Imidazoleacetic Acid Research Articles

Analysis of N tau-methyl imidazole acetic acid by electron impact gas chromatography/mass spectrometry.

A method for the quantitative analysis of N tau-methyl imidazole acetic acid, a major urinary metabolite of histamine, using electron impact gas chromatography/mass spectrometry is described, as are the results of its application to a problem of clinical interest.

The biological activity of hydrogen peroxide: IV. Enhancement of its clastogenic actions by coadministration of L-histidine

An enhancing effect of L-histidine ( L-His) was detected on the induction by hydrogen peroxide (H 2O 2) of chromosomal aberrations of both the chromosome type and the chromatid type, in human embryonic fibroblasts. The maximum efficiency of induction was about 8-fold higher in the presence of L-His than in the presence of H 2O 2 alone, at a concentration of L-His of 50 μM. D-His and DL-His showed lower enhancing effects than L-His, with approximately 2-fold and 5-fold enhancement of induction of chromosomal aberrations, respectively. L-Histidinol and L-His-methyl ester, among various derivatives of L-His tested, also enhanced this process. However, the effects of these derivatives were smaller than those of L-His in a range of concentrations equivalent to that of the most effective dose of L-His (50 μM), while they produced greater enhancement than L-His at concentrations higher than 200 μM. Other derivatives of L-His, such as L-carnosine, urocanic acid, imidazolepyruvic acid, 1-methyl- L-His, imidazolelactic acid, imidazoleacetic acid and histamine and imidazole itself did not enhance the frequency of chromosomal aberrations induced by H 2O 2. These results indicate that at least both the imidazole ring and the amino group are essential components of the chemical structure of L-His required for the enhancing effect. Moreover, in order to cause such an enhancing effect, L-His had to be applied together with H 2O 2 to cells, because the enhancing effect of L-His was not observed with cells which were washed after pretreatment with L-His. The preliminary study suggested that this enhancing effect depends on the His-peroxide adduct derived from L-His and H 2O 2. None of the amino acids tested other than His produced any enhancing effect on the induction of chromosomal aberrations by H 2O 2.

Simultaneous determination of imidazoleacetic acid and n τ-and n π-methylimidazoleacetic acids in human urine by high-performance liquid chromatography with fluorescence detection

A sensitive method for the simultaneous determination of urinary imidazoleacetic acid and N τ-and N π-methylimidazoleacetic acids which employs high-performance liquid chromatography with fluorescence detection is described. The compounds were converted into the corresponding fluorescent esters by reaction with 4-bromomethyl-7-methoxycoumarin. These derivatives are separated by liquid chromatography on a Radial-Pak silica column. The detection limits for imidazoleacetic acid and N τ and N π-methylimidazoleacetic acids in urine are 15, 10 and 20 pmol/ml, respectively. The 24-h urinary excretion of imidazoleacetic acid and N τ- and N π-methylimidazoleacetic acids by healthy persons was 5.7–39.9, 4.3–24.6 and 1.5–19.3 nmol/mg of creatinine, respectively.

