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PubMed1975

Properties of a subpopulation of T cells bearing histamine receptors.

C57BL/6 mice immunized i.p. with alloantigen (P815 mastocytoma cells) develop cytolytically active thymus-derived (T) splenic lymphocytes. The definition of specific histamine receptor sites on effector T cells has been studied by measuring the in vitro effects of the hormone on cytolytic activity. Histamine was found to inhibit cytolysis reversibly and to increase lymphoid cell cyclic AMP levels. Both of these histamine activities were reversed by burimamide and metiamide; neither activity was affected by diphenhydramine or pyrilamine. These findings indicate that modulation of effector T cell activity by histamine is mediated only by one of the subtypes of tissue histamine receptors, designated a histamine-type 2 receptor. This receptor appears to be present on cytolytically active cells; there is no evidence for activation by histamine of auxiliary or "suppressor" cells. The estimated dissociation constant (KB) for the burimamide-receptor complex (9 times 10-minus 6 tm) and for the metiamide-receptor complex (8 times 10-minus 7 M) indicated that the histamine receptor on T cells is quite similar to histamine-type 2 receptors in other tissues. Cells bearing such receptors could not be isolated by passage through a column of histamine-coated tsepharose beads. The cytolytic activity of spleen cells taken from mice early (days 7-9) after immunization is virtually unaffected by histamine in vitro. In contrast, the activity of spleen cells taken from mice later in the immune response is progressively more susceptible to inhibition by histamine. After reaching a maximum at day 11, the spleen cell cytolytic activity falls in a pattern that parallels the increase in susceptibility to histamine. The susceptibility of effector T cells to histamine appears also to reflect their site of origin, for peritoneal exudate effector cells were found to be significantly less sensitive than spleen cells to inhibition by histamine. The progressive increase in inhibition by histamine apparently reflects the appearance of greater numbers of specific histamine-type 2 receptors, and is probably a general phenomenon, for spleen cells from A/J or C3H mice immunized with either P815 mastocytoma (H-2d) or EL-4 (H-2b) cells showed the same effect. However, the appearance of histamine receptors could be altered by prior immunization with an unrelated alloantigen: thus, when A/J mice are preimmunized with EL-4, a subsequent immunization with mastocytoma cells results in peak spleen anti-H-2d activity at day 9 instead of days 11-13, and the appearance of significant (greater than 40 percent) inhibition by histamine as early as day 8 instead of day 16. The physiological role of the histamine receptors is as yet undefined, though their unexpected rate of appearance on effector T cells, coincident with a decline in the number of lytically active cells in vivo, may be a significant hint that hormone receptors play a role in the control of T-cell proliferation.

Animals↗
PubMed1992

Presynaptic histamine H1 and H3 receptors modulate sympathetic ganglionic synaptic transmission in the guinea-pig.

1. To study the effects of histamine on the efficacy of sympathetic ganglionic synaptic transmission, extracellular recordings of the postganglionic compound action potential (CAP) and intracellular recordings of excitatory postsynaptic potentials (EPSPs) elicited by preganglionic electrical stimulation were obtained from isolated guinea-pig superior cervical ganglia (SCG). 2. In different preparations, superfusion with histamine (0.1-100 microM) either potentiated or depressed the postganglionic CAP elicited by electrical stimulation of the cervical sympathetic trunk (0.2-3.0 Hz). The direction of response produced by histamine did not depend on stimulation frequency or histamine concentration; potentiation and depression both showed concentration dependence over the range of histamine concentrations tested. 3. Experiments employing a variety of histamine receptor agonists or antagonists revealed that histamine-induced potentiation of the postganglionic CAP could be attributed to histamine H1 receptor activation, and depression to H3 receptor activation. 4. Histamine similarly potentiated or depressed the intracellularly recorded EPSP. However, these opposite effects occurred at different synapses. In agreement with the studies on the postganglionic CAP, histamine H1 antagonists prevented histamine-induced potentiation of the EPSP and H3 receptor antagonists prevented histamine-induced depression. 5. Direct quantal analyses of histamine-induced synaptic potentiation and depression were implemented to determine the pre- and postsynaptic components of these effects. Quantal size was estimated by measuring the amplitude of spontaneous miniature EPSP amplitudes. Histamine-induced potentiation and depression of the evoked EPSP were found to be accompanied by increased or decreased quantal content respectively, and unchanged quantal size, providing evidence that presynaptic mechanisms were involved in mediating both effects. 6. Some guinea-pigs were actively sensitized to ovalbumin. Subsequent exposure of the isolated SCG from these animals to the sensitizing antigen produced changes in the EPSP amplitude that correlated significantly to the response produced by exogenously applied histamine at the same synapse. 7. The correspondence between the effects of specific antigen challenge and exogenous histamine on evoked EPSPs at a synapse provides evidence that endogenous histamine released during an immunological response to antigen challenge can activate histamine H1 and H3 receptors to modulate synaptic efficacy in sympathetic ganglia.

Action Potentials↗
PubMed2000

Gastric submucosal microdialysis: a method to study gastrin- and food-evoked mobilization of ECL-cell histamine in conscious rats.

