The effect of the histidine decarboxylase inhibitor brocresine (NSD-1055) on gastric acid secretion in rats

The effect of the histidine decarboxylase inhibitor brocresine (NSD-1055) given by mouth, intraperitoneally or intravenously on tetragastrin-, histamine- and bethanechol-stimulated gastric acid secretion was examined in rats. Intravenous injection of brocresine slightly reduced the tetragastrin-stimulated secretion. Histamine-stimulated secretion was markedly increased by both intraperitoneal and intravenous injection of brocresine but it had no effect on the bethanechol-stimulated secretion. It was concluded that either histidine decarboxylase is not effectively inhibited by brocresine or any inhibition induced does not affect gastric acid secretion. The enhanced histamine-stimulated secretion points towards an inhibition of diamine oxidase by brocresine.     

The disposition of a histidine decarboxylase inhibitor (S)-alpha-fluoromethylhistidine in rats

An amino acid analyser method using ninhydrin was developed for (S)-alpha-fluoromethylhistidine (FMH) with a minimum quantitation limit of 0.2 microgram mL-1. The assay was used to study the kinetics of FMH in rat. After bolus intravenous administration of FMH hydrochloride hemihydrate (50 mg kg-1), plasma concentration decreased biexponentially with half-lives of 4.4 and 32.7 min. The distribution volumes of the central and peripheral compartments were 127.4 and 166.3 mL kg-1, respectively. The tissue concentration of FMH was highest in the kidney and also decreased biphasically. The FMH concentrations in other tissues were lower, but their tissue/plasma ratios of FMH increased continuously after FMH injection, indicating that FMH partitioned into these tissues and was lost from them very slowly.     

4-imidazolyl-3-amino-2-butanone (McN-A-1293), a new specific inhibitor of histidine decarboxylase

4-Imidazolyl-3-amino-2-butanone (McN-A-1293) was shown to be an effective inhibitor of fetal rat histidine decarboxylase, but not guinea pig kidney aromatic l-amino acid decarboxylase in vitro. McN-A-1293 was a more potent inhibitor than α-methylhistidine, but less potent than brocresine (NSD-1055) and other aminooxyamines. Kinetic studies using fetal rat histidine decarboxylase indicated the inhibition to be reversible and competitive with histidine. McN-A-1293 in vitro was a less potent inhibitor of diamine oxidase than brocresine and was only a weak inhibitor of imidazole-N-methyltransferase. Administration of McN-A-1293 (200 mg/kg, i.p.) to fed rats resulted in 55 per cent inhibition of gastric histidine decarboxylase, while gastric aromatic l-amino acid decarboxylase was only slightly inhibited (17 per cent). Brocresine (200 mg/kg, i.p.) inhibited both gastric decarboxylases > 60 per cent. Doses of McN-A-1293 as low as 50 mg/kg, i.p., inhibited gastric histidine decarboxylase activity. In fasted rats, McN-A-1293 (200 mg/kg, i.p.) was found to inhibit the elevation in gastric histidine decarboxylase induced by gastrin or insulin. 4-Imidazolyl-3-amino-2-butanone (McN-A-1293) is an effective and specific inhibitor of histidine decarboxylase both in vitro and in vivo and should be a useful agent for studies on the role of histidine decarboxylase in histamine physiology.     

The effect of brocresine (NSD-1055) on the histidine decarboxylase activity in the rat gastric mucosa

The effect of the histidine decarboxylase inhibitor brocresine (NSD-1055) on the specific histidine decarboxylase in the gastric mucosa was investigated in rats. The inhibiting potencies of brocresine were compared after oral and intraperitoneal administration with and without 2-deoxy-d -glucose. Furthermore, different doses of brocresine were added directly to an incubation medium containing an homogenate of the gastric mucosa of untreated animals. The gastric histidine decarboxylase of the brocresine-pretreated animals was not inhibited. Addition of brocresine to the incubation medium produced a dose dependent blockade of the enzyme. 50% inhibition was accomplished by a concentration of 1·4 times 10^?6M. The results demonstrated an inhibition of the rat stomach histidine decarboxylase in vitro, but not in vivo, indicating the inability of brocresine to interfere with the biosynthesis of histamine in the rat stomach.     

Phosphopyridoxal complexes with histamine and histidine. (2) The influence of presumed complex on histidine decarboxylase activity in rat gastric mucosa.

It was found that in vitro, histidine and histamine form a complex compound with pyridoxal-5'-phosphate (PLP). The purpose of the present experiments was to find whether formation of this complex can influence histidine decarboxylase activity. It was found that excess PLP inhibits rat's gastric mucosa histidine decarboxylase activity in vitro. The inhibitory action of PLP depends on the histidine concentration and is independent on the amount of crude enzyme preparation. The