Histamine N-methyltransferase Inhibitor Research Articles

Effect of amodiaquine, a histamine N-methyltransferase inhibitor, on, Propionibacterium acnes and lipopolysaccharide-induced hepatitis in mice

We examined whether treatment with amodiaquine, a potent inhibitor of histamine N-methyltransferase protects mice from Propionibacterium acnes ( P. acnes)-primed and lipopolysaccharide (LPS)-induced hepatitis. The subcutaneous injection of amodiaquine (2 and 5 mg/kg) significantly increased the histamine levels in the liver in comparison to saline treated mice. Pretreatment with amodiaquine also improved the survival rate of the hepatitis mice, and this improvement was partially associated with the decrease in serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Amodiaquine partially suppressed increases of tumor necrosis factor (TNF)-α in the serum and TNF-α mRNA expression in the liver, whereas the expression of interleukin (IL)-18, interferon (IFN)-γ and IL-12 in the liver was not changed by amodiaquine treatment. In conclusion, the present findings suggested that the elevation of endogenous histamine by amodiaquine may thus play a protective role through the regulation of TNF-α production in endotoxin-induced hepatic injury mice.

Histamine enhances inhibitory avoidance memory consolidation through a H 2 receptor-dependent mechanism

Several evidences suggest that brain histamine is involved in memory consolidation but the actual contribution of the hippocampal histaminergic system to this process remains controversial. Here, we show that when infused into the CA1 region of the dorsal hippocampus immediately after training in an inhibitory avoidance task, but not later, histamine induced a dose-dependent promnesic effect without altering locomotor activity, exploratory behavior, anxiety state or retrieval of the avoidance response. The facilitatory effect of intra-CA1 histamine was mimicked by the histamine N-methyltransferase inhibitor SKF-91844 as well as by the H 2 receptor agonist dimaprit and it was blocked completely by the H 2 receptor antagonist ranitidine. Conversely, the promnesic action of histamine was unaffected by the H 1 receptor antagonist pyrilamine, the H 3 receptor antagonist, thioperamide, and the NMDAr polyamine-binding site antagonist ifenprodil. By themselves, ranitidine, pyrilamine, thioperamide, and ifenprodil did not affect IA memory consolidation. Our data indicate that, when given into CA1, histamine enhances memory consolidation through a mechanism that involves activation of H 2 receptors; however, endogenous CA1 histamine does not seem to participate in the consolidation of IA memory at least at the post-training times analyzed.

In-Silico Pharmacodynamics

Adverse effects are exhibited by most drugs in current clinical practice, the causes for which are often not known. In this post genomic era, bioinformatics has the potential to address several issues in understanding the mechanism of drug action and in designing improved drugs. This study describes the analysis of the possible pharmacodynamic behaviour of antihistamines blocking the histamine H(2) receptor (H(2)-antihistamines), by adopting the basic tenets of a systems biology approach. The different components that could form an appropriate sub-system are identified, thus providing a system landscape. Docking and analysis of the chosen antihistamines into each of these components resulted in identifying histamine N-methyl transferase (HNMT) as a potential unintended target for H(2)-antihistamines. Correlation with experimental data available from the literature indicates the inhibition of HNMT to be a possible cause for the adverse effects exhibited by these drugs. Implications for design of safer H(2)-antihistamines are discussed. The method reported here has the potential for application as a general strategy in understanding drug effects.

Structural Basis for Inhibition of Histamine N-Methyltransferase by Diverse Drugs

