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PubMed2005

Excitatory effect of histamine on neuronal activity of rat globus pallidus by activation of H2 receptors in vitro.

Previous studies have revealed distribution of histaminergic fibers and presence of histamine receptors in globus pallidus (GP). In this study, the brain slice preparation of adult rats was used to examine the effect of histamine on the spontaneous unitary discharge of GP neurons and the underlying receptor mechanism. Ninety-five GP neurons were extracellularly recorded from 42 slices containing the GP, of which 87 (91.6%) were excited by the stimulation of histamine. The histamine-induced excitation was concentration-dependent and persisted in low Ca2+/high Mg2+ medium (n = 9), demonstrating that the action of histamine on the GP neurons was postsynaptic. The excitatory effect of histamine on the GP neurons was not blocked by selective histamine H1 receptor antagonist triprolidine (n = 16) or chlorpheniramine (n = 6), but was effectively suppressed by ranitidine, a highly selective histamine H2 receptor antagonist (n = 21). On the other hand, highly selective histamine H2 receptor agonist dimaprit mimicked the excitatory effect of histamine on the GP neurons (n = 23), while histamine H1 receptor agonists, including 2-pyridylethylamine (n = 22), 2-thiazolyethylamine (n = 9) and betahistine (n = 9), did not cause GP neurons any response. The dimaprit-induced GP neuronal excitation was effectively antagonized by selective histamine H2 receptor antagonist ranitidine (n = 14) but not influenced by selective histamine H1 receptor antagonist triprolidine (n = 12). Moreover, adenylate cyclase (AC) activator forskolin (n = 7) was observed to evoke GP neurons an excitatory response, whereas the histamine-induced excitation was effectively reduced by H-89 (n = 9), a selective and potent inhibitor of protein kinase A (PK(A)). Finally, it was noted that neurons of both subdivisions of the GP, the internal (GPi, n = 35) and external (GPe, n = 60) segment, showed no differences in their responses to stimulations of the tested histaminergic reagents. These results demonstrated that histamine excited GP (including GPi and GPe) neurons via histamine H2 receptors and H2 receptors linked intracellular G-protein-AC-PK(A) signaling pathway, suggesting that the hypothalamic histaminergic afferent fibers innervating GP may play an important modulatory role in motor control through its excitatory effect on GP neurons.

Action Potentials↗

PubMed2004

Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation.

1. During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H(4) but not H(3) receptors. The possible effects of histamine on eosinophils and the receptor mediating these effects were investigated in our studies. 2. Histamine (0.01-30 microm) induced a rapid and transient cell shape change in human eosinophils, but had no effects on neutrophils. The maximal shape change was at 0.3 microm histamine with EC(50) at 19 nm. After 60 min incubation with 1 microm histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01-1 microm) also enhanced the eosinophil shape change induced by other chemokines. 3. Histamine-induced eosinophil shape change was mediated by the H(4) receptor. This effect was completely inhibited by H(4) receptor-specific antagonist JNJ 7777120 (IC(50) 0.3 microm) and H(3)/H(4) receptor antagonist thioperamide (IC(50) 1.4 microm), but not by selective H(1), H(2) or H(3) receptor antagonists. H(4) receptor agonists imetit (EC(50) 25 nm) and clobenpropit (EC(50) 72 nm) could mimic histamine effect in inducing eosinophil shape change. 4. Histamine (0.01-100 microm) induced upregulation of adhesion molecules CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on eosinophils. This effect was mediated by the H(4) receptor and could be blocked by H(4) receptor antagonists JNJ 7777120 and thioperamide. 5. Histamine (0.01-10 microm) induced eosinophil chemotaxis with an EC(50) of 83 nm. This effect was mediated by the H(4) receptor and could be blocked by H(4) receptor antagonists JNJ 7777120 (IC(50) 86 nm) and thioperamide (IC(50) 519 nm). Histamine (0.5 microm) also enhanced the eosinophil shape change induced by other chemokines. 6. In conclusion, we have demonstrated a new mechanism of eosinophil recruitment driven by mast cells via the release of histamine. Using specific histamine receptor ligands, we have provided a definitive proof that the H(4) receptor mediates eosinophil chemotaxis, cell shape change and upregulation of adhesion molecules. The effect of H(4) receptor antagonists in blocking eosinophil infiltration could be valuable for the treatment of allergic diseases. The histamine-induced shape change and upregulation of adhesion molecules on eosinophils can serve as biomarkers for clinical studies of H(4) receptor antagonists.

Cell Adhesion Molecules↗

PubMed1980

Pharmacological analysis of salivary and blood flow responses to histamine of the submandibular gland of the dog.