Central receptor binding and cardiovascular effects of GABA analogues in the cat

1. 1. Several structural analogues of GABA were shown to be inhibitors of GABA A receptor binding in membranes from cat cerebral cortex. 2. 2. These compounds were 3-aminopropanesulfonic acid (APS; IC 50 = 0.04 μM), imidazoleacetic acid (IMA; IC 50 = 0.4 μM), morpholinopropanesulfonic acid (MOPS; IC 50 = 1.6 μM), 5-phenylpyrrolepropionic acid (PPP; IC 50 = 15 μM), aminoethanethiosulfonic acid (AETS; IC 50 = 22 μM), 3-amino-3-phenylpropionic acid (APP; IC 50 = 35 μM), meta-aminobenzoic acid (MABA; IC 50 = 58 μM) and urocanic acid (UCA; IC 50 = 354 μM). The IC 50 value for GABA was 0.03 μM. 3. 3. GABA, PPP, AETS, MABA and UCA were previously shown to reduce arterial pressure in the cat after intracerebroventricular infusion. 4. 4. In the present study MOPS (ED 50 = 0.26 nmol/kg), APS (ED 50 = 4.7 nmol/kg), APP (ED 50 = 49 nmol/kg), and IMA (ED 50 = 350 nmol/kg) were also found to be able to decrease blood pressure when infused into the fourth ventricle. 5. 5. All nine compounds reduced blood pressure to the same extent, but in some cases their relative potencies (ED 50 values) exhibited significant differences. 6. 6. When the IC 50 values for receptor binding were plotted against the ED 50 values for the cardiovascular effects, no significant correlation emerged. 7. 7. This lack of a correlation does not necessarily imply that the reductions in blood pressure elicited by the drugs are not related to an activation of central GABA A receptors. 8. 8. Instead, it highlights the difficulties that are sometimes encountered in attempting to obtain quantitative measurements after intracerebroventricular infusion.

3H]Muscimol binding to a putative GABA receptor in honey bee brain and its interaction with avermectin B 1a

A putative GABA receptor was identified in honey bee brain by virtue of its specific binding of [ 3H]muscimol and its drug specificity. [ 3H]Muscimol bound with two affinities ( K d 1 of 3 n M and K d 2 of 144 n M), comparable to its affinities for binding to mammalian brain. The high-affinity binding was most sensitive to GABA agonists with the following decreasing order of potencies: muscimol>GABA>imidazole acetic acid> DL-GABOB>Zβ-guanidine propionic acid. However, it was insensitive to the antagonist bicuculline, which is potent on [ 3H]muscimol binding to the mammalian GABA A receptor. It was also insensitive to baclofen, which is a potent agonist of mammalian GABA B receptor, as well as to picrotoxinin, pentobarbital, flunitrazepam, and ethyl-β-carboxylate, which bind to allosteric sites in mammalian GABA receptor. The low-affinity [ 3H]muscimol binding was inhibited with GABA agonists with the following decreasing order of potencies: imidazole acetic acid = β-guanidine propionic acid> dl-GABOB. The two muscimol binding affinities may represent binding to two sites on the same GABA receptor or to two kinds of GABA receptor. The most potent inhibitor of the high-affinity [ 3H]muscimol binding to honey bee brain was avermectin B 1a (AVM), whose IC 50 was 0.01 n M. AVM also inhibited the low-affinity [ 3H]muscimol binding with an IC 50 of 2 μ M.

Regulation of acetohydroxy acid synthase activities in Escherichia coli K-12 by small metabolites

The effects of several metabolites (indole acetic acid, imidazole acetic acid and indole) on acetohydroxy acid synthase activities have been examined in both cya + and cya − strains. Specifically, indole acetic acid caused an increase in the rate of acetohydroxy acid synthase synthesis under both in vivo and in vitro conditions. Taken together, these data suggest that small metabolites, other than cAMP, can alter acetohydroxy acid synthase gene expression.

Attempts to antagonize the effect of histamine on the cold-stimulated thyrotropin secretion in male rats.

Histamine given directly into the 3rd ventricle inhibits the enhancement of thyrotropin secretion induced by cold-exposure (4 degrees, 30 min.) in male rats. This effect was antagonized neither by mepyramine, a H1-receptor antagonist, nor by cimetidine, a H2-receptor antagonist. Histamine would not have an indirect mechanism of action through adrenergic alpha 1- or alpha 2-receptors in rat hypothalamus, since pretreatment with neither phenoxybenzamine nor yohimbine had any effect on histamine suppressed TSH cold-response. Further, it was also tested if histamine could decrease the TSH secretion through cholinergic-, GABA-, serotonergic- or dopaminergic receptors but no results supporting such a mechanism of action were obtained. The effect of histamine was not modified by pretreatment with naloxone or desipramine either. Imidazole acetic acid, IAA, a metabolite of histamine, had no effect on cold-induced TSH secretion. It is concluded that the effect of exogenous histamine on cold-stimulated TSH secretion is not mediated through H1- or H2-receptors. Histamine may decrease brain noradrenergic activity which is important in the generation of TSH cold-response. In addition, the effect of exogenous histamine might be due to decreased endogenous histaminergic activity in rat brain.