Rat stomach ECL cells are rich in histamine and chromogranin A-derived peptides, such as pancreastatin. Gastrin causes the parietal cells to secrete acid by flooding them with histamine from the ECL cells. In the past, gastric histamine release has been studied using anaesthetized, surgically manipulated animals or isolated gastric mucosa, glands or ECL cells. We monitored gastric histamine mobilization in intact conscious rats by subjecting them to gastric submucosal microdialysis. A microdialysis probe was implanted into the submucosa of the acid-producing part of the stomach (day 1). The rats had access to food and water or were deprived of food (48 h), starting on day 2 after implantation of the probe. On day 4, the rats received food or gastrin (intravenous infusion), and sampling of microdialysate commenced. Samples (flow rate 1.2 microl min(-1)) were collected every 20 or 60 min, and the histamine and pancreastatin concentrations were determined. The serum gastrin concentration was determined in tail vein blood. Exogenous gastrin (4-h infusion) raised microdialysate histamine and pancreastatin dose-dependently. This effect was prevented by gastrin receptor blockade (YM022). Depletion of ECL-cell histamine by alpha-fluoromethylhistidine, an irreversible inhibitor of the histamine-forming enzyme, suppressed the gastrin-evoked release of histamine but not that of pancreastatin. Fasting lowered serum gastrin and microdialysate histamine by 50%, while refeeding raised serum gastrin and microdialysate histamine and pancreastatin 3-fold. We conclude that histamine mobilized by gastrin and food intake derives from ECL cells because: 1) Histamine and pancreastatin were released concomitantly, 2) histamine mobilization following gastrin or food intake was prevented by gastrin receptor blockade, and 3) mobilization of histamine (but not pancreastatin) was abolished by alpha-fluoromethylhistidine. Hence, gastric submucosal microdialysis allows us to monitor the mobilization of ECL-cell histamine in intact conscious rats under various experimental conditions not previously accessible to study. While gastrin receptor blockade lowered post-prandial release of ECL-cell histamine by about 80%, unilateral vagotomy reduced post-prandial mobilization of ECL-cell histamine by about 50%. Hence, both gastrin and vagal excitation contribute to the post-prandial release of ECL-cell histamine.

Animals↗
PubMed1992

Cholinergic and H1-receptor influences of histamine on slowly adapting pulmonary stretch receptor activity in the rabbit.

Afferent impulses of slowly adapting pulmonary stretch receptors (SARs) were obtained by dissecting fine slips from the left vagus nerve (LVN) and by leaving the rest of the nerve intact. In the same SAR preparation, changes of the receptor activity in response to right atrial injections of histamine (10 and 60 micrograms/kg) were successively examined before and after atropine (1 mg/kg), partial vagal efferent ablation, and mequitazine (1 mg/kg) in 10 rabbits. Administration of histamine led to an increase in the SAR activity, and this effect became more pronounced by increasing the dose of histamine. Atropine treatment diminished the responses of SARs to histamine at different doses. Partial vagal efferent ablation produced by denervation of the rest of the intact LVN slightly reduced the response of SARs to histamine at 10 micrograms/kg but had no significant effect on the SAR response to 60 micrograms/kg histamine. In the absence of vagal afferent and efferent activities on the left side, mequitazine, a potent H1-receptor blocker, completely blocked low- and high-dose effects of histamine on SARs. We compared the responses of the receptor activity to aerosol histamine (1 and 4%) and to topical application of histamine (0.1 ml, 0.025% and 0.1%) in six SAR preparations. The magnitude and duration of increased SAR activity became more prominent by increasing the concentration of histamine. The firing pattern and discharge rate of SARs following aerosol or intratracheal administration of histamine were similar to those after intra-atrial histamine. In addition, we also examined the excitatory responses of SAR activity to right atrial injections of histamine at 10 and 60 micrograms/kg before and after topical administration of atropine (0.1 ml, 1%, n = 6) or mequitazine (0.1 ml, 1%, n = 6) in 12 SAR preparations. Intratracheal atropine diminished the response of SARs to 10 micrograms/kg of histamine but had no significant effect on the response of SARs to histamine at 60 micrograms/kg. All the responses of SARs to histamine were completely blocked by topical application of mequitazine. These results suggest that the change of SAR activity produced by histamine at 10 micrograms/kg occurs mainly as a result of the release of acethylcholine (ACh) via the vagovagal reflex and that the activation of H1-receptors of the airway smooth muscle contributes importantly to the response of SARs to histamine at 60 micrograms/kg.

Acetylcholine↗
PubMed2001

Inhibition of effects of endogenously synthesized histamine disturbs in vitro human dendritic cell differentiation.