1 The submandibular gland in situ was perfused with blood through the glandular artery at constant pressure in anaesthetized dogs. Drugs were administered intra-arterially. 2 Histamine produced both salivation and an increase in blood flow, each response having an early and a late component. 3 Marked tachyphylaxis to histamine developed in both of the salivary responses but only in the late blood flow response to histamine. 4 The early and late salivary responses were abolished and the late blood flow response was diminished by infusion of tetrodotoxin in doses that abolished the salivary and blood flow responses to electrical stimulation of the chorda-lingual nerve. 5 The whole salivary response to histamine was abolished by infusion of (--)-hyoscyamine in doses that greatly antagonized the salivary and blood flow responses to acetylcholine, whereas the blood flow responses to histamine were scarcely modified. These doses of (--)-hyoscyamine abolished the salivary response to chorda-lingual nerve stimulation but left the blood flow response to it unaffected. 6 The salivary and blood flow responses to histamine were unaffected by infusion of hexamethonium in doses that almost abolished the salivary and blood flow responses to chorda-lingual nerve stimulation. 7 The whole salivary response to histamine was abolished and the late blood response to histamine was partially inhibited by the histamine H1-receptor antagonist, mepyramine, but not by the histamine H2-receptor antagonist, metiamide. 8 The early blood flow response to histamine was antagonized by both mepyramine and metiamide but mepyramine was far more effective than metiamide. 9 These results led to the following conclusions: (1) the whole salivary response and a part of the late blood flow response to histamine are due entirely to excitation of parasympathetic postganglionic neurones; (2) neuronal histamine receptors involved are exclusively of the H1-type; (3) histamine has no direct stimulant action on the glandular cells; (4) the early blood flow response and the remaining part of the late blood flow response to histamine result from the direct action on vascular smooth muscle in the glandular vascular bed; (5) vascular histamine receptors consist of H1- and H2-receptors.

Animals↗

PubMed1982

Histamine: correlative studies in nucleus accumbens.

The role of histamine as a neurotransmitter has been the subject of considerable controversy. Recent evidence suggests it to be involved in such complex activities as arousal and affect. The purpose of the present study is to examine the possible source, function, and pharmacology of histamine in the nucleus accumbens, an area of the brain also implicated in complex activities such as affect. The anatomical studies suggest that the most probable source of the histamine in nucleus accumbens is the complex region lateral to the mammillary nuclei. These areas are the intercalated nucleus and the tuberomammillary nucleus (nuclei gemini hypothalami). To a lesser degree, the supramammillary complex may also contribute histamine-containing axons to the accumbens area. Adenylate cyclase in the rabbit nucleus accumbens displayed activation in response to histamine agonists (histamine, 2-Me-histamine, and 4-Me-histamine). The action of the H1 antagonist promethazine was greater than the H2 antagonist metiamide in reducing enzyme activation by histamine and 2-Me-histamine. In contrast, metiamide was more potent than promethazine toward antagonism of the action of 4-Me-histamine. However, no additive effects were noted when agonists were added in combination. Based upon these data, it is suggested that activation of adenylate cyclase in the rabbit nucleus accumbens is mediated in part by mixed H1 and H2 receptors or cellular disruption reflects the loss of receptor specificity. Physiological studies demonstrated that the H2 agonist 4-Me-histamine had an inhibitory effect on the activity of neurons driven by stimulation of the fimbria. The magnitude of the effect was frequency dependent. The H1 agonist 2-Me-histamine had no significant effect. Iontophoretic application of 4-Me-histamine had minimal effect upon low frequency volleys (0.5 Hz) but had a pronounced effect upon higher frequency volleys (6.0 Hz). These effects were antagonized by metiamide. Iontophoretic application of metiamide alone produced an effect only upon the P component of the field response, which is also bicuculline sensitive. Bicuculline coadministration was also effective in antagonizing the 4-Me-histamine effect. The physiological data suggest that histamine works through H2 receptors in nucleus accumbens, perhaps by potentiating the effects of gamma-aminobutyric acid (GABA). Thus, histamine in nucleus accumbens appears to function as a modulatory substance whose effect is dependent upon the activity of other transmitter and afferent systems.

Adenylyl Cyclases↗

PubMed1989

Induction of histamine release from human skin mast cells by bradykinin analogs.

Kinins are potent proinflammatory peptides that induce histamine release from rodent mast cells. We examined the ability of bradykinin, lysylbradykinin and a series of kinin analogs to cause histamine release from human basophils, human lung mast cells and human skin mast cells. At concentrations ranging from 0.1 microM to 1 mM, bradykinin failed to cause histamine release from any of the human histamine-containing cells studied. Lysylbradykinin was also without effect on basophils and lung mast cells, but was a weak secretagogue for human skin mast cells, inducing 5.5 +/- 3% (mean +/- SD) of total cellular histamine release at a concentration of 10(-5) M. Similarly, when sixteen recently developed bradykinin antagonists were examined, these compounds had no effect on basophils or lung mast cells but all sixteen induced dose-dependent histamine release from skin mast cells. The release process was temperature dependent and, at a concentration of 10(-5) M, the antagonists induced 8-27% histamine release. Although preincubation of cells with 10(-3) M bradykinin or des(Arg9) bradykinin significantly inhibited antagonist-induced histamine release, the requirement for such high concentrations of these peptides to cause inhibition suggested that histamine release is not mediated by either B1 or B2 kinin receptors. To understand further the mechanism of histamine release, we examined a series of bradykinin analogs with single amino acid substitutions in the bradykinin sequence. Replacement of proline7 in the bradykinin sequence with D-phenylalanine is the essential change used to convert kinin analogs into antagonists, and 10(-5) M [DPhe7]-bradykinin induced 8-10% histamine release. Other analogs, devoid of antagonist activity, however, such as [DPhe6]-bradykinin and [LPhe7]-bradykinin were able to induce equivalent levels of histamine release. The ability to induce histamine release appears to be related, at least in part, to aromaticity, since [DTrp6]-bradykinin and [DTrp7]-bradykinin induced greater amounts of histamine release than equivalent [DPhe]-analogs, causing approximately 20% histamine release at 10(-5) M. By contrast, [DAla7]-bradykinin was an ineffective stimulus. In summary, a single amino acid substitution can convert bradykinin into a secretagogue for human skin mast cells. The ability of kinin analogs to induce histamine release from skin mast cells, but not lung mast cells or basophils, emphasizes the heterogeneity of human histamine-containing cells.