The effects of histamine and some related compounds on conditioned avoidance response in rats

When histamine (Hi) and other agonists were applied intraventricularly, Hi caused a dose-dependent inhibition of the avoidance response in rats; its ED50 was 3.60 μg. l-methylHi, l-methylimidazole acetic acid and imidazole acetic acid which are major metabolites of Hi produced no inhibitory effect even at 50 μg. H 1-agonists (2-methylHi and 2-thiazolylethylamine) also depressed the avoidance response; their dose-response lines run parallel to that of Hi. The depressant effects of H 2-agonists (4-methylHi and dimaprit) were relatively weak; their dose-response lines were not parallel to that of Hi. When antagonists were pretreated intravenously, Hi action was clearly antagonized by diphehydramine and pyrilamine, but not by cimetidine or ranitidine. Intraventricular injection of Hi mixed with cimetidine or ranitidine did not change the effect induced by Hi alone. The avoidance response was not affected by noradrenaline, dopamine or 5-hydroxytryptamine. Although acetylcholine (ACh) suppressed the avoidance response dose-dependently, its effect was much weaker than that of Hi. Pretreatment with cholinergic blocking drugs (atropine and scopolamine) antagonized ACh action but not Hi action. From these results, it is assumed that the inhibitory effect of Hi on the avoidance response is preferentially linked to the H 1-receptor. After intraventicular application of 3HHi, the highest radioactivity was determined in the hypothalamus.

Inhibition of in vivo histamine metabolism in rats by foodborne and pharmacologic inhibitors of diamine oxidase, histamine N-methyltransferase, and monoamine oxidase

When [ 14C]histamine was administered orally to rats, an average of 80% of the administered radioactivity was recovered in the urine at the end of 24 hr. About 10% of the total dose was excreted via the feces. Analysis of 4-hr urine samples found imidazoleacetic acid to be the predominant metabolite (60.6%), with N τ-methylimidazoleacetic acid (8.6%), N τ-methylhistamine (7.3%), and N-acetylhistamine (4.5%) to be the minor metabolites. Histamine metabolism was inhibited by simultaneous oral administration of aminoguanidine, isoniazid, quinacrine, cadaverine, putrescine, tyramine, and β-phenylethylamine. The administration of inhibitors resulted in an increased amount of unmetabolized histamine and a decreased amount of metabolites reaching the urine. Pharmacologic inhibitors were found to be more potent and have a longer duration of action than foodborne ones. The inhibitors could potentiate food poisoning caused by histamine by inhibiting its metabolism.

Modulation of 5-hydroxytryptamine-induced head-twitch response by drugs acting at GABA and related receptors.

The effects of drugs acting at the gamma-aminobutyric acid (GABA) receptors and other chloride ionophore-related sites have been studied for their ability to modulate the head-twitch induced by 1-5-hydroxytryptophan (5-HTP) in the mouse. The GABAa receptor agonists, muscimol, imidazoleacetic acid and 3-aminopropanesulphonic acid, produced a dose-related potentiation, while bicuculline inhibited the head-twitch. The GABAb receptor agonist, baclofen, produced dose-related inhibition. Diazepam potentiated the head-twitch while the 'inverse' benzodiazepine receptor agonist ethyl-beta-carboline-3-carboxylate inhibited the head-twitch. The antagonist Ro15-1788 also produced inhibition. Ro05-4864, a ligand for the benzodiazepine 'acceptor' site, potentiated the head-twitch. Pentobarbitone and pentylenetetrazol potentiated the 5-HTP-induced head-twitch at low doses, changing to inhibition as the dose was increased. Picrotoxin in subconvulsant doses, produced only potentiation. More than one site may be involved in the action of these substances. GABA, amino-oxyacetic acid and 1-2-4-diaminobutyric acid inhibited the head-twitch, while the GABA-depletor, 3-mercaptopropionic acid potentiated it. Of all the agents tested, only muscimol produced head-twitching when given alone. It was concluded that both GABAa and GABAb receptors modulate the head-twitch response to 5-HTP.