Histamine, a principal mediator in various physiological and pathological cell functions is synthesized from L-histidine exclusively by histidine decarboxylase, an enzyme, which is expressed in many tissues of mammalian organism. Histamine plays a role in various cellular functions, including cell differentiation. The aim of this study was to determine the presence and to characterize the role of the endogenously produced histamine during in vitro dendritic cell (DC) differentiation induced by interleukin-4 (IL-4) and granulocyte-monocyte colony stimulating factor (GM-CSF). The changes in intracellular histamine content, biosynthesis and gene expression of histidine decarboxylase were investigated during this process. One also studied how histamine receptor antagonists and a histamine synthesis blocker influence the expression of differentiation antigens on the DC during in vitro maturation. During in vitro differentiation parallel culture incubations were performed by adding H1 receptor antagonist triprolidine, H2 receptor antagonist tiotidine, the tamoxifene derivate DPPE which blocks the intracellular binding of histamine, and an irreversible blocker of histidine decarboxylase, alpha-fluoromethyl histamine (alpha-FMH). The results show simultaneous increase in both histidine decarboxylase level and histamine content during differentiation of elutriated monocytes toward DC. Both blockade of de novo histamine production (by alpha-FMH) and inhibition of histamine binding (by H1 and H2 receptor antagonists, triprolidine and tiotidine, respectively) markedly decreased CD40 expression and that of CD45 from the 3rd day of treatment. DPPE by disturbing intracellular interaction of histamine with cytochrome P-450 moieties was able to decrease the expression of CD45, CD86, HLA-DR, CD33, CD40 and CD11c. Based on the data it is suggested that endogenous histamine is actively synthesized during cytokine-induced in vitro DC differentiation. The functional relevance and autocrine and paracrine action of endogenously produced histamine is supported by the data showing that inhibition of histamine synthesis by HDC, blocking of histamine binding by both 'extracellular' histamine receptors (by specific antagonists, triprolidine and tiotidine) and 'intracellular' antagonists (DPPE) disturb the differentiation of DC. This conclusion is supported by the fact, that by the inhibition of histamine acting in an autocrine/paracrine way, the expression pattern of differentiation markers on DC is markedly changed.

Antigens, CD↗
PubMed1998

R-(-)-alpha-methyl-histamine has nitric oxide-mediated vasodilator activity in the mesenteric vascular bed of the cat.

Responses to the histamine H3 receptor agonist R-(-)-alpha-methyl-histamine were investigated in the mesenteric vascular bed of the cat under constant-flow conditions. Injections of R-(-)-alpha-methyl-histamine and histamine caused dose-related decreases in mesenteric perfusion pressure with R-(-)-alpha-methyl-histamine being 1000-fold less potent than histamine when doses were compared on a nmol basis to take molecular weight into account. Responses to R-(-)-alpha-methyl-histamine were not altered by histamine H1 or H2 receptor antagonists at a time when responses to histamine were significantly reduced. The histamine H3 receptor antagonist thioperamide reduced responses to R-(-)-alpha-methyl-histamine but was without effect on responses to histamine [6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoro-methylphenyl)heptaneca rdoxamide dimaleate] (HTMT), or dimaprit. These data suggest the presence of histamine H1, H2 and H3 receptors mediating vasodilation in the mesenteric vascular bed. Responses to R-(-)-alpha-methyl-histamine and histamine were reduced by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) but were not altered by the cyclooxygenase inhibitor meclofenamate, the alpha-adrenoceptor blocker phentolamine, or adrenergic nerve terminal depleting agent reserpine. The present data suggest that histamine H3 receptors mediating vasodilation are present in the mesenteric vascular bed and that responses are mediated by the release of nitric oxide but not vasodilator prostaglandins or an effect on the adrenergic nervous system. These results indicate that vasodilator responses to histamine involve the activation of histamine H1 and H2 receptors and the release of nitric oxide in the mesenteric vascular bed of the cat.

Animals↗
PubMed1993

Desensitization of histamine H1 receptor-mediated inositol phosphate production in HeLa cells.