Basophils↗

PubMed1968

Absorption of histamine from the gastrointestinal tract of dogs in vivo.

1. In anaesthetized dogs, various amounts of [(14)C]histamine were introduced into the lumen of a ligated intestinal loop or of the ligated stomach and the absorption of this histamine was studied by determining the radioactive histamine in the venous blood coming from the ligated part.2. After the introduction of 5-5000 mug [(14)C]histamine, into a loop of jejunum, or of 50 mug into a loop of duodenum, ileum or colon, radioactive histamine was detected in all eight successive 15 min samples of venous blood collected during 2 hr. The percentage recovery of the [(14)C]histamine in the blood during this period varied between 0.04 and 3.7.3. After the introduction of 10 mg [(14)C]histamine into the stomach, radioactive histamine was detected in all samples of gastric venous blood collected at various times during the following 4 hr.4. After the introduction of 50-5000 mug [(14)C]histamine into a loop of jejunum, radioactive histamine was also detected in the general arterial blood.5. When a jejunal loop was perfused through its artery with a dextransaline solution, the absorption of [(14)C]histamine from the lumen into the venous effluent was much greater than when the blood supply was kept intact.6. A large part of the [(14)C]histamine introduced into an intestinal loop was inactivated or destroyed either in the lumen or the wall since only a part was recovered in the venous blood, contents and wall of the loop at the end of 2 hr. When different amounts of [(14)C]histamine were introduced into a jejunal loop the recovery was shown to be dependent on the dose. With 5 mug it amounted to about 1% whereas with 5000 mug to 29-42%. The recovery of the [(14)C]histamine introduced into a perfused jejunal loop was greater.7. In dogs and cats large amounts of free histamine were found in the contents of the stomach 2 hr after a meat meal, and much smaller amounts in the contents of loops from the small intestine. The amounts found in the contents of loops from the colon varied greatly.8. In eighteen commercial dog and cat foods the free histamine contents were found to vary over fiftyfold, from 0.06 to 3.5 mg/100 g.9. The significance of the results is discussed in relation to the role of histamine as a humoral agent in the ;gastric' and ;intestinal phases' of gastric secretion.

Absorption↗

PubMed1992

Histamine increases cytosolic Ca2+ in HL-60 promyelocytes predominantly via H2 receptors with an unique agonist/antagonist profile and induces functional differentiation.

Histamine H1 receptors mediate activation of phospholipase C, with subsequent increases in cytosolic Ca2+ concentration ([Ca2+]i), and H2 receptors mediate accumulation of cAMP. HL-60 promyelocytes possess H2 receptors, but it is not known whether these cells also possess H1 receptors. We studied the effects of histamine on [Ca2+]i and the functional importance of histamine receptors in HL-60 promyelocytes. In these cells, histamine and dimaprit increased [Ca2+]i with EC50 values of 15 microM and 30 microM, respectively. Diphenhydramine inhibited the effect of histamine (100 microM) on [Ca2+]i up to 40%, with an IC50 of 100 nM. Famotidine and cimetidine diminished the effect of histamine (100 microM) up to 75%, with IC50 values of 85 nM and 300 nM, respectively. Diphenhydramine plus famotidine abolished histamine-induced rises in [Ca2+]i. Impromidine, with an IC50 of 100 nM, abolished the effect of histamine (100 microM) on [Ca2+]i. Diphenhydramine, famotidine, cimetidine, and impromidine showed marked noncompetitive antagonism with histamine. Histamine-induced increases in [Ca2+]i were largely due to influx of Ca2+ from the extracellular space. Ca2+ influx was inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). Histamine activated phospholipase C. Histamine induced expression of formyl peptide receptors, which effect was abolished by famotidine. In U-937 promonocytes and in the human erythroleukemia cell lines HEL and K-562, histamine did not induce rises in [Ca2+]i. Our data suggest the following. (i) In HL-60 promyelocytes, histamine increases [Ca2+]i predominantly via H2 receptors and to a lesser extent via H1 receptors. (ii) The agonist/antagonist profile of the H2 receptor-mediated increases in [Ca2+]i differs markedly from that for cAMP accumulation, suggesting the involvement of different H2 receptor subtypes. (iii) In HL-60 promyelocytes, histamine activates nonselective cation channels and induces functional differentiation via H2 receptors.

