migration after wounding; this effect was inhibited only by H2 antagonism. (3) When stimulated with histamine, VKC fibroblasts produced significantly more PIP than those in control media. Furthermore, VKC-derived fibroblasts were more sensitive to histamine challenge, producing significantly more PIP than normal fibroblasts. H1 and H2 antagonists did not modify histamine-stimulated PIP production. The enhanced proliferative and productive capacity of VKC fibroblasts may be the result of a selective overgrowth of one or more fibroblast subpopulations in a chronically inflamed tissue. Histamine increased proliferation, migration and collagen production in both normal and VKC fibroblasts. Since H2 antagonism modulated both cell growth and migration, but not histamine-induced collagen production, the latter may be mediated by a different receptor. These results showed that histamine is at least partially responsible for fibroblast stimulation.

Cell Culture Techniques↗
PubMed1995

The role of gastric histamine release in the acid secretory response to pentagastrin and methacholine in the dog.

We have previously demonstrated that both pentagastrin and methacholine can stimulate histamine release from the canine stomach during short term administration of the secretagogues into the gastrosplenic artery. In this study we tested the hypothesis that gastric histamine release determines the acid secretory response to acid secretagogues. Increasing doses of pentagastrin (2, 6, and 20 ng/kg/min) and methacholine (0.1, 0.3, and 1 micrograms/min) were infused into the gastrosplenic artery in dogs, while gastric acid output, histamine and N tau-methyl histamine secretory rates were monitored. Histamine and N tau-methyl histamine concentrations in plasma were measured using GC/NICI-MS. Increasing doses of pentagastrin resulted in increasing gastric output. Total histamine secretory rate expressed as the sum of histamine and N tau-methyl histamine secretory rate showed a significant increase above basal with the two highest doses of pentagastrin. Regression analysis correlating the dose of pentagastrin to gastric acid output gave a correlation coefficient of 0.586 which was very significant. Regression analysis correlating the total histamine secretory rate to acid output gave a correlation coefficient of 0.498 which was also very significant. Increasing doses of methacholine also resulted in a dose-dependent increase in acid output. Histamine secretory rates showed a statistically significant increase above basal only at the 1 microgram/min infusion rate, however, the total histamine secretory rates (histamine + N tau-methyl histamine) were no longer significant at any of the doses of methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Influence of histamine release on postoperative vomiting (POV) following gynaecological laparoscopic surgery.

OBJECTIVE: The mechanisms leading to the high incidence of postoperative vomiting (POV) after gynaecological laparoscopic surgery are still unknown. The effectiveness of POV-prophylaxis using H1 + H2-receptor antagonists has been demonstrated, suggesting a role for histamine in the pathogenesis of POV. However, histamine levels were not measured in these studies. The aim of this study was to investigate the incidence of plasma histamine release and its association with POV after gynaecological laparoscopic surgery. MATERIAL OR SUBJECTS: Twenty-two female patients, aged 20-56 y, classified ASA physical status I or II, undergoing elective gynaecological laparoscopic surgery were enrolled in the study. Blood samples for plasma histamine measurements were drawn at defined time points perioperatively. Emetic symptoms were recorded within the first 24 h after operation. A standardized balanced anaesthesia without any prophylactic antiemetic medication was applied. Formal causality analysis for histamine as a determinant for POV was performed. RESULTS: The overall incidence of POV was 40.9% (9 out of 22 patients). Twelve out of 22 patients (54.5%) demonstrated a histamine release reaction during the whole observation period. Six out of 9 patients with POV (66.7%) had a histamine release. There was no difference in mean plasma histamine levels between POV-positive and POV-negative patients. The conditional probability for POV with histamine release was 6/12 = 0.5, in contrast to 3/10 = 0.3 for POV without histamine release. CONCLUSIONS: A high incidence of plasma histamine release was demonstrated in most but not all patients with POV. The probability of POV with histamine release (0.5) was higher than without histamine release (0.3), thus histamine release was shown to be one of the contributory determinants for POV in this clinical study. Thus, patients at risk for POV may benefit from a H1 + H2-receptor antagonists prophylaxis alone or in combination with other antiemetic strategies.

Adult↗
PubMed2003

Histamine-induced chloride secretion is mediated via H2-receptors in the pig proximal colon.