Formation of [formula omitted]-ribosylhistidime, a novel histidine derivative found in the urine in histidinemia, from histidine and NAD(P) + catalyzed by an NAD(P) + glycohydrolase system

The formation of N τ -ribosylhistidine (His-R), a novel histidine derivative found in the urine of histidinemic patients, was studied. A most possible synthetic pathway catalyzed by imidazole acetic acid (ImAA) phosphoribosyltransferase was not substantiated, because p.o. administration to humans and rats of aspirin, an inhibitor of the enzyme, did not change the urinary excretion of His-R, whereas aspirin decreased the excretion of ImAA-R with concomitant increase in that of ImAA. His-R was produced on incubation of a rat liver homogenate or its membrane fraction with histidine, NAD(P) + and MgCl 2, but not with only histidine or NAD(P) +. Nicotinamide inhibited the formation of His-R. Thus the enzymes responsible for the formation of His-R were suggested to be NAD(P) + nucleosidase, nucleotide pyrophosphatase and 5′-nucleotidase.

Evidence for GABA tolerance in barbiturate-dependent and withdrawn mice

Mice were rendered tolerant and dependent to barbital by a chronic feeding schedule of barbital over 5 weeks. The behavioural effects of muscimol, imidazole-acetic acid (ImAA), and gamma-hydroxybutyric acid (GHB) were measured in control, barbital-dependent, and mice dependent on barbital 48 hr after withdrawal of the drug. The sedative effects of the GABA-mimetics imidazole-acetic acid and muscimol were increased in dependent mice, but reduced in withdrawn mice. Subanaesthetic doses of barbital, given acutely, also increased the sedative effects of imidazole-acetic acid and muscimol but not of gamma-hydroxybutyric acid. Assay of plasma barbital levels by GLC indicated that a negligible amount of barbital was present 48 hr after withdrawal compared to levels of between 60 and 120 μg ml during chronic treatment with barbital. The binding of [ 3H]GABA to membrane preparations from brain indicated that the values of k d and B max for low affinity binding were not significantly altered in mice withdrawn from chronic treatment with barbital, but that the K d for high affinity binding was significantly increased from 4.38 to 6.06 nM in barbital-withdrawn mice. There was no difference in the enhancement of GABA binding by pentobarbital between the two groups. It is concluded that barbital-tolerant and dependent mice are cross-tolerant to GABA and that this is possibly mediated by a change in the affinity of the GABA receptor for its ligand.

Measurement of imidazoleacetic acid in urine by gas chromatography—mass spectrometry

Imidazoleacetic acid (IAA), a histamine and histidine metabolite, was quantified in human urine by gas chromatography—mass spectrometry (GC—MS). The acid was separated by ion-exchange chromatography, derivatized as the n-butyl ester with boron trifluoride—butanol and the derivative extracted with chloroform. GC—MS analysis was carried out by selected-ion monitoring of ions m/z 81 and m/z 83 corresponding, respectively, to IAA and [ 15N, 15N′]IAA used as internal standard. The mean IAA content in urine was about 8.02 nmol/mg of creatinine. The specificity of measurement was rigorously established by GC retention time, peak shape, ion abundance ratios, and recovery experiments. The method is capable of quantifying IAA in 0.05 ml of urine and in amounts as low as 0.20 nmol.

Histamine metabolism in patients with histidinemia: determination of urinary levels of histamine, N tau-methylhistamine, imidazole acetic acid, and its conjugate(s).