In mammals, histamine action is terminated through metabolic inactivation by histamine N-methyltransferase (HNMT) and diamine oxidase. In addition to three well-studied pharmacological functions, smooth muscle contraction, increased vascular permeability, and stimulation of gastric acid secretion, histamine plays important roles in neurotransmission, immunomodulation, and regulation of cell proliferation. The histamine receptor H1 antagonist diphenhydramine, the antimalarial drug amodiaquine, the antifolate drug metoprine, and the anticholinesterase drug tacrine (an early drug for Alzheimer's disease) are surprisingly all potent HNMT inhibitors, having inhibition constants in the range of 10-100nM. We have determined the structural mode of interaction of these four inhibitors with HNMT. Despite their structural diversity, they all occupy the histamine-binding site, thus blocking access to the enzyme's active site. Near the N terminus of HNMT, several aromatic residues (Phe9, Tyr15, and Phe19) adopt different rotamer conformations or become disordered in the enzyme-inhibitor complexes, accommodating the diverse, rigid hydrophobic groups of the inhibitors. The maximized shape complementarity between the protein aromatic side-chains and aromatic ring(s) of the inhibitors are responsible for the tight binding of these varied inhibitors.

Role of histaminergic neurons in development of epileptic seizures in EL mice

The EL mouse is an animal model for hereditary temporal lobe epilepsy. When the mice receive weekly vestibular stimulation, e.g., 30 “tosses”, 10–15 cm vertically, they start to convulse after 1–2 weeks. The aim of this study was to evaluate the role of the histaminergic neurons in the regulation of seizure development in the EL mice. The obtained results indicated that administration of either histidine, a substrate for histamine synthesis, or metoprine (2,4-diamino-5-(3,4-dichlorophnyl)-6-methyl-pyrimidine), an inhibitor of histamine N-methyltransferase (HNMT), retarded the onset of seizure episodes in the mice. The co-administration of histidine and metoprine caused a more marked delay in it. The histamine levels in the brain significantly increased in response to any of these treatments. The intraperitoneal injection of diphenhydramine, a H1-antagonist accelerated the initiation of seizure episodes in the mice, whereas thioperamide, a H3-antagonist caused a delay in the response. There were significant increases in the brain histamine levels upon injection of any of these drugs with concomitant rises in the activity of the histidine decarboxylase (HDC). These results, taken together, suggest that the histaminergic neurons play crucial roles in the development of seizures in the EL mice. They inhibit convulsion in a H1-dependent fashion, while the neurons enhance it in a H3-receptor-mediated way.

Involvement of arginine vasopressin in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

Histamine is a potent stimulator of arginine vasopressin (AVP) release and therefore, the role of AVP was studied in the reversal of critical haemorrhagic hypotension induced by endogenous central histamine after inhibition of histamine N-methyltransferase (HNMT) activity in rats. In 48 ethylurethane-anaesthetised male Wistar rats cardiovascular parameters and plasma hormone concentrations were measured. Haemorrhage-shocked rats with mean arterial pressure (MAP) 20-25 mmHg were injected intracerebroventricularly (icv) with HNMT inhibitor metoprine (20 microg) after pre-treatment with V(1a), V(1b) and V(2) receptor antagonists - [beta-mercapto-beta,betacyclopentamethylenepropionyl(1), O-me-Tyr(2),Arg(8)]AVP (10 microg/kg; iv), SSR149415 (10 mg/kg; ip) and [adamantaneacetyl(1),O-Et-D-Tyr(2),Val(4), aminobutyryl(6),Arg(8,9)]AVP (10 microg/kg; iv), respectively, or saline. MAP, heart rate (HR) and regional haemodynamics were monitored within 2 h after treatment or to death if it occurred earlier. Plasma hormone concentrations were measured using enzyme immunoassays. ANOVA followed by Neuman-Keules test, and Fisher's exact test were used to compare the results. Metoprine produced a long-lasting increase in MAP, HR, renal, hindquarters and mesenteric blood flows, and a 100% survival at 2 h (P < 0.05 vs. the control group). The action was associated with increased plasma AVP concentration (587.5 +/- 98.9 vs. 387.3 +/- 125.2 pg/ml; P < 0.05) in comparison to the control group as measured at 20 min after treatment. V(1a), but not V(1b) and V(2), receptor antagonist inhibited metoprine-induced haemodynamic effects, with no influence on survival at 2 h. SSR149415 did not influence ACTH and adrenaline plasma concentrations in the metoprine-treated group. AVP, acting via V(1a) receptors, is involved in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

Cardiac and regional haemodynamic effects of histamine N-methyltransferase inhibitor metoprine in haemorrhage-shocked rats.