1. Histamine stimulated the accumulation of total [3H]-inositol phosphates (IPn) in control HeLa cells with an EC50 of 3.7 +/- 0.7 microM in the presence of 10 mM LiCl. The maximum response to histamine after 15 min incubation was 43 +/- 5% over basal accumulation and occurred at a concentration of 1 mM histamine. 2. The histamine-induced IPn production in HeLa cells was confirmed as H1 receptor-mediated, since the H1 antagonist mepyramine (10(-6) M) inhibited the histamine response (10(-4) M) by 83 +/- 7%, whereas the H2 antagonist, ranitidine (10(-4) M), and H3 antagonist, thioperamide (10(-6) M), were ineffective. 3. Histamine (10(-4) M) pretreatment of HeLa cells for 30 min desensitized the subsequent histamine-induced IPn accumulation. The desensitized cells accumulated IPn in response to histamine with an EC50 of 1.7 +/- 0.7 microM after 15 min incubation. The maximum histamine-induced IPn accumulation at 10(-4) M was 19 +/- 5% over basal and was significantly lower (P < 0.03) than the maximum response in control cells. 4. The desensitization of histamine-induced IPn accumulation was time-dependent and, at a desensitizing histamine concentration of 10(-4) M, the half-maximal attenuation occurred after approximately 9 min and maximum desensitization was achieved by 15-20 min. The desensitization of the IPn accumulation was a reversible phenomenon and full recovery of the response occurred 150 min after the removal of the desensitizing histamine-containing medium. The half-time for the recovery of the histamine-induced response was estimated at 120 min. 5. Bradykinin stimulated IPn, accumulation in HeLa cells, and the ECm in control cells of 1.9 +/- 0.2 nM was not significantly different from the EC50 value from histamine-pretreated cells of 1.6 +/- 0.9 nM. The bradykinin response at 1 microM was 194 +/- 48% over basal IPn accumulation in control cells and this value was significantly different (P <0.04) from the 1 microM bradykinin-induced IPn accumulation in histamine pretreated HeLa cells of 143 +/- 38% over basal.6. NaF stimulated IP,, accumulation in control HeLa cells in a dose-related manner, with the maximum effect occurring at 15-20 mM. The EC50 value for NaF-stimulated IPn accumulation in control cells was 10.5 +/- 1.1 mm and the maximum response was 136 +/- 41% over basal after 20 min incubation. In histamine desensitized HeLa cells the EC50 value for NaF was 12.3 +/- 0.4 mM after 20 min stimulation,which was not significantly different from the value obtained in control cells. The maximum NaF stimulated IPn formation in desensitized cells of 68 +/- 23% over basal occurred at 15 -20 mM and was significantly lower (P<0.01) than that obtained in control cells.7. We show here that the acute histamine pretreatment of HeLa cells results in the desensitization of histamine H1 receptor-mediated IPn production. The desensitization was not restricted to the H1 receptor-mediated signal transduction pathway, but also includes both the bradykinin- and NaF mediated responses, supporting a heterologous desensitization mechanism. Our results are consistent with the site of attenuation being at or distal to the G-protein and the underlying mechanism being a slowed time-course for the production of inositol phosphates.

Bradykinin↗
PubMed1971

Further studies on histamine catabolism in vivo.

1. Histamine catabolism in vivo was studied in mice and rats; tissues from animals killed 2.5 min after intravenous injection of (14)C-histamine were assayed for (14)C-histamine and total (14)C. Aminoguanidine, a diamine oxidase inhibitor, and methylhistamine, an inhibitor of the histamine methylating enzyme, were used to evaluate the roles of these enzymes in individual tissues.2. Mouse liver and lung appeared to catabolize exogenous histamine rapidly and completely by methylation. In vivo histamine methylating activity was also found in mouse muscle, heart, kidney and lymph node, but not in stomach or intestine.3. In rats (14)C-histamine was inactivated more slowly than in mice. Catabolism was most rapid in intestine where both diamine oxidase and methylating activities were found. Liver had only diamine oxidase activity. Heart showed no catabolism but had extraordinary ability to extract (14)C-histamine from blood.4. The in vivo evaluation of histamine methylation by individual mouse and rat tissues agrees closely with in vitro findings by another laboratory.5. Aminoguanidine reduced uptake of blood (14)C-histamine by some tissues presumably by occupying sites where histamine is normally bound.6. The marked differences between tissues of mice and rats in destroying (14)C-histamine support earlier evidence that there is no apparent relationship between histamine catabolism and function.7. Urine from mice with both major catabolic pathways blocked showed evidence of an abnormal excretory product of (14)C-histamine. Paper chromatograms of urine of male and female mice showed no evidence of a sex difference in catabolism of injected (14)C-histamine.8. A procedure which may permit evaluating contributions of individual tissues to histamine formation in vivo is presented.9. Pretreatment of mice with antihistamines, or with a histamine analogue, betahistine, did not significantly affect the rate of in vivo(14)C-histamine inactivation.

Amine Oxidase (Copper-Containing)↗
PubMed2003

Molecular and pharmacological characterization of the mouse histamine H3 receptor.

Human, guinea pig and rat histamine H(3) receptors have been investigated at both pharmacological and molecular levels in recent years. Here we report the cloning, molecular, and pharmacological characterization of the mouse histamine H(3) receptor. The amino acid sequence of the mouse histamine H(3) receptor exhibits high homology to rat, guinea pig and human histamine H(3) receptors with 98%, 95%, 94% identities, respectively. The distribution of the mRNA encoding the mouse histamine H(3) receptor was predominant in the brain as detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and RNase protection assay. Although several splice forms have been reported for human, guinea pig and rat histamine H(3) receptor mRNAs, we did not detect equivalent isoforms in the mouse in several tissues by either RNase protection assay or robust Polymerase Chain Reaction (PCR) amplifications. Human embryonic kidney (HEK)-293 cells transiently transfected with mouse histamine H(3) receptor cDNA and Gq(i5) exhibited increases of intracellular Ca(2+) in response to histamine and several histamine H(3) receptor agonists. COS-7 (African green monkey kidney) cells transfected with mouse histamine H(3) receptor cDNA showed high affinity binding for histamine H(3) receptor ligands in competition binding assays. The pharmacological comparison of human, guinea pig, rat and mouse histamine H(3) receptors indicated that, as expected, the mouse histamine H(3) receptor exhibited a more similar pharmacological profile to the rat histamine H(3) receptor than to either the human or the guinea pig histamine H(3) receptor. Taken together, these findings allow a further appreciation of the histamine H(3) receptor at the molecular level and provide an additional species to assist in the pharmacological assessment of histamine H(3) receptor function.