Adenosine Triphosphate↗

PubMed1985

Autoregulation of histamine release in brain by presynaptic H3-receptors.

Regulation of histamine release was studied mainly on brain slices prelabeled with L-[3H]-histidine and depolarized by increased extracellular K+ concentration or veratridine in a non-superfused system. The released 3H-labeled amines, isolated by ion-exchange chromatography from a large excess of 3H-labeled precursor consisted by more than 95% of unchanged [3H]histamine. Exogenous histamine reduced the release of neosynthesized [3H]histamine via stimulation of previously characterized H3-receptors whereas it did not modify the 3H-labeled amine release from slices prelabeled with preformed [3H]histamine. The maximal inhibitory effect of exogenous histamine progressively diminished as the strength of the depolarizing stimulus or the external Ca2+ concentration were elevated. On the contrary H3-receptor antagonists like impromidine or burimamide enhanced the depolarization-induced release of [3H]histamine, an effect which was particularly marked when slices were loaded with histamine by preincubation with [3H]histidine in high concentration. These results suggest that the inhibition of [3H]histamine release by exogenous histamine acting via H3-receptor stimulation is mediated by a restricted access of Ca2+ and that its extent is influenced by the degree of autostimulation by endogenous histamine as well as, possibly, by actual internal Ca2+ concentration. In addition the decrease in external Ca2+ concentration shifted rightwards the concentration-response curve to histamine. The autoinhibitory effect of exogenous histamine was found on slices from various regions, known from lesion studies to contain terminals of extrinsic histaminergic neurons. It did not apparently involve interneurones, not being prevented in slices in which the traffic of action potentials was blocked by tetrodotoxin. It also remained unaffected in striatal slices in which the neuronal cell-bodies were selectively destroyed by prior local infusion of kainic acid. Finally exogenous histamine inhibited [3H]histamine release from depolarized synaptosomes of rat cerebral cortex, with an EC50 value similar to that found with slices and was antagonised by impromidine with an apparent Ki value similar to that displayed at H3-receptors. It is concluded that histamine modulates its own release from cerebral neurones by interacting with H3-presynaptic autoreceptors and via mechanisms similar to those previously evidenced on other aminergic systems.

Animals↗

PubMed2000

alpha-fluoromethylhistidine depletes histamine from secreting but not from non-secreting rat stomach ECL cells.

Histamine in the oxyntic mucosa of the rat stomach occurs in mast cells (10%) and ECL cells (90%). Unlike the mast cells, the ECL cells operate under the control of gastrin. alpha-Fluoromethylhistidine, an irreversible inhibitor of the histamine-forming enzyme, histidine decarboxylase depletes ECL-cell but not mast-cell histamine. This report shows that the effectiveness by which histidine decarboxylase inhibition depletes ECL-cell histamine depends on the rate of histamine secretion. Rats received alpha-fluoromethylhistidine by continuous subcutaneous infusion for 24 h. Maximally effective doses (>/=3 mg/kg/h) inhibited histidine decarboxylase and reduced oxyntic mucosal histamine in fed rats by 80-90%. In fasted rats, the reduction was 50%. alpha-Fluoromethylhistidine greatly reduced the number of histamine-immunoreactive ECL cells (immunocytochemistry) and of secretory vesicles in the ECL cells (electron microscopy) in fed but not in fasted rats. The half-life of oxyntic mucosal histamine (determined upon histidine decarboxylase inhibition) was 2.6 h in fed rats and 19.4 h in fasted rats. The amount of histamine secreted in response to gastrin (monitored by gastric submucosal microdialysis) was greatly reduced by alpha-fluoromethylhistidine in fed rats but not in fasted rats. ECL cells were isolated from rat stomach by elutriation (80% purity). Their histamine content was determined after culture, with or without alpha-fluoromethylhistidine, in the presence of varying concentrations of gastrin. In a medium containing 10 nM gastrin, ECL cells responded to a maximally effective concentration of alpha-fluoromethylhistidine (0.1 nM) with 80% reduction in histamine content. In the absence of gastrin, ECL cells responded to alpha-fluoromethylhistidine with 45% reduction of histamine; the releasable histamine pool was unaffected. In conclusion, the combination of histidine decarboxylase inhibition and a high rate of histamine secretion will promptly exhaust the ECL-cell histamine pool, while histidine decarboxylase inhibition and a low secretion rate will affect the histamine pool much less.

Animals↗

PubMed1984

Actions and metabolism of histamine in glomeruli and tubules of the human kidney.