OBJECTIVE: The aim of this study was to investigate the action of histamine on function of epithelia in the pig proximal colon. MATERIAL AND METHODS: Isolated epithelia of the pig proximal colon were prepared by slide-stripping and mounted in Ussing chambers. Short-circuit current (Isc) was measured after serosal addition of histamine (20 micromol/l) with or without pretreatment with histamine receptor antagonists (H1: chlorpyramine, 10 micromol/l; H2: famotidine, 100 micromol/l; H3: thioperamide, 10 micromol/l), a cyclooxygenase inhibitor (indomethacin, 10 micromol/l), or a neuronal conduction blocker (tetrodotoxin, 1 micromol/l). Alternatively, histamine receptor agonists (H1: 2-pyridylethylamine; H2: dimaprit; H3: R-alpha-methylhistamine, each 100 micromol/l) were added to the serosal side. Flux studies using 14C-mannitol, 22Na+ and 36Cl- were performed in the presence of 100 micromol/l histamine on the serosal side. RESULTS: Serosal application of histamine induced a rapid rise in Isc with a maximum 3 min after addition, followed by a slow decrease. Only pretreatment with famotidine decreased the epithelial response to histamine. Pretreatments with chlorpyramine, thioperamide, indomethacin or tetrodotoxin did not change histamine-induced increases in Isc. Action of histamine could be simulated by dimaprit, but not by 2-pyridylethylamine or R-alpha-methylhistamine. Histamine induced an increase in serosal-to-mucosal chloride flux leading to a decrease of chloride net absorption. Fluxes of sodium and mannitol were not affected by histamine. CONCLUSIONS: In contrast to the importance of H1-receptors in other gut epithelia, histamine acts directly via H2-receptors in the porcine proximal colon. Changes in Isc after histamine addition are primarily due to chloride secretion. The paracellular permeability is not influenced by histamine.

Animals↗
PubMed1993

Perioperative nonspecific histamine release: a new classification by aetiological mechanisms and evaluation of their clinical relevance.

As a consequence of the performance of a randomized controlled clinical trial on perioperative histamine release and cardiovascular and respiratory disturbances, several types of increases in plasma histamine had to be distinguished instead of only two which existed at the beginning of the study: drug-induced allergic and pseudoallergic reactions. First of all, the new classification by aetiology (clinical epidemiology) was derived from a meta-analysis (secondary analysis) of the most recent literature. According to that histamine release in the perioperative period has several, different causes and is involved in several, different disease manifestations. A clear distinction (classification), however, is necessary if histamine release as an unwanted (adverse) effect has to be recognized, value judged according to its clinical relevance and therefore also prevented by histamine antagonists. Histamine release by neuro-endocrine and neuro-inflammatory mechanisms, cytotoxic histamine release and local, cytokine induced histamine release have been distinguished from pseudoallergic histamine release, but its functions are not yet clear. It has been analysed in prospective trials which used special clinical situations as models: patients on a normal ward or before and during upper GI endoscopy without premedication, but also in specific phases of laparoscopic cholecystectomy (trocar phase and dissection phase). Their existence in the clinical reality is now very likely, but new trials must investigate the pathophysiological effects such as in metabolism, coagulation, pulmonary haemodynamics (shunt volume) and gastric acid secretion. Histamine release by pseudoallergic mechanisms, however, was identified in the very vulnerable post-induction phase of anaesthesia up to skin incision. Its incidence was much higher than ever expected and its clinical relevance was demonstrated by the severity of reactions and the intervention strategies of the anaesthetists who were blinded concerning the type of the plasma substitute given and the prophylaxis with antihistamines. Pseudoallergic histamine release was clearly unwanted (adverse). Its occurrence in the other phases of anaesthesia has to be further evaluated in the tedious procedure of data analysis of the Mainz-Marburg-trial. The overall incidence of histamine release in the trial was so incredible high (72% of all patients, some of them with up to 4 episodes of histamine release) that a distinction between pseudoallergic (unwanted) and other types of histamine release (possibly less unwanted or even beneficial) is urgently needed. In the phase of steady state (maintenance) of anaesthesia the H1-(+)H2-prophylaxis was highly effective. Further analysis must show whether this is also the case during the phases of induction of anesthesia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1997

Histamine is released in the wheal but not the flare following challenge of human skin in vivo: a microdialysis study.