Alternative Splicing↗
PubMed2002

Excitatory effects of histamine on cerebellar interpositus nuclear cells of rats through H(2) receptors in vitro.

Neuroanatomical studies have revealed a direct hypothalamocerebellar histaminergic pathway, and our previous studies have demonstrated an excitatory effect of histamine on granule and Purkinje cells of the cerebellar cortex. In this study, we further investigated the effect of histamine on the neuronal firing of cerebellar interpositus nucleus (IN) by using cerebellar slice preparations. Eighty-seven IN cells were recorded from 38 slices. The vast majority of the cells responded to histamine stimulation with an excitatory response (79/87, 90.8%), and the rest of them showed no reaction (8/87, 9.2%). The histamine-induced excitation was not blocked by application of low-Ca(2+)/high-Mg(2+) medium (n=8), supporting a direct postsynaptic action of histamine. The histamine H(2) receptor antagonist ranitidine effectively blocked the excitatory response of IN cells to histamine (n=23), but the histamine H(1) receptor antagonist triprolidine could not significantly block the histamine-induced excitation, or only very slightly decreased the excitatory effect of histamine on the cells (n=21). On the other hand, the highly selective histamine H(2) receptor agonist dimaprit mimicked the excitatory effect of histamine on IN cells and the dimaprit-induced excitation was also blocked by ranitidine (n=14). Successively perfusing slices with the medium containing ranitidine and triprolidine, respectively, we found that ranitidine exhibited the same blocking effect on the dimaprit-induced excitation, but triprolidine had no such effect (n=8). Moreover, the histamine H(1) receptor agonist 2-pyridylethylamine did not show any effect on the IN cells (n=9). These results demonstrate that histamine excites cerebellar IN cells via the histamine H(2) receptor mechanism. Together with our previous results, we suggest that the hypothalamocerebellar histaminergic fibers may modulate neuronal activities of the cerebellar cortex and deep nuclei in parallel. The significance of the excitatory effect of histamine on the cerebellar nuclear cells is discussed.

Animals↗
PubMed1992

The role of gastric secretagogues in regulating gastric histamine release in vivo.

The effect of short-term intragastric arterial infusion of pentagastrin and methacholine on histamine and N tau-methyl histamine secretory rates was evaluated in mongrel dogs in vivo. Doses of pentagastrin and methacholine were chosen that stimulate gastric acid secretion equivalently. Histamine and N tau-methyl histamine secretory rates were evaluated by measuring the arterial and gastric venous plasma histamine and N tau-methyl histamine concentrations at several time points during the secretagogue infusion, and gastric blood flow was continuously monitored. Histamine and N tau-methyl histamine plasma concentrations were analyzed by stable isotope dilution technique using gas chromatography/negative ion-chemical ionization mass spectrometry. Histamine and N tau-methyl histamine secretory rates were calculated by subtracting the arterial from the venous plasma concentrations and multiplying the difference by gastric plasma flow. Infusion of pentagastrin resulted in large pulsed increase of histamine release from 1.5 +/- 0.7 ng/min at time 0 to 72 +/- 20 ng/min at 5 minutes, which decreased to a plateau of 20 +/- 8 ng/min at 20 minutes. N tau-Methyl histamine secretory rate increased from 6.7 +/- 1.9 ng/min at baseline to a maximum of 42.5 +/- 13.1 ng/min at 10 minutes, and the increase was maintained for the duration of the pentagastrin infusion. Methacholine infusion was associated with a small but sustained increase in histamine release, from a baseline of 1.6 +/- 0.6 ng/min to 5.9 +/- 1.7 ng/min at 5 minutes. N tau-Methyl histamine secretory rate was unchanged by methacholine. Gastric blood flow changes to pentagastrin roughly paralleled the extent of histamine release, but methacholine is a gastric vasodilator in its own right. Our data indicate that pentagastrin is a much more effective stimulator of gastric histamine release than methacholine and that the overall role of histamine in gastrin-stimulated acid output is likely to be different from the role of histamine in cholinergic-mediated gastric acid output.

Analysis of Variance↗
PubMed1995

The role of histamine in human penile erection.