The effects of histamine on cAMP and cGMP accumulation and the intrarenal metabolism of histamine were studied in glomeruli and cortical tubules of nine human kidneys. Histamine stimulated cAMP but not cGMP accumulation in glomeruli (delta + 100% to + 265%) in a dose- (10(-6) to 10(-4) M range) and time-dependent manner. This effect of histamine was inhibited by the histamine H2 antagonist cimetidine but not the H1 antagonist diphenhydramine. Moreover, the H2 agonist dimaprit but not the H1 agonist 2-pyridylethylamine stimulated cAMP accumulation. Histamine had no effect on cAMP or cGMP accumulation in tubules. Because the content of histamine (congruent to 2 X 10(-6) M) in glomeruli was far above the circulating levels of plasma histamine in humans (less than 10(-8) M), we explored whether histamine is formed in human renal tissue. Incubation of glomeruli with 1 mM of the histamine precursor L-histidine resulted in an increase in histamine levels (+ delta 6.08 +/- 0.5 pmoles/mg protein, N = 7 kidneys) while a marked drop in histamine levels was observed in tubules (- delta 13.8 +/- 2.4 pmoles/mg protein, N = 7 kidneys). The increase in histamine levels in glomeruli was abolished by the histidine decarboxylase inhibitor bromocresine. These results indicate that human glomeruli have histamine H2 receptors, which mediate enhanced cAMP accumulation, and that glomeruli are major sites of histamine production in the human kidney. Histamine acting via cAMP may influence glomerular function of the human kidney.

Adult↗

PubMed2003

Pro-apoptotic effect of high concentrations of histamine on human neutrophils.

Histamine receptors are expressed on neutrophils, and therefore, are likely to modulate neutrophil function. In this study, we investigated whether histamine modulates human neutrophil survival. Neutrophils were found to rapidly undergo spontaneous apoptosis upon culture in vitro and this was accelerated by high concentrations of histamine. Moreover, the percentage of apoptotic neutrophils was also markedly increased by treating with 10 mM histamine in the presence of inflammatory mediators, such as lipopolysaccharide (LPS), granulocyte macrophage-colony stimulating factor (GM-CSF), dibutyryl-cAMP (db-cAMP), or dexamethasone. Histamine-induced neutrophil apoptosis was inhibited by pyrilamine, a histamine receptor 1 antagonist, and by ranitidine, a selective histamine receptor 2 antagonist. In addition, diphenylene iodonium (DPI), an inhibitor of NADPH-oxidase, significantly blocked the apoptotic effect of histamine. Moreover, the induction of apoptosis by histamine was almost completely inhibited by zVAD-fmk, a pan-caspase inhibitor. In addition, immunoblotting showed that histamine induced the proteolytic activation of procaspase-3 in cell lysates treated with histamine. And, the protein kinase C (PKC)-delta inhibitor, rottlerin (5 microM) significantly blocked the apoptotic effect of histamine, though the cleavage of PKC-delta in 20 h cultured neutrophils was increased by histamine. However, an inhibitor of conventional PKC, Go6976 (100 nM) and a p38 mitogen-activated protein kinase inhibitor, SB203580 (10 microM), failed to block histamine-induced neutrophil apoptosis. These results suggest that high concentrations of histamine in local inflammatory and allergic lesions induce neutrophil apoptosis, and that this histamine-induced apoptosis is mediated by caspase activation and PKC-delta signaling.

Apoptosis↗

PubMed1998

Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine-induced increase in [Ca2+]i and force in middle cerebral artery of the rabbit.

1. The effect of cilostazol, an inhibitor of phosphodiesterase type III (PDE III), on the contraction induced by histamine was studied by making simultaneous measurements of isometric force and the intracellular concentration of Ca2+ ([Ca2+]i) in endothelium-denuded muscle strips from the peripheral part of the middle cerebral artery of the rabbit. 2. High K+ (80 mM) produced a phasic, followed by a tonic increase in both [Ca2+]i and force. Cilostazol (10 microM) did not modify the resting [Ca2+]i, but it did significantly decrease the tonic contraction induced by high K+ without a corresponding change in the [Ca2+]i response. 3. Histamine (3 microM) produced a phasic, followed by a tonic increase in both [Ca2+]i and force. Cilostazol (3 and 10 microM) significantly reduced both the phasic and tonic increases in [Ca2+]i and force induced by histamine, in a concentration-dependent manner. 4. Rp-adenosine-3':5'-cyclic monophosphorothioate (Rp-cAMPS, 0.1 mM), a PDE-resistant inhibitor of protein kinase A (and as such a cyclic AMP antagonist), did not modify the increases in [Ca2+]i and force induced by histamine alone, but it did significantly decrease the cilostazol-induced inhibition of the histamine-induced responses. 5. In Ca2+-free solution containing 2 mM EGTA, both histamine (3 microM) and caffeine (10 mM) transiently increased [Ca2+]i and force. Cilostazol (1-10 microM) (i) significantly reduced the increases in [Ca2+]i and force induced by histamine, and (ii) significantly reduced the increase in force but not the increase in [Ca2+]i induced by caffeine. 6. In ryanodine-treated strips, which had functionally lost the histamine-sensitive Ca2+ storage sites, histamine (3 microM) slowly increased [Ca2+]i and force. Cilostazol (3 and 10 microM) lowered the resting [Ca2+]i, but did not modify the histamine-induced increase in [Ca2+]i, suggesting that functional Ca2+ storage sites are required for the cilostazol-induced inhibition of histamine-induced Ca2+ mobilization. 7. The [Ca2+]i-force relationship was obtained in ryanodine-treated strips by applying ascending concentrations of Ca2+ (0.16-2.6 mM) in Ca2+-free solution containing 100 mM K+. Histamine (3 microM) shifted the [Ca2+]i-force relationship to the left and increased the maximum Ca2+-induced force. Under the same conditions, whether in the presence or absence of 3 microM histamine, cilostazol (3-10 microM) shifted the [Ca2+]i-force relationship to the right without producing a change in the maximum Ca2+-induced force. 8. It is concluded that, in smooth muscle of the peripheral part of the rabbit middle cerebral artery, cilostazol attenuates the histamine-induced contraction both by inhibiting histamine-induced Ca2+ mobilization and by reducing the myofilament Ca2+ sensitivity. It is suggested that the increase in the cellular concentration of cyclic AMP that will follow the inhibition of PDE III may play an important role in the cilostazol-induced inhibition of the histamine-contraction.