BACKGROUND: The mediator mechanisms of the cutaneous wheal and flare response, which underlies allergic skin and urticarial conditions, are controversial. The wheal results primarily from a direct effect of histamine on the local vascular bed but to what extent does histamine diffuse within the wheal? The flare is neurogenic, in origin, being disseminated within the dermis by axon reflexes, but do the neuropeptides released from the nerve endings cause the vasodilatation directly or do they induce the further release of histamine which then transduces the flare? OBJECTIVE: We have addressed these questions by inserting 216 microns diameter microdialysis fibres into the dermis within the different areas of the wheal and flare to monitor changes in histamine levels provoked by intradermal injections of histamine, allergen, codeine and substance P. Twenty-one subjects participated in the investigations. RESULTS: The histamine concentration in unprovoked skin was 10.5 +/- 0.6 nM. As the dialysis efficacy was approximately 50%, this equates to tissue concentrations of 20 nM. All provicants released large amounts of histamine at the injection site, maximum histamine levels being 337-1293 nM. Diffusion of histamine within the wheal was poor, levels at 2.3 mm and 3.7 mm from the site of injection being 4-22% and 0.2-3.7% respectively of those 1 mm from the injection site. No increased histamine levels were detected in the flare with any provicant. Atraumatic delivery to the skin of histamine in infusion concentrations of 30-10,000 nM caused concentration-related effects, at least 100 nM being necessary to induce a significant increase in skin blood flow, a threshold of 300-1000 being required to stimulate a visible flare and a measurable erythema, and 3000-10,000 nM being the minimum for induction of a wheal. Thus the skin blood vessels and nerves are responsive to histamine, but at relatively high concentrations. CONCLUSIONS: These data support the theory that the flare reaction to focal histamine injection or release is a neurogenic reflex not involving histamine release at its effector end.

Adult↗
PubMed1992

Short-term desensitization of the histamine H1 receptor in human HeLa cells: involvement of protein kinase C dependent and independent pathways.

1. In this study we have investigated the effects of short-term exposure of cells to histamine on the subsequent H1 receptor responsiveness in HeLa cells, using Ca2+ fluorescence microscopy and video digital imaging. 2. In HeLa cells, histamine (100 microM) induces an immediate H1 receptor-mediated biphasic elevation of the intracellular Ca2+ concentration ([Ca2+]i) (basal [Ca2+]i: 81 +/- 30 nM, histamine-induced Ca2+ response: first phase: 1135 +/- 79 nM; second phase: 601 +/- 52 nM, n = 11). 3. The histamine H1 receptors on HeLa cells are readily susceptible to desensitization since repetitive exposure of the same group of cells to histamine (100 microM) markedly affected the release and influx component of the induced Ca2+ response (second application of histamine: first phase: 590 +/- 92 nM, second phase: 279 +/- 47 nM; third application of histamine: first phase: 454 +/- 127 nM, second phase: 240 +/- 45 nM, n = 6). Video digital imaging revealed an increase in the lag time between stimulation and monitoring of the Ca2+ response and a reduced increase in [Ca2+]i after desensitization with histamine. 4. Neither the release component of the ATP response (50 microM) nor the caffeine (3 mM)-induced Ca2+ release were found to be affected by desensitization with 100 microM histamine. However, the second phase of the ATP response was significantly reduced after desensitization with histamine (control cells: 516 +/- 33 nM; desensitized cells: 331 +/- 96 nM, n = 4, P < 0.05).5. Activation of protein kinase C (PKC) by phorbol-12-myristate-1 3-acetate was found to inhibit the histamine as well as ATP-induced Ca2" response in a dose-dependent manner.6. In PKC downregulated cells the second phase of the histamine-induced Ca2+ response was significantly elevated, indicating the involvement of PKC in the negative feedback on the Ca2+ influx(control cells: second phase: 601 +/- 52 nM (n = 11); PKC downregulated cells: second phase:890 +/- 90nM, n = I0, P<0.05).7. Homologous desensitization of H, receptor responsiveness was still observed in PKC downregulated cells, implying the rapid activation of a regulatory mechanism other than PKC.8. Based on our experimental data we suggest that short-term desensitization of the histamine H,receptor evolves from two different processes: a selective reduction of the histamine-induced Ca2+ release, mediated by a PKC-independent pathway, and a non-selective inhibition of the receptormediated Ca2+ influx activated by a PKC-dependent pathway.

Adenosine Triphosphate↗
PubMed1981

Effect of pentagastrin on histamine output from the stomach in patients with duodenal ulcer.