OBJECTIVE: To investigate the relaxant action of histamine on human corpus cavernosum in vitro and the erectile response caused by the intracavernous injection of histamine in patients with psychogenic impotence. PATIENTS AND METHODS: Human corpus cavernosum (HCC) tissue was cut into strips of approximately 2 cm and suspended in a cascade bioassay. The strips were then superfused with oxygenated and warmed Krebs solution and precontracted with noradrenaline (3 microM). Glyceryl trinitrate, acetylcholine and histamine were injected as a single bolus in the absence or in the presence of mepyramine and cimetidine. For the in vivo studies, histamine (30-60 micrograms) was injected intracavernously as a single bolus into the right corpus cavernosum 1 cm from the balamo-preputial sulcus. Similar protocols were carried out for papaverine (50 mg). The erectile response was divided into four grades: no response, tumescence, partial and full erection. RESULTS: In vitro studies demonstrated that histamine (3-100 micrograms) caused dose-dependent relaxation of the HCC strips which was significantly inhibited by cimetidine (5-10 microM). The histamine H1 receptor antagonist mepyramine (1 microM) potentiated histamine-induced relaxation. The co-infusion of both mepyramine and cimetidine did not abolish histamine-induced relaxation. When injected intracavernously in humans, histamine (30 micrograms) caused full erection in 13% of the patients, whereas 87% had partial erection or tumescence. A higher dose of histamine (60 micrograms) caused full erection in 26% of the patients and 74% had partial erection or tumescence. Papaverine induced full erection in the majority of patients (66%). In contrast to papaverine, the duration of erection induced by histamine was markedly shorter (mean 200 and 6.5 min, respectively). The penile erections induced by papaverine were associated with complications such as pain, haematoma and priapism. Histamine did not induce any complications. Treatment of eight male patients with psychogenic impotence with the histamine H1 receptor antagonist astemizol (10 mg orally once daily for 1 week) did not affect histamine-induced erectile responses. CONCLUSION: These results indicate that histamine may play a role in human penile erection. The erection-promoting action of histamine is probably due to H2 receptor activation, although another histamine receptor, possibly H3, also seems to be involved. This study suggests that histamine could be a valuable tool in the diagnosis of erectile dysfunction.

Adult↗
PubMed1991

Histamine-induced inositol phosphate accumulation in HeLa cells: lithium sensitivity.

1. In the presence of 10 mM Li+ the histamine-stimulated accumulation of [3H]-inositol monophosphates [( 3H]-IP1) in HeLa cells prelabelled with [3H]-inositol increased over 10-20 min to a plateau level, which was normally maintained up to 60 min. Levels of [3H]-inositol bis- and trisphosphates [( 3H]-IP2 and [3H]-IP3) initially increased rapidly but declined to near basal levels by 20 min. 2. The same pattern of histamine-induced [3H]-IP1 accumulation was observed in cells in which [3H]-inositol was present 30 min before and during the incubation with histamine. Concentration-response curves for histamine measured in the presence of 10 mM Li+ were closely similar in cells prelabelled for 24 h with [3H]-inositol and in cells exposed to [3H]-inositol for only 30 min before addition of histamine, without removing the [3H]-inositol. The EC50 for histamine was 1.6 +/- 0.2 microM. 3. [3H]-IP1 accumulation induced by a sub-maximal concentration of histamine, 1 microM, also reached a plateau, but at a lower level than with 1 mM histamine. 4. Addition of 10 mM NaF at the plateau phase of [3H]-IP1 accumulation induced by 1 mM histamine resulted in a further increase in the level of [3H]-IP1. The level of [3H]-IP1 in the presence of histamine + NaF was 1.4 +/- 0.2 fold of that of the sum of the responses to histamine and NaF acting alone (basal levels subtracted). 5. Addition of 1 microM mepyramine at the plateau phase of [3H]-IP1 accumulation induced by 1 mM histamine in the presence of 10mM Li + resulted in a decline in the level of [3H]-IP1, implying that the metabolism of [3H]-IP1 is not completely blocked by 10mM Li' in HeLa cells. 6. Omission of the 15 min preincubation period with 10mM Li+ before stimulation with 100 microM histamine for 15 min resulted in an approximate halving of the level of [3H]-IP1, without any significant change in basal accumulation. Periods of preincubation with 10mM Li' longer than 15min did not produce any further increase in the level of [3H]-IP1 induced by histamine. 7. Basal and histamine-induced levels of [3H]-IP, increased as the concentration of Li+ was increased from 0 to 60mm, but the effect on the histamine-induced response was greater than on the basal level. Increasing the concentration of Li+ from 0 to 60 mm had only a small and mostly statistically insignificant effects on the levels of [3H]-1P2 and [3H]-1P3. The EC50 for histamine-induced [3H]-4P1 accumulation in the presence of 30mm Li + was 2.4 +/- 0.4 microM. 8. The results indicate that IP1 metabolism in HeLa cells is much less sensitive to Li+ than in mammalian brain. The plateau phase of histamine-induced [3H]-IP1 accumulation in the presence of 10mM Li+ thus represents a steady-state level. On a simple model the plateau level will be proportional to the rate of [3H]-IP1 formation at that time. The lower the concentration of Li' present, the better the approximation will be. The information obtained is thus not the same as when [3H]-1P, metabolism is completely blocked, in which case [3H]-IP1 accumulated can be used to calculate a mean rate of formation over the whole of the incubation period.

Fluorides↗
PubMed1986

H1-histamine receptors on human astrocytoma cells.