The increase in central histamine concentrations after inhibition of histamine N-methyltransferase (HNMT) activity is associated with the reversal of critical haemorrhagic hypotension, therefore the present study examines cardiac and regional haemodynamic effects of HNMT inhibitor metoprine in haemorrhage-shocked rats. Cardiovascular parameters were measured in 72 and central histamine concentrations in 12 male Wistar rats anaesthetised with ketamine/xylazine. Metoprine (5, 15 mg/kg) was administered intraperitoneally to normotensive and critically-hypotensive rats with mean arterial pressure (MAP) 20-25 mmHg. Haemorrhage-shocked rats were pre-treated intracerebroventricularly with histamine H(3) receptor agonist R(-)-alpha-methylhistamine (10 microg) or saline. MAP, heart rate (HR) and cardiac and regional haemodynamics were monitored within 2 h after treatment, or to death if it occurred earlier. Histamine concentrations were measured using enzyme immunoassay. ANOVA followed by Neuman-Keules test, and Fisher's exact test were used to compare the results. Bleeding resulted in an extreme decrease in cardiac index (CI), an increase in total peripheral resistance index (TPRI) and the death of control animals within 30 min. Metoprine induced increases in MAP and HR which were significantly higher in hypotensive than in normotensive animals. The resuscitating effect of metoprine (15 mg/kg) was associated with a rise in CI, a decrease in TPRI, and a 100% survival at 2 h. TPRI changes resulted from decreased renal, hindquarters and mesenteric vascular resistance. R(-)-alpha-methylhistamine inhibited metoprine-induced increases in endogenous histamine concentrations in the cerebral cortex (0.89 +/- 0.12 vs. 1.25 +/- 0.29 nmol/g of wet tissue; P < 0.05), hypothalamus (4.37 +/- 0.42 vs. 5.74 +/- 0.47 nmol/g of wet tissue; P < 0.01) and medulla oblongata (0.39 +/- 0.07 vs. 0.65 +/- 0.28 nmol/g of wet tissue; P < 0.05), diminished haemodynamic effects and decreased the survival rate at 2 h to 33% (P < 0.05 vs. the saline-pre-treated group). The results support the hypothesis that histaminergic system activation leads to mobilisation of compensatory mechanisms in haemorrhagic hypotension.

Endogenous central histamine-induced reversal of critical hemorrhagic hypotension in rats: studies with L-histidine.

Activation of the histaminergic system is characteristic of response to the action of adverse or potentially dangerous stimuli that disturb circulatory homeostasis, such as dehydration and changes in blood pressure. Previous study demonstrates that inhibition of histamine N-methyltransferase, which catabolizes histamine released from neurons, leads to the increase in endogenous central histamine concentrations and to the reversal of critical hemorrhagic hypotension. In the present study, the influence of intraperitoneal loading with histamine precursor L-histidine on central cardiovascular regulation was studied in a model of irreversible pressure-controlled hemorrhagic shock. Experiments were carried out in male Wistar rats anesthetized with ketamine/xylazine subjected to critical hemorrhagic hypotension of 20 to 25 mmHg, which resulted in the death of all control saline-treated animals within 30 min. L-histidine administered in 5 min of critical hypotension produced dose-dependent increases in mean arterial pressure and heart rate (100-500 mg/kg), and a 100% survival rate of 2 h (500 mg/kg), whereas in normotensive animals, it did not influence cardiovascular parameters. The resuscitating effect of L-histidine (500 mg/kg) was associated with increases in histamine concentrations in the cerebral cortex (0.97 +/- 0.11 nmol/g of wet tissue vs. 0.67 +/- 0.22 nmol/g of wet tissue; P<0.05), hypothalamus (4.78 +/- 0.58 nmol/g of wet tissue vs. 4.08 +/- 0.43 nmol/g of wet tissue; P<0.01), and medulla oblongata (0.55 +/- 0.18 nmol/g of wet tissue vs. 0.34 +/- 0.09 nmol/g of wet tissue; P<0.05), as well as with no changes in plasma histamine concentrations in comparison with the saline-treated group 20 min after injection. Pretreatment with (S)-alpha-fluoromethylhistidine (alpha-FMH, 0.5 mg intracerebroventricularly), an irreversible inhibitor of L-histidine decarboxylase, produced a decrease in central histamine concentrations and diminished volumes of blood required to achieve critical hypotension. Moreover, alpha-FMH inhibited L-histidine-induced increases in central histamine concentrations and its resuscitating effect. In conclusion, the increase in central histamine concentrations after loading with L-histidine in rats subjected to critical hemorrhagic hypovolemia leads to the reversal of hypotension and the improvement in the survival rate of 2 h. On the other hand, inhibition of L-histidine decarboxylase activity, and thus histamine synthesis, produces a decrease in hemodynamic stability in hypotension, which suggests the histaminergic system-induced activation of compensatory mechanisms in hemorrhagic shock.