The role of histamine in acid secretion is controversial. Improvements in the techniques of histamine assay allow a better assessment of the relationship of histamine to acid secretion. Patients with duodenal ulcers were studied to determine the mucosal histamine responses to pentagastrin stimulation to relate the appearance of histamine in the gastric juice to acid production during stimulation, and to detect changes in the plasma histamine concentration during pentagastrin stimulation. There was a mean 27% fall (range 0-60%) in mucosal histamine concentration after pentagastrin. The output of histamine into gastric juice closely paralleled acid output in peak output acid duration. The histogram profiles of acid and histamine were similar in shape. In contrast with previous studies, plasma histamine concentration was found to rise during peak acid secretion (mean rise 65%). There was no relationship between initial mucosal histamine concentration and acid secretion or maximal gastric juice histamine. The association of histamine and gastric acid release found in these studies was so close that a functional relationship may be presumed. Our data are compatible with the hypothesis that pentagastrin acts on the parietal cell indirectly by causing histamine release in the gastric mucosa, which in turn releases acid from the parietal cells.

Duodenal Ulcer↗
PubMed1990

Uptake and methylation of histamine by dispersed gastric mucosal cells and its possible influence on acid secretion.

Inactivation of histamine by gastric mucosal tissue was examined in dispersed rabbit gastric mucosal cells. Mucosal cells were incubated with [14C]histamine. The formed radioactive metabolites were separated and identified by thin layer co-chromatography and quantitated, in both the cellular and extracellular mediums. Gastric mucosal cells internalized histamine, most of which was immediately methylated primarily to N tau-methylhistamine and released. Cellular histamine product accumulation reached a plateau. The rate of histamine methylation increased with increasing extracellular histamine concentration, moving towards a plateau above 5 microM. Histamine methylation was greatly decreased but not abolished at 4 degrees C, in the absence of Na+ and by phlorizin (0.5 mM), an inhibitor of Na(+)-dependent co-transport. Inhibition of histamine N-methyltransferase decreased intracellular methylhistamine content dose dependently without increasing intracellular histamine. The secretagogues pentagastrin and carbachol did not influence histamine metabolism but ethanol inhibited methylation. The data suggest that gastric mucosal cells take up histamine by a Na(+)-dependent and Na(+)-independent process. The histamine uptake capacity appears to be linked to the methylation activity within the cell. The decrease in histamine uptake and metabolism caused by ethanol could potentially increase histamine concentrations near the target cells and be the reason for the stimulatory effect of ethanol on acid secretion.

Animals↗
PubMed1988

The suppressive effect of histamine on anti-DNP antibody production in mice.

To clarify the effect of histamine on antibody production, histamine was injected intravenously into DNP-KLH immunized C3H/HeN female mice. The number of anti-DNP plaque-forming splenic cells decreased in immunized and histamine-injected mice. Decreased PFC responses similarly occurred in recipient mice into which Lyt-2.1 T cells obtained from histamine-injected mice were transferred before immunization. The effect of histamine is not due to inhibition on plaque formation. The results indicated that histamine induced the augmentation of suppressor T cell (Ts) function and caused the decrease of antibody production in histamine-injected mice. The maximum activity of Ts in recipient mice was obtained from mice injected with histamine 3 days before the cell transfer. The suppressive activity of histamine was not antigen specific because Ts was induced in histamine-injected, nonimmunized mice. The treatment of histamine type 2 (H2) agonist showed decreased PFC responses in the mouse as well as histamine did. When mice were treated with an H2 antagonist followed by histamine, antibody production was not reduced. The above results indicated that histamine seemed to regulate antibody production through H2 receptors on lymphocyte membranes.

Adjuvants, Immunologic↗
PubMed1995

Histamine distribution in human basophil secretory granules undergoing FMLP-stimulated secretion and recovery.

We examined subcellular histamine localizations in purified human basophils that were stimulated to degranulate with FMLP using an ultrastructural enzyme-affinity technique. Basophils were collected at early (0, 20 seconds, 1 minute) and late (10 minutes to 6 hours) time points poststimulation and were prepared for routine ultrastructural and diamine oxidase-gold (DAO-gold) cytochemical analysis. Histamine was present in unaltered cytoplasmic secretory granules (30.77 gold particles per square micrometer; P < .001 compared with background); specificity controls (histamine absorption, diamine oxidase digestion) abrogated granule labeling for histamine. Altered granules in stimulated cells were not significantly labeled for histamine, as compared with background (P = not significant); unaltered granules in the same cells contained more histamine than altered granules (P < .05). During recovery times, spanning 10 minutes to 6 hours, granules again appeared to be electron-dense and contained histamine (33.49/microns2; P = not significant as compared with unaltered granules in 1-minute FMLP-stimulated cells, and P < .05 as compared with altered granules in 1-minute FMLP-stimulated samples). Other structures devoid of histamine in actively secreting cells included extruded granules and intragranular and extruded Charcot-Leyden crystals. Recovering basophils displayed morphologic evidence of material and membrane conservation, granule content condensation, and biosynthesis. Subcellular histamine-rich sites in actively recovering basophils included condensing granules and collections of cytoplasmic vesicles in three locations: beneath the plasma membrane, adjacent to granules, and in the Golgi region. These studies show that unaltered granules of actively releasing human basophils, as well as similar granules that are reconstituted after FMLP-stimulated degranulation, contain histamine, but that altered granules in stimulated cells undergoing degranulation are devoid of histamine. Reconstitution of histamine-rich granules is associated with DAO-gold-positive cytoplasmic vesicles, suggesting transport of histamine derived from either new synthesis, re-uptake of released histamine, or both, to reconstituted granules.