The H1-histamine receptor antagonist [3H]mepyramine bound with high affinity (Kd = 3-5 nM) to membranes derived from 1321N1 human astrocytoma cells. The H1-receptor antagonists triprolidine and diphenhydramine inhibited [3H]mepyramine binding with Kj values of 1-5 nM, whereas the Kj of the H2-histamine receptor antagonist cimetidine was greater than 100 microM. Histamine also inhibited [3H]mepyramine binding to 1321N1 cell membranes, and the histamine inhibition curve was shifted to the right and steepened in the presence of 1 microM guanosine 5'-O-(3-thiotriphosphate). Treatment of 1321N1 cells with pertussis toxin had no effect on the capacity of histamine to inhibit [3H]mepyramine binding either in the absence or presence of guanosine 5'-O-(3-thiotriphosphate). Therefore, agonist-occupied histamine receptors in these cells apparently interact with a guanine nucleotide regulatory protein that is not the inhibitory guanine nucleotide regulatory protein of adenylate cyclase. Although adenylate cyclase activity was not affected by histamine in a cell-free preparation, incubation of 1321N1 cells with histamine resulted in an attenuation of cyclic AMP accumulation. Analysis of cyclic AMP degradation in the presence of histamine indicated that the effects of histamine on cyclic AMP accumulation are mediated through activation of phosphodiesterase. This idea was supported by the fact that the phosphodiesterase inhibitor 1-isobutyl 3-methylxanthine blocked attenuation of cyclic AMP accumulation by histamine in a noncompetitive manner. Histamine also markedly increased phosphoinositide breakdown and 45Ca2+ efflux in 1321N1 cells. These histamine-induced effects apparently are mediated through H1-receptors, since triprolidine, but not cimetidine, potently inhibited histamine action. As for histamine interaction with its receptor, pertussis toxin had no effect on histamine-induced phosphoinositide breakdown, 45Ca2+ efflux, or attenuation of cyclic AMP accumulation. Taken together, these data indicate that 1321N1 human astrocytoma cells are a useful model system for the study of H1-histamine receptors and the biochemical responses mediated through these receptors.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Paracellular tightness and catabolism restrict histamine permeation in the proximal colon of pigs.

Luminal histamine concentrations can be very high in the intestine without eliciting clinical histaminosis. The intestinal mechanisms that possibly prevent systemic intoxication by luminal histamine were investigated in the present study. Porcine colonic epithelia were mounted in Ussing chambers. After unilateral application of partially (3)H-labelled histamine, mucosal-to-serosal (MS) and serosal-to-mucosal (SM) flux rates were calculated from the contralateral appearance of histamine and the radioactive histamine label (hist-rad; representing histamine plus catabolites). A discrepancy between histamine and hist-rad fluxes was observed in both flux directions, indicating efficient histamine catabolism at all histamine concentrations tested (5, 50 and 100 microM). Catabolism exceeded 65% at 100 microM histamine and reached approximately 100% at 5 microM histamine. Blockade of histamine N-methyltransferase by amodiaquin (100 microM) abolished catabolism completely, whereas blockade of diamine oxidase by aminoguanidine (100 microM) was less effective. MS fluxes of histamine and hist-rad correlated with mannitol fluxes. Mast cell stimulation with the calcium ionophore A23187 (1 microM) induced a twofold larger histamine appearance on the serosal side than the mucosal application of 100 microM histamine. It is concluded that histamine permeation across the porcine proximal colon is restricted by low permeability and sequential catabolism by histamine N-methyltransferase and diamine oxidase.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Characteristics of histamine-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery.

1. The main objective of this study was to analyse the role and mode of action of the mast cell mediator histamine in leukocyte-endothelium interactions in small venules in vivo. For this purpose, we used a histological approach (combined with intravital microscopy) that allows studies of rapid mediator-induced venular leukocyte accumulation, reflecting leukocyte rolling, in the undisturbed microcirculation of the rat mesentery where rolling is normally absent. 2. We first examined the relative importance of histamine and 5-hydroxytryptamine (5-HT) in acute mast cell-dependent leukocyte recruitment. The mast cell secretagogue compound 48/80 (i.p. for 15 min) induced a marked venular accumulation of polymorphonuclear leukocytes (PMNL) which was almost abolished by combined histamine1 (H1)- and histamine2 (H2)-receptor blockade. In contrast, the 5-HT-receptor antagonist methysergide was inactive in this regard. Moreover, exogenous 5-HT was less active than exogenous histamine in evoking venular PMNL accumulation (histamine response dose-dependent; 5-HT response bell shaped). Prostaglandin D2 did not cause PMNL accumulation. 3. The venular PMNL response to exogenous histamine peaked between 15 min and 1 h, was still significantly elevated at 2 h, and then returned to prechallenge values after 3 h. At all time points, the histamine-induced PMNL accumulation was nearly abolished by i.v. treatment with the polysaccharide fucoidin (which blocks rolling but not firm adhesion per se), suggesting that the PMNL response to histamine was due to rolling rather than firm adhesion over the entire 3 h period. At no time point did histamine trigger accumulation of mononuclear leukocytes (MNL). 4. To examine the role of histamine-receptors in the histamine-induced PMNL accumulation (i.e. rolling), the animals were pretreated with diphenhydramine (H1-receptor antagonist), cimetidine, or ranitidine (H2-receptor antagonists). Diphenhydramine alone inhibited the venular PMNL response to histamine by 52%, while both H2-receptor antagonists were completely inactive. However, the combination of cimetidine and diphenhydramine reduced the histamine-induced PMNL rolling by 82%. Furthermore, in contrast to an H3-receptor agonist, challenge with either the H1-receptor agonist 2-thiazolylethylamine or two different H2-receptor agonists (impromidine, dimaprit) was sufficient to provoke significant venular PMNL accumulation. 5. Treatment with the nitric oxide-synthase inhibitor L-NAME did not affect the histamine-induced PMNL rolling. On the other hand, 3 h pretreatment with dexamethasone reduced the PMNL response to histamine by 73%, and flow cytometric analysis showed that the dexamethasone treatment almost completely inhibited binding of soluble P-selectin to rat isolated PMNLs. 6. We conclude that initial leukocyte recruitment after mast cell activation in the rat mesentery is critically dependent on histamine release. The cellular response to histamine was specifically due to PMNL rolling, involved activation of both H1- and H2-receptors, and lasted for 2 3 h. Moreover, the histamine-induced PMNL rolling was not dependent on nitric oxide synthesis, but was sensitive to glucocorticoid treatment, possibly via inhibition of expression or function of leukocytic P-selectin ligand(s).