Animals↗

PubMed1966

Skin histamine in cats: Its depletion and subsequent recovery after injection of compound 48-80.

1. The histamine content of the skin has been determined in untreated cats, in cats injected with the histamine liberator, compound 48/80, and in cats injected subcutaneously with an oily suspension of histamine or histidine after treatment with compound 48/80.2. Skin histamine in cats varied from 2.2 to 37.5 mug/g. Apart from regional variations in the histamine content of the abdominal skin, lower values were obtained from cats kept on a laboratory diet which included aureomycin (mean 8.5 mug/g, range 2.2-13.1) than from cats on a high protein diet without aureomycin (mean 17.5 mug/g, range 5.2-37.5).3. Compound 48/80 caused a depletion of skin histamine which was never complete, and a residue of 3-7% remained; in cats which originally had a low histamine content of skin, depletion was even less and up to 20% of the original histamine remained.4. Recovery of skin histamine in cats after injections of compound 48/80 was slow, at least 110 days being required for full restoration. The rate of recovery was not altered by daily subcutaneous injections of histidine, but an effect was found with daily subcutaneous injections of histamine. Histamine had no effect for the first 33 days, but at 55 days the percentage histamine content of the skin was greater than in the cats treated with histidine or the oily suspending vehicle, and at 110 days the histamine content was not only much greater than the other two groups but was greater than that before injection of compound 48/80.5. No in vitro histamine formation was detected in the skin samples either before compound 48/80 treatment or at any time during the subsequent recovery of the histamine to control levels.6. The results support the theory that the histamine found in skin tissues of the cat is not formed there but is taken up from the blood stream.

Animals↗

PubMed2005

Interactions between histamine and bradykinin in stimulation of ischaemically sensitive cardiac afferents in felines.

Cardiac spinal afferents are activated during myocardial ischaemia. Our previous studies have shown that during ischaemia, histamine and bradykinin (BK) stimulate cardiac spinal afferents. Because the two mediators are released together during ischaemia, the present study examined the interactions between these two mediators with respect to their influence on ischaemically sensitive cardiac afferents. Single-unit cardiac afferent activity was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) in anaesthetized cats. Fifty-five ischaemically sensitive cardiac afferents (conduction velocity (CV) = 0.2-5.6 m s(-1), 8 Adelta- and 47 C-fibres) were identified. Administration of histamine (10 microg kg(-1)) and BK (1 microg) in combination into the left atrium (LA) caused an additive response in 16 afferents compared with administration of either BK or histamine alone (2.62 +/- 0.39 versus 1.67 +/- 0.20 versus 1.24 +/- 0.23 impulses s(-1) (imp s(-1)), BK + histamine versus BK versus histamine). To further evaluate interactions between these mediators, we observed that injection of histamine (10 microg kg(-1), LA) 4 min after the administration of BK (1 microg, LA) induced a significantly larger cardiac afferent response than the response to histamine before BK (1.24 +/- 0.23 versus 1.96 +/- 0.39 imp s(-1), before versus after, n = 10). In contrast, six other afferents responded reproducibly to repeated injections of histamine (10 microg kg(-1), LA) in the absence of BK. BK sensitization of the afferent response to histamine lasted for less than 10 min. Cyclooxygenase blockade with indomethacin (5 mg kg(-1), i.v.) abolished BK sensitization of the response to histamine (1.09 +/- 0.11 versus 1.11 +/- 0.10 imp s(-1), n = 10). Conversely, the response of most (7/9) cardiac afferents to repeat application of BK (1 microg, LA) 4 min after histamine (10 microg kg(-1), LA) was attenuated compared with the BK response before histamine (1.84 +/- 0.25 versus 1.31 +/- 0.18 imp s(-1), before versus after, P < 0.05). Repeat BK (1 microg, LA) induced a consistent response in five other afferents in the absence of histamine. Thus, BK interacts with histamine, and together they cause a larger response than either one alone. BK sensitizes cardiac afferents responding to histamine in a time-dependent fashion, and the BK sensitization effect is dependent on an intact cyclooxygenase pathway. Conversely, histamine reduces the response of most afferents to BK.

Action Potentials↗

PubMed1982

Dynamics of renal histamine in normal rat kidney and in nephrosis induced by aminonucleoside of puromycin.