Amine Oxidase (Copper-Containing)↗
PubMed1982

Dysrhythmias caused by histamine release in guinea pig and human hearts.

Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heart in vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heart in vitro. Arrhythmogenic effects of histamine include enhancement of normal automaticity, induction of abnormal automaticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction, and increase in the vulnerability of the ventricles to fibrillation. A combination of H1 and H2 antihistamines is needed to block the arrhythmogenic effects of histamine. Certain arrhythmogenic effects of histamine (e.g. induction of slow responses and delayed afterdepolarizations) can also be blocked by drugs which inhibit the influx of cations through slow channels. In contrast, the commonly-used drug digitalis potentiates the arrhythmogenic effects of histamine. We propose that histamine release produced by drugs and surgical procedures may be an overlooked factor in fatal cardiac arrhythmias. Experimental studies suggest that selective pharmacological methods can be developed to block the arrhythmogenic effects of histamine.

Animals↗
PubMed1994

Rapid desensitization of the histamine H2 receptor on the human monocytic cell line U937.

In the present study we have subjected the histamine H2 receptor on the monocytic cell line U937 to a thorough pharmacological characterization using a series of selective histamine H1, H2 and H3 receptor agonists and antagonists. Recent reports have demonstrated the existence of a histamine H2 receptor on HL-60 and HGT-1 cells with a pharmacological profile distinct from the commonly described histamine H2 receptor. U937 cells, however, seem to express classical histamine H2 receptors. Histamine and dimaprit dose dependently induce the formation of cAMP, whereas dimaprit's inactive analogues, nordimaprit and homodimaprit, show reduced potencies. Histamine H1 and H3 receptor agonists do not show histamine H2 receptor activity. Various histamine H2 receptor antagonists are able to block the histamine induced production of cAMP with an antagonistic profile comparable to that observed in the guinea-pig right atrium. Furthermore, endogenous histamine H2 receptors in U937 cells are found to be susceptible to receptor desensitization, a mechanism which may become apparent under pathophysiological conditions or during drug therapy. A 30-min pre-exposure of U937 cells to histamine (100 microM) results in a 50% attenuation of the production of cAMP to a subsequent application of an agonist. Desensitization of the histamine H2 receptor in U937 cells is found to be homologous as the beta-adrenoceptor mediated response remained unaffected.

Cells, Cultured↗
PubMed2000

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.

Animals↗
PubMed1997

Role of endothelium and nitric oxide in histamine-induced responses in human cranial arteries and detection of mRNA encoding H1- and H2-receptors by RT-PCR.

1. Histamine induces relaxation of human cranial arteries. Studies have revealed that the relaxant histamine H1-receptor predominates in human cerebral and the H2-receptor in temporal arteries, while H1- and H2-receptors are of equal importance in the middle meningeal artery. The purpose of the present study was to examine the role of the endothelium and nitric oxide in histamine-induced responses and to show the presence of mRNA encoding H1- and H2-receptors in human cranial arteries. 2. Electrophoresis of polymerase chain reaction (PCR) products from human cerebral, middle meningeal and temporal arteries, demonstrated products corresponding to mRNA encoding both H1- and H2-receptors in arteries with and without endothelium. The amplified PCR products were sequenced and showed 100% homology with the published sequences of these histamine receptors. 3. A sensitive in vitro system was used to study vasomotor responses to histamine. In precontracted cerebral, middle meningeal and temporal arteries with and without endothelium, histamine caused a concentration-dependent relaxation with Imax values between 87% and 81% and pIC50 values between 8.14 and 7.15. In arteries without endothelium the histamine-induced relaxation was significantly less potent (Imax values between 87% and 66% and pIC50 values between 7.01 and 6.67) than in cranial arteries with an intact endothelium. 4. This addition of histamine to arteries without endothelium and pretreated with the histamine H2-antagonist, cimetidine (10(-5) M), caused a concentration-dependent contraction of the cranial arteries with Emax values between 86% and 29% and pEC50 values between 7.53 and 6.77. This contraction was blocked by the histamine H1-receptor antagonist, mepyramine (10(-7) M), and even turned into a relaxation with Imax values between 84% and 14% and pIC50 values between 7.42 and 5.86. 5. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-5) M) significantly inhibited the relaxant response to histamine in cerebral and temporal arteries (pIC50 values between 7.43 and 7.13). The combined treatment with L-NAME (3 x 10(-5) M) and cimetidine (10(-5) M) caused a further displacement of the concentration-response curve (pIC50 values between 7.14 and 6.57) and decreased the maximum relaxant responses in all three cranial arteries (Imax values between 62% and 39%). 6. In conclusion, this is the first study which show mRNA encoding histamine H1- and H2-receptors in human cranial arteries. The results indicate that histamine-induced relaxation of human cranial arteries is partially mediated via an endothelial H1-receptor coupled to the production of nitric oxide and partially via a H2-receptor associated with the smooth muscle cells. In addition, there is evidence for a contractile H1-receptor in the smooth muscle cells in these arteries.

Cerebral Arteries↗
PubMed1999

Lack of histamine synthesis and down-regulation of H1 and H2 receptor mRNA levels by dexamethasone in cerebral endothelial cells.

The purpose of this work was to determine whether cerebral endothelial cells have the capacity to synthesize histamine or to express mRNA of receptors that specifically respond to available free histamine. The histamine concentrations and the expression of L-histidine decarboxylase (HDC) and histamine H1 and H2 receptor mRNA, both in adult rat brain and in cultured immortalized RBE4 cerebral endothelial cells, were investigated. In this study endothelial cells were devoid of any kind of detectable histamine production, both in vivo and in the immortalized RBE4 cells in culture. Both the immunostainings for histamine and the in situ hybridizations for HDC were negative, as well as histamine determinations by HPLC, indicating that endothelial cells do not possess the capacity to produce histamine. Also, glucocorticoid (dexamethasone) treatment failed to induce histamine production in the cultured cells. Although the cerebral endothelial cells lack histamine production, a nonsaturable uptake in RBE4 cells is demonstrated. The internalized histamine is detected both in the cytoplasm and in the nucleus, which could indicate a role for histamine as an intracellular messenger. Histamine H1 and H2 receptor mRNA was expressed in RBE4 cells, and glucocorticoid treatment down-regulated the mRNA levels of both H1 and H2 receptors. This mechanism may be involved in glucocorticoid-mediated effects on cerebrovascular permeability and brain edema.

Animals↗
PubMed1983

Metabolism and function of gastric histamine in health and disease.

Histamine is not uniformly distributed in the human and animal organisms, but occurs in high concentrations in the gastric mucosa. The enzymes responsible for its metabolism--histidine decarboxylase, histamine N-methyltransferase and diamine oxidase--seem to be less predominantly localized in the stomach. Considerable effort was necessary to detect and measure histamine formation in the gastric mucosa. This was a controversial subject that only was solved recently. Histamine inactivation by histamine methyltransferase occurs in man in the fundic gastric mucosa that has reasonable enzymic activity. However, liver, spleen and intestine show much higher activities indicating less specificity of histamine catabolism in the gastric mucosa. Finally, diamine oxidase activity was once thought to be absent in the corpus mucosa, but more recently, moderate activities of this enzyme were found in several species, including man. Thus, histamine metabolism in the gastric mucosa is by no means unique in mammalian tissues, but the presence of these enzymes may be regarded as an indicator of its physiological function. To some extent enzymic activities involved in histamine formation and inactivation are regulated in the process of acid secretion. Histidine decarboxylase and histamine N-methyltransferase activities are enhanced by gastrin, but are not influenced by vagal stimulation. Hitherto, only histamine methylation was found to be diminished in duodenal ulcer disease. Vagotomy and histamine H2-receptor antagonists modulate histamine catabolism by histamine methyltransferase. The implication of these findings for treatment of duodenal ulcer are discussed.

Amine Oxidase (Copper-Containing)↗
PubMed1997

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.

Action Potentials↗