ECL cell histamine mobilization studied by gastric submucosal microdialysis in awake rats: methodological considerations.

The ECL cells are endocrine/paracrine cells in the acid-producing part of the stomach. They secrete histamine in response to circulating gastrin. Gastric submucosal microdialysis has been used to study ECL-cell histamine mobilization in awake rats. In the present study we assess the usefulness and limitations of the technique. Microdialysis probes were implanted in the gastric submucosa. Histological analysis of the stomach wall around the probe revealed a moderate, local inflammatory reaction 1-2 days after implantation; the inflammation persisted for at least 10 days. Experiments were conducted 3 days after the implantation. The "true" submucosal histamine concentration was determined by perfusing at different rates (the zero flow method) or with different concentrations of histamine at a constant rate (the no-net-flux method): in fasted rats it was calculated to be 87+/-5 (means+/-S.E.M.) nmol/l and 76+/-9 nmol/l, respectively. The corresponding histamine concentrations in fed rats were 93+/-5 and 102+/-8 nmol/l, respectively. With a perfusion rate of 74 microl/hr the recovery of submucosal histamine was 49%, at 34 microl/hr the recovery increased to 83%. At a perfusion rate below 20 microl/hr the microdialysate histamine concentration was close to the actual concentration in the submucosa. The ECL-cell histamine mobilization was independent of the concentrations of Ca2+ in the perfusion medium (0-3.4 mmol/l Ca2+). In one experiment, histamine mobilization in response to gastrin (10 nmol/kg/hr subcutaneously) was monitored in rats pretreated with prednisolone (60 mg/kg) or indomethacin (15 mg/kg). The two antiinflammatory agents failed to affect the concentration of histamine in the microdialysate either before or during the gastrin challenge, which was in accord with the observation that the inflammatory reaction was modest and that inflammatory cells were relatively few around the probe and in the wall of the probe. In another experiment, rats were given aminoguanidine (10 mg/kg) or metoprine (10 mg/kg) 4 hr before the start of gastrin infusion (5 nmol/kg/hr intravenously). Metoprine (inhibitor of histamine N-methyl transferase) did not affect the microdialysate histamine concentration, while aminoguanidine (inhibitor of diamine oxidase) raised both basal and gastrin-stimulated histamine concentrations. We conclude that microdialysis can be used to monitor changes in the concentration of histamine in the submucosa of the stomach, and that the inflammatory reaction to the probe is moderate and does not affect the submucosal histamine mobilization.

Endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats--studies with histamine N-methyltransferase inhibitor SKF 91488.

Activation of the histaminergic system is associated with mobilisation of compensatory mechanisms in response to the action of stimuli which disturb homeostasis. Therefore, the effects of endogenous histamine in central cardiovascular regulation were studied in a rat model of irreversible haemorrhagic hypotension. Cardiovascular parameters were measured in 66 and central histamine concentrations in 12 male Wistar rats anaesthetised with ketamine/xylazine. Haemorrhage-shocked rats with mean arterial pressure (MAP) 20-25 mmHg were injected intracerebroventricularly (icv) with histamine N-methyltransferase inhibitor SKF 91488 after icv pre-treatment with H, H2 and H3 histamine receptor antagonists--chlorpheniramine (100 nmol), ranitidine (200 nmol) and thioperamide (100 nmol), respectively, or saline. Arterial pressure and heart rate (HR) changes were monitored within 2 h after icv treatment, or to death if it occurred earlier. Histamine concentrations were measured using enzyme immunoassay. ANOVA followed by a test of Neuman-Keules, and Fisher's exact test were used to compare the results. SKF 91488 produced dose-dependent, significantly higher compared to normovolaemic animals, increases in MAP and HR with the improvement in survival rates. The action of SKF 91488 (100 microg) was associated with an increase in endogenous histamine concentrations in the cerebral cortex (1.19 +/- 0.09 vs. 0.77 +/- 0.21 nmol/g; p < 0.05), hypothalamus (5.62 +/- 0.68 vs. 4.18 +/- 0.45 nmol/g; p < 0.01) and medulla oblongata (0.53 +/- 0.17 vs. 0.29 +/- 0.05 nmol/g; p < 0.05) in comparison to saline-treated animals. SKF 91488-induced effects were inhibited by chlorpheniramine, whereas neither ranitidine nor thioperamide influenced the action. Endogenous central histamine, after SKF 91488 treatment, via activation of H, receptors produces reversal of hypotension, with improvement in the survival rate at 2 h after treatment, in rats subjected to critical haemorrhagic hypovolaemia.

Expression of diamine oxidase (histaminase) in guinea-pig tissues

The expression of mRNA for diamine oxidase (histaminase) and the enzyme activity in guinea-pig tissues were investigated. Reverse transcription-polymerase chain reaction analysis revealed that the message corresponding to the long form present in humans and rats was expressed abundantly in the small intestine and liver. Small but detectable amounts of diamine oxidase mRNA were observed in the kidney, stomach, cerebellum, thalamus+hypothalamus, and cerebral cortex. Northern blot analysis showed that the message (2.8 kb in size) was observed abundantly in the liver and small intestine and was detectable in the kidney and stomach but not in the brain or lung. In situ hybridization showed that diamine oxidase mRNA was localized throughout the liver and epithelial cells of the small intestine. Diamine oxidase activity was detected at various levels in different tissues of the guinea-pig at the following relative abundance: liver>small intestine>lung, kidney>stomach. Histamine dose-dependently induced the contraction of sections of the guinea-pig small intestine, and the pretreatment of the tissue section with aminoguanidine (100 μM), a diamine oxidase inhibitor, but not with S-[4-( N, N-dimethylamino)butyl]isothiourea (100 μM), an inhibitor of histamine N-methyltransferase, shifted the dose–response curve of histamine-induced contraction to lower concentrations. These results suggest that diamine oxidase has a crucial role in the degradation of histamine in the guinea-pig small intestine and probably in the liver.

Development of a new class of nonimidazole histamine H(3) receptor ligands with combined inhibitory histamine N-methyltransferase activity.

In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H(3) receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H(3) receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H(3) receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H(3) receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH(3), K(i) = 0.09 nM; HMT, IC(50) = 51 nM). This class of compounds showed high antagonist potency and good H(3) receptor selectivity in functional assays in guinea pig on H(1), H(2), and H(3) receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.

Histamine N-methyltransferase regulates histamine-induced phosphoinositide hydrolysis in guinea pig cerebellum

We report here that the dose-response curve of the histamine-stimulated phosphoinositide hydrolysis in the guinea pig cerebellar slices was shifted to the left when the slices were pretreated with SKF 91488 (100 μM), a specific inhibitor of histamine N-methyltransferase (HMT). In contrast, the pretreatment of the cerebellar slices with aminoguanidine (100 μM–1 mM), an inhibitor of diamine oxidase, had no effect on histamine-induced phosphoinositide hydrolysis. HMT mRNA was expressed abundantly in cerebellum, especially in Purkinje cells. These observations suggest that HMT regulates histaminergic neurotransmission in guinea pig cerebellum more predominantly than diamine oxidase in histamine degradation.

Airway hyperresponsiveness to histamine in mycoplasmal infection: role of histamine N-methyltransferase

To elucidate the modulatory role of histamine-degrading enzymes in airway constrictor responses in mycoplasmal infection, we studied hamster tracheal segments under isometric conditions in vitro. Nasal inoculation with Mycoplasma pneumoniae potentiated the contractile responses to histamine but not to methacholine. Pretreatment of tissues with the histamine N-methyltransferase inhibitor SKF 91488 abolished the infection-induced potentiation, whereas, the diamine oxidase inhibitor aminoguanidine had no effect. The histamine N-methyltransferase but not diamine oxidase activity in tracheal tissues was decreased in infected animals. These results suggest that M. pneumoniae causes airway hyperresponsiveness to histamine probably through a reduction of endogenous histamine N-methyltransferase activity.

HMT regulates histamine-induced glycoconjugate secretion from human airways in vitro

To determine whether histamine N-methyltransferase (HMT) regulates mucus glycoprotein (MGP) secretion from airways, we examined the effect of an HMT inhibitor, SKF 91488, on MGP secretion from human airways in vitro. MGP secretion from human airway explants (with epithelium) and isolated submucosal glands was estimated by measuring trichloroacetic acid (TCA) precipitable glycoconjugates using secretory indices. Histamine induced significant MGP secretion from both explants and isolated glands. Pretreatment with SKF 91488 significantly inhibited histamine-induced secretion from explants, while it did not alter significantly the secretion from isolated glands. H 1-blocker significantly reversed the inhibition by SKF 91488 of the secretion from explants, while H 2-blocker abolished histamine-induced secretion from both explants and isolated glands. Prostaglandin E 2 (PGE 2) significantly inhibited histamine-induced secretion from isolated glands. The inhibitory action of SKF 91488 in airway explants was blocked by indomethacin and was significantly reduced by a prostanoid EP 4 receptor antagonist (AH23848B). These findings suggest that HMT regulates MGP secretion from human airway submucosal glands through an interaction with epithelial cells which involves the release of PGE 2.

Histamine H 2 receptor-mediated airway goblet cell secretion and its modulation by histamine-degrading enzymes

Background: Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions. Methods: We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge. Results: Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H 2-receptor antagonist cimetidine but not with the H 1-receptor antagonist mepyramine or the H 3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H 2-receptor agonist, likewise decreased mucus score; whereas stimulation of H 1- and H 3-receptors with 2-methylhistamine and (R)-α-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 ± 0.12 to 0.48 ± 0.09 mg/ml ( p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity. Conclusion: These findings suggest that histamine stimulates airway goblet cell secretion through H 2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine. (J Allergy Clin Immunol 1997;99:233-8.)

Histamine N-methyltransferase inhibitor potentiates histamine- and antigen-induced airway microvascular leakage in guinea pigs

Background: Histamine N-methyltransferase (HMT) modulates histamine- and antigen-induced bronchoconstriction. However, it is unclear whether vascular permeability evoked by an allergic reaction can be exaggerated by inhibition of HMT activity. Methods: We studied the effects of intravenously injected SKF 91488, a specific HMT inhibitor, on increases in plasma extravasation induced by intravenously injected histamine in unsensitized guinea pigs and by intravenously injected ovalbumin antigen in guinea pigs sensitized to ovalbumin in vivo with Evans blue dye as a marker. Results: Pretreatment with SKF 91488 shifted, in a dose-dependent fashion, the dose-response curves of the leakage of dye to histamine to lower concentrations in the trachea, main bronchi, and nasal mucosa. Likewise, pretreatment with SKF 91488 (20 mg/kg intravenously) significantly increased the leakage of dye induced by ovalbumin antigen (200 μg/kg intravenously) in three parts of the airway ( p < 0.05). In contrast to SKF 91488, intravenously injected aminoguanidine, a specific inhibitor of diamine oxidase (16 mg/kg intravenously), did not alter the leakage of dye induced by histamine (from 0.001 μg/kg to 10 μg/kg intravenously) ( p > 0.20). HMT activities were observed in the nasal mucosa, as well as in the trachea and main bronchi, as shown in a previous study. Conclusion: These findings suggest that HMT modulates the effects of exogenous histamine and endogenously released histamine induced by antigen challenge on plasma extravasation in the airway in guinea pigs in vivo. (J A LLERGY C LIN I MMUNOL 1995;96:910-6.)

The effect of metoprine on glucoprivic feeding induced by 2-deoxy- D-glucose

Metoprine is a histamine N-methyltransferase inhibitor that elevates endogenous histamine (HA) levels. Because the histaminergic mechanism may be involved in the regulation of feeding behavior as well as in body glucose homeostasis, the effect of metoprine on glucoprivic feeding was studied in Wistar rats. Although metoprine treatment (10 and 20 mg/kg, IP) decreased feeding, the rats still responded to the administration of 400 mg/kg of 2-deoxy- D-glucose (2-DG) by increasing their feed intake. No difference was seen in the 6-h cumulative feed intake after administration of 2-DG between the metoprine- and solvent-treated rats. However, the response was delayed, and with 20 mg/kg metoprine the feed intake was significantly reduced during 2 h after 2-DG application. Both 2-DG and metoprine elevated plasma glucose concentration despite their opposite effects on feeding. Hypothalamic HA or its metabolite levels were not affected by 2-DG. The results suggest that the effects of metoprine and 2-DG are largely independent of each other, and that the feeding modulating function of HA is on such a level that it does not prevent the glucoprivic emergency response.

HMT regulates histamine-induced Cl − secretion across the canine tracheal epithelium

Although histamine N-methyltransferase (HMT), the primary enzyme responsible for the inactivation of histamine, has been shown to exist in the airway epithelium, it is still unknown whether this enzyme regulates ion transport across the airway epithelium. Using an Ussing chamber, we examined the effect of a HMT inhibitor, SKF 91488, on potential difference (PD) and short circuit current (SCC) in epithelial membranes from the posterior portion of canine trachea. SKF 91488 itself did not significantly alter PD or SCC values. Pretreatment with SKF 91488 significantly augmented PD and SCC induced by histamine. Amiloride did not significantly alter the augmentation by SKF 91488 in histamine-induced PD and SCC rises. These findings indicate that HMT regulates Cl − secretion across airway epithelium.

Viral respiratory infection causes airway hyperresponsiveness and decreases histamine N-methyltransferase activity in guinea pigs.

We investigated the effects of viral respiratory infection by Sendai virus on bronchial responses to aerosolized histamine in anesthetized guinea pigs and on the activity of histamine N-methyltransferase (HMT). We measured the change in total pulmonary resistance induced by histamine in the presence or absence of a specific HMT inhibitor, SKF 91488, in noninfected and infected animals. In the absence of SKF 91488, the bronchoconstrictor response to histamine was greater in infected than in noninfected animals. SKF 91488 (10(-2) M, 90 breaths) potentiated the responses to histamine in noninfected animals, and the magnitude of augmented responses to histamine by SKF 91488 was similar to that by viral infection. Furthermore, SKF 91488 did not further potentiate the responses to histamine in infected animals. However, responses to aerosolized acetylcholine were unaffected by viral infection and SKF 91488. The HMT activity decreased by 56% in the trachea, 86% in the bronchi, and 52% in the parenchymal tissue in the infected animals. In contrast to HMT activity, acetylcholinesterase activity was unaffected by viral infection. These results suggest that respiratory infection by Sendai virus causes enhanced bronchial responsiveness to histamine by decreasing HMT activity in airways.