Histamine is known to have a profound effect on capillary permeability in nonrenal tissues and this effect is presumably mediated by cyclic (c)AMP. Because in our previous experiments we found that histamine stimulates cAMP accumulation in glomeruli (Torres, V. E., T. E. Northryn, R. M. Edwards, S. V. Shah, and T. P. Dousa. 1978. Modulation of cyclic nucleotides in isolated rat glomeruli. J. Clin. Invest.62: 1334.), we now explored whether this amine is formed in renal tissue, namely in glomeruli, and whether its renal metabolism is altered in experimental nephrosis induced by puromycin aminonucleoside (PA) in rats. In normal rats, histamine content was higher (Delta + 240%) in cortex than in medulla. In glomeruli isolated from renal cortex, histamine content was significantly higher (Delta + 260%) than in tubules. Incubation of isolated glomeruli with l-histidine resulted in a time-dependent increase of histamine content in glomeruli, but no change was found in tubules. The increase in glomerular histamine was blocked by the histidine decarboxylase inhibitor bromocresine. In rats with PA nephrosis induced by a single intraperitoneal injection of PA (15 mg/100 g body wt) urinary excretion of histamine was markedly increased (>Delta + 200%), but control rats did not differ from rats with PA nephrosis in urinary excretions of l-histidine and of creatinine. At the peak of proteinuria (day 9 after injection of PA) the plasma level of histamine was slightly elevated, and plasma histidine slightly decreased in animals that developed PA nephrosis. The content of histamine was markedly higher and the level of histidine was significantly lower in the renal cortex of PA-nephrotic rats as compared with controls; PA-nephrotic and control rats did not differ in the content of histidine and histamine in the liver. In addition, the content of histamine was higher in glomeruli isolated from PA-nephrotic rats; lesser difference was found in cortical tubules. The results further indicate that PA-nephrotic rats have higher content of histamine in the renal cortex, predominently in glomeruli with increased urinary histamine excretion. The elevated renal cortical histamine is not due to higher availability of histamine precursor l-histidine. Results thus show that glomeruli are a major site of intrarenal histamine synthesis and accumulation, and also suggest that abnormal renal metabolism of this amine in PA nephrosis may be related, as a cause or as a consequence, to the pathogenesis of this disease.

Animals↗

PubMed1998

Effects of H1 antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging.

Histamine plays an important part in the cutaneous weal and flare response which underlies many allergic skin conditions. It has a direct effect on the local vasculature to promote vasodilatation and increase microvascular permeability and may also initiate the more widely spread neurogenic flare. Quantification of these responses and studies of the mediator mechanisms underlying them have been limited by the lack of appropriate techniques to investigate them. To address this we have used two relatively new techniques, scanning laser Doppler imaging (LDI) and dermal microdialysis to measure changes in skin blood flow and the release of histamine within the weal and flare, following intradermal injection of histamine or bradykinin. These measurements have been made both in the absence and presence of the H1 receptor blockers cetirizine and loratadine. Scanning LDI of the inflammatory response revealed marked differences in both the development and steady state responses to the intradermal injection of histamine (1-3 mumol/L) and bradykinin (1 mumol/L). The development of the flare and the weal response to both histamine and bradykinin was significantly reduced by cetirizine but not by loratadine. The histamine-induced flare area fell by 57 +/- 4% (mean +/- SEM, n = 10, P < 0.001) after cetirizine and the area of the weal fell by 73 +/- 11% (P < 0.009). Bradykinin-induced inflammatory responses were similarly reduced by cetirizine, the weal by 60 +/- 16% (P < 0.02) and the flare by 61 +/- 4% (P < 0.005). Measurement of histamine concentration in skin using microdialysis, in six subjects, confirmed that histamine levels rose in the dialysate collected from the weal to 310 +/- 16 nmol/L following injection of histamine. Histamine levels also rose following bradykinin injection in some subjects (mean 147 +/- 46 nmol/L, range 18-336). Little increase in histamine concentration was seen in the dialysate from the flare following injection of either histamine or bradykinin. The histamine concentration in dialysate from unprovoked skin was 4.19 +/- 0.75 nmol/L. These data reveal differences in the dermal responses to different mediators when assessed using scanning LDI. They confirm that histamine is released within the weal but not the flare response to the intradermal injection of both histamine and bradykinin and that its effects on the local vasculature to cause the oedematous weal and the axon reflex-mediated flare are significantly attenuated by the H1 antagonist cetirizine and to a lesser extent by the H1 antagonist loratadine.

Adult↗

PubMed1996

The histamine H1 receptor in GT1-7 neuronal cells is regulated by calcium influx and KN-62, a putative inhibitor of calcium/calmodulin protein kinase II.

1. In GT1-7 cells, histamine stimulated the initial [Ca2+]i transient in a dose-dependent manner with a best-fit EC50 value of 4.2 +/- 4.2 microM (mean +/- s.e.mean, n = 4) and a best-fit maximal effect of 138 +/- 56 nM (n = 4) increase above basal calcium levels. 2. Pretreatment of cells with 30 microM histamine for 30 min desensitized the population mean peak calcium signal by 53% to 75 +/- 9 nM, (n = 3, P < 0.04). Analysis of the individual cells revealed that 39 +/- 7% (n = 94 cells from 8 experiments) of pretreated cells exhibited desensitized histamine-stimulated [Ca2+]i transients of < or = 1 standard deviation below the control cells mean calcium transient level. 3. The desensitization induced by histamine was prevented (P < 0.01) by KN-62 (10 microM), a putative inhibitor of the calcium/calmodulin-dependent protein kinase II (CaMKII). KN-62 (10 microM) alone did not induce [Ca2+]i mobilization, nor did it antagonize the histamine-stimulated [Ca2+]i signal. In addition, KN-62 did not appear to have its effect by hastening the rate of recovery from desensitization. 4. Histamine pretreatment in nominal (zero calcium + 0.2 mM EGTA) or in low (0.3 mM) extracellular calcium did not induce histamine receptor desensitization, supporting a role for extracellular calcium in the homologous H1 receptor desensitization process. 5. Histamine (30 microM) stimulated at least four different types of [Ca2+]i signals in GT1-7 cells. The majority (61%) were of single spikes with the remaining cells showing some form of calcium oscillatory behaviour. The proportion of GT1-7 cells showing histamine-induced calcium oscillations was histamine concentration-dependent and significantly reduced after acute desensitization. KN-62, when present during histamine pretreatment, prevented this fall in calcium oscillation. Under the conditions of nominal or 0.3 mM extracellular calcium the proportion of cells exhibiting histamine-stimulated calcium oscillations was not significantly different from the controls. 6. Bradykinin stimulated a [Ca2+]i transient in GT1-7 cells with a population mean peak response of 147 +/- 8 nM (n = 5) over basal levels. The bradykinin-induced [Ca2+]i signal was without any calcium oscillatory activity. Histamine pretreatment caused the heterologous desensitization of the bradykinin [Ca2+]i signal (44% reduction, P < 0.007), which was unaffected by KN-62. 7. The results presented here suggest that the histamine-mediated homologous H1 receptor desensitization process involves extracellular calcium and can be blocked by KN-62, a putative inhibitor of CaMKII. In contrast, KN-62 does not appear to prevent the histamine-mediated heterologous desensitization cascade. These findings suggest fundamental differences in the mechanisms underlying homologous and heterologous H1 receptor desensitization pathways in GT1-7 neuronal cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Histamine-induced increases in cyclic AMP levels in bovine adrenal medullary cells.

1. The effect of histamine on cellular cyclic AMP levels in cultured bovine adrenal medullary cells has been studied. 2. Histamine (0.3-30 microM) increased cyclic AMP levels transiently, with a maximal response after 5 min, a smaller response after 20 min, and no increase seen after 80 or 180 min. The EC50 at 5 min was approximately 2 microM. Histamine had no effect on cyclic AMP release from the cells over 5 min, but increased it after 90 min. 3. The cyclic AMP response to 5 microM histamine was reduced by 45% by 1 microM mepyramine and by almost 30% by 1 microM cimetidine, and was abolished by the combination of both antagonists. Cimetidine at 100 microM did not inhibit the response to histamine more than 1 microM cimetidine. The H3-receptor antagonist, thioperamide (1 microM), had no effect on the response to histamine. 4. The H1-receptor agonist, 2-thiazolyethylamine (5-100 microM) and the H2-receptor agonist, dimaprit (5-100 microM), each induced a cyclic AMP response, and gave more-than-additive responses when combined. The H3 agonist (R) alpha-methylhistamine (100 microM) had no effect either on its own or in combination with either the H1 or the H2 agonist. The response to 100 microM 2-thiazolylethylamine was unaffected by cimetidine (100 microM). 5. The cyclic AMP responses to 5 microM histamine, 100 microM thiazolylethylamine and 100 microM dimaprit were each weakly enhanced in the presence of 1 mM 3-isobutyl-1-methylxanthine. The response to dimaprit was enhanced more than 10 fold in the presence of 0.3 microM forskolin, while the responses to histamine and thiazolylethylamine were weakly enhanced.6. The cyclic AMP response to 5 microM histamine was partially reduced in the absence of extracellular Ca2 and the residual response was fully antagonized by 1 microM cimetidine and was unaffected by 1 microM mepyramine.In the absence of Ca2 , the cyclic AMP response to 100 microM thiazolylethylamine was abolished, while that to 100 microM dimaprit was unaffected.7. Reincubation of 5 microM histamine solutions with a second set of chromaffin cells, following prior incubation with another set of cells, induced a cyclic AMP response in the fresh cells. This response was reduced by a combination of mepyramine and cimetidine to the same degree as the response to fresh 5 microm histamine solutions.8. The results indicate that histamine increases cellular cyclic AMP levels in bovine chromaffin cells by three mechanisms: by acting on H1 receptors, by acting on H2 receptors, and by an interaction between H, and H2 receptors. The H1 response does not require concomitant activation of H2 receptors, is fully dependent on extracellular Ca2 +, does not depend on secreted chromaffin cell products, and is not due to reduced cyclic AMP degradation or export. The H2 cyclic AMP response is the first functional response reported for H2 receptors on chromaffin cells, is independent of Ca2 , is not due to reduced cyclic AMP export or degradation, and is likely to be mediated via a direct action through Gs. The role of these different mechanisms in the regulation of cyclic AMP-dependent processes in chromaffin cells by histamine is under investigation.

1-Methyl-3-isobutylxanthine↗