Animals↗
PubMed2003

Submucosal microinfusion of endothelin and adrenaline mobilizes ECL-cell histamine in rat stomach, and causes mucosal damage: a microdialysis study.

Rat stomach ECL cells release histamine in response to gastrin. Submucosal microinfusion of endothelin or adrenaline, known to cause vasoconstriction and gastric lesions, mobilized striking amounts of histamine. While the histamine response to gastrin is sustainable for hours, that to endothelin and adrenaline was characteristically short-lasting (1-2 h). The aims of this study were to identify the cellular source of histamine mobilized by endothelin and adrenaline, and examine the differences between the histamine-mobilizing effects of gastrin, and of endothelin and adrenaline. Endothelin, adrenaline or gastrin were administered by submucosal microinfusion. Gastric histamine mobilization was monitored by microdialysis. Local pretreatment with the H1-receptor antagonist mepyramine and the H2-receptor antagonist ranitidine did not prevent endothelin- or adrenaline-induced mucosal damage. Submucosal microinfusion of histamine did not cause damage. Acid blockade by ranitidine or omeprazole prevented the damage, suggesting that acid back diffusion contributes. Gastrin raised histidine decarboxylase (HDC) activity close to the probe, without affecting the histamine concentration. Endothelin and adrenaline lowered histamine by 50-70%, without activating HDC. Histamine mobilization declined upon repeated administration. Endothelin reduced the number of histamine-immunoreactive ECL cells locally, and reduced the number of secretory vesicles. Thus, unlike gastrin, endothelin (and adrenaline) is capable of exhausting ECL-cell histamine. Microinfusion of alpha-fluoromethylhistidine (known to deplete ECL cells but not mast cells of histamine) reduced the histamine-mobilizing effect of endothelin by 80%, while 1-week pretreatment with omeprazole enhanced it, supporting the involvement of ECL cells. Somatostatin or the prostanoid misoprostol inhibited gastrin-, but not endothelin-stimulated histamine release, suggesting that endothelin and gastrin mobilize histamine via different mechanisms. While gastrin effectively mobilized histamine from ECL cells in primary culture, endothelin had no effect, and adrenaline, a modest effect. Hence, the striking effects of endothelin and adrenaline on ECL cells in situ are probably indirect, possibly a consequence of ischemia.

Animals↗
PubMed2005

Histamine-induced vasodilation and vasoconstriction in the mesenteric resistance artery of the rat.

The present study was designed to examine the vascular response to histamine in rat perfused mesenteric vascular beds with active tone. In preparations with intact endothelium, perfusion of histamine (1 nM-100 microM) produced a concentration-dependent vasodilation. Histamine-induced vasodilation was attenuated by L-NAME (nitric oxide (NO) synthase inhibitor, 100 microM) and olopatadine (histamine H(1) receptor antagonist, 1 microM) but not by lafutidine (histamine H(2) receptor antagonist, 1 microM). Cold-storage denervation (4 degrees C for 72 h) of the preparation with intact endothelium attenuated the histamine-induced vasodilation. In preparations without endothelium, histamine at low concentrations (1-100 nM) produced only a small and rapid vasodilation, whereas histamine at concentrations higher than 1 muM produced triphasic vascular responses: initial sharp vasodilation followed by transient vasoconstriction and subsequent gradual vasodilation. Lafutidine abolished only the histamine-induced initial vasodilation. Olopatadine abolished the histamine-induced second vasoconstriction and third vasodilation. Cold-storage denervation of the denuded preparation abolished the histamine-induced second vasoconstriction and third vasodilation. These findings suggest that histamine induced endothelium-dependent vasodilation via endothelium histamine H(1) receptors and endothelium-independent vasodilation via smooth muscle histamine H(2) receptors. It is also suggested that the histamine-induced endothelium-independent vasoconstriction and vasodilation are mediated by histamine H(1) receptors and perivascular nerves.

Animals↗