Histamine metabolism in histidinemic patients was studied by measuring the urinary levels of histamine and its metabolites. The urinary excretions of histamine, N tau-methylhistamine, imidazole acetic acid, and its conjugate(s) were higher in patients with histidinemia than in controls, and these levels of excretion were correlated with the plasma histidine level. The urinary histamine levels of patients with eczema-like dermatitis were twice that of those without dermatitis. The urinary excretion of 3-methylhistidine showed a close correlation with the urinary histidine excretion. Thus, it was concluded that histamine metabolism is higher in histidinemic patients than in normal controls.

Histamine uptake and metabolism in the blood vessels of rats.

In vitro radiolabeled histamine uptake and metabolism were investigated in abdominal aorta, iliac artery, mesenteric artery and hepatic portal vein of the rat. Histamine uptake was rapid and remained linear over the initial 10 min of the accumulation period. The uptake rate was temperature sensitive with marked reduction in rate at 0 degrees C. The accumulation at 0 degrees C represents nonspecific uptake. The uptake of histamine was observed to be related to the amount of tissue stores of histamine as well as extracellular sodium ion concentration. The only histamine metabolite detected in the vasculature examined was imidazoleacetic acid representing almost 80% of the chromatogram radioactivity. This observation indicates the primary metabolic pathway for histamine in rat vasculature involves the enzyme, diamine oxidase.

Determination of imidazole acetic acid and its conjugate(s) levels in urine, serum and tissues of rats: studies on changes in their levels under various conditions

A convenient and reproducible method for assay of imidazole acetic acid (ImAA) was developed as a modification of that described previously (Watanabe et al., 1983). ImAA conjugate(s) (ImAA-C), mainly consisting of imidazole acetic acid riboside, could be measured by this method after its hydrolysis to ImAA. The ImAA and ImAA-C levels in various tissues of rats were measured and the effects of various agents on these levels were studied. The renal clearance values of ImAA-C in rats and man were similar to the creatinine clearance values, but those of ImAA were 1/40 of those of ImAA-C, suggesting that the latter is readily excreted in the urine. Consistent with this idea, the urinary excretion of ImAA-C was found to increase much more than that of other histamine metabolites during late pregnancy, when the foetus produces much histamine.

Stress-induced enhancement of suppression of [3H]GABA release from striatal slices by presynaptic autoreceptor.

The effect of cold and immobilization stress on presynaptic GABAergic autoreceptors was examined using the release of [3H]GABA (gamma-aminobutyric acid) from slices of rat striatum. It was found that in vitro addition of delta-aminolevulinic acid, as well as GABA agonists such as muscimol and imidazoleacetic acid, exhibited a significant suppression of the striatal release of [3H]GABA evoked by the addition of high potassium, whereas delta-aminovaleric acid had no significant effects on the evoked release. These suppressive actions were antagonized invariably by the GABA antagonists, bicuculline and picrotoxin, but not by the glycine antagonist, strychnine. Cholinergic agonists, such as pilocarpine and tetramethylammonium, also attenuated significantly the evoked release of [3H]GABA from striatal slices, while none of its antagonists, including atropine, hexamethonium and d-tubocurarine, affected the release. On the other hand, in vitro addition of dopamine receptor agents such as dopamine, apomorphine, and haloperidol, or the inhibitory amino acids, glycine, beta-alanine, and taurine failed to influence the evoked release of [3H]GABA from striatal slices. Application of a cold and immobilization stress for 3 h was found to induce a significant enhancement of the suppressive effects by muscimol and delta-aminolevulinic acid on the evoked release of [3H]GABA, without affecting that by pilocarpine and tetramethylammonium. These results suggest that the release of GABA from striatal GABA neurons may be regulated by presynaptic autoreceptors for this neuroactive amino acid, and may play a significant functional role in the exhibition of various symptoms induced by stress.

The γ-aminobutyric acid receptor in catfish brain

1. When the binding of [ 3H]γ-aminobutyric acid (GABA) to its receptor in catfish synaptic membranes was studied, a high affinity ( K d = 8.4 nM) and a low affinity ( K d = 65 nM) binding component was observed. 2. Muscimol, thiomuscimol, tetrahydroisoxazole-5,4- c-pyridin-3-ol, imidazole acetic acid and bicuculline each competitively inhibited both high affinity and low affinity [ 3H]GABA binding. 3. The potency of these inhibitors was similar to that reported for the GABA receptor from mammalian brain. 4. It is concluded that the GABA receptor from catfish brain has very similar properties to the receptor from mammalian central nervous system and consequently has not undergone any obvious evolutionary changes.

Depolarizing action of GABA (γ-aminobutyric acid) on myelinated fibers of peripheral nerves

The inhibitory neurotransmitter GABA (gamma-aminobutyric acid) has been shown to have a depolarizing action on myelinated axons of both mammalian and amphibian peripheral nerves. In initial in vivo observations intravenous injections of GABA caused an increase in the excitability of the low-threshold, fast conducting fibers of the superficial radial and median nerves of the cat. Similar, graded, reversible effects were confirmed (using changes in the amplitude/integral of the stimulus-evoked A-fiber submaximal compound action potential to assess excitability) in in vitro studies with the isolated, desheathed frog sciatic nerve. GABA caused a mean maximal increase in half-maximal action potential of 29.8% (S.E. +/- 2.7), with an ED50 value of 0.09 mM and Hill coefficient of 0.70. This effect did not appear to desensitize, and could be reversibly antagonized by both bicuculline and picrotoxin. Comparison of agonist sensitivities showed a rank order of potency with muscimol greater than 3-aminopropanesulfonic acid greater than GABA greater than beta-guanidinopropionic acid greater than imidazole-acetic acid greater than guanidoacetic acid greater than delta-aminovaleric acid. With structure activity analysis the maximal activity was found to be related to N+-C separation near the 5 A value. Partial substitution of chloride ions in the superfusate by isethionate reversibly depressed the effect of GABA. These observations support the conclusion that extrasynaptic receptors for GABA are present on the myelinated axons of peripheral nerves.

Catabolism of histamine in the isolated glomeruli and tubules of the rat kidney

Histamine alters renal hemodynamics including the glomerular microcirculation, and histamine receptors are present in rat glomeruli. We have recently shown that isolated rat glomeruli, but not cortical tubules, incubated with the histamine substrate L-histidine synthesize histamine. This study explores the catabolic pathways of histamine in isolated glomeruli and cortical tubules of the rat kidney. Glomeruli and cortical tubules were incubated with radiolabelled histamine, and the products were separated on thin layer chromatography (TLC). Glomeruli predominantly catabolized histamine to acid metabolites of the diamine oxidase (histaminase) pathway, imidazole acetic acid and ribosylimidazole acetic acid, and to a lesser extent to the inactive methylation product, N tau-methylhistamine (7.5% vs. 2.5%). Tubules on the other hand catabolized histamine to N tau-methylhistamine and to a lesser degree to acid metabolites (7.6% vs. 2.3%). The methyl donor S-Adenosyl-methionine (SAM) (10(-4) M) markedly enhanced the production of N tau-methylhistamine in both glomeruli and tubules (delta + 600%) but had no effect on the production of acid metabolites. In the presence of equimolar concentrations of SAM, tubules continued to methylate histamine to a greater extent than glomeruli (46.0% vs. 18%). In both glomeruli and tubules, the diamine oxidase inhibitor, amino-guanidine, abolished the production of acid metabolites while amodiaquine and pyrilamine, inhibitors of the methylation pathway, markedly reduced the production of N tau-methylhistamine. In addition, in the presence of SAM, tubules catabolized nonlabelled histamine to a greater extent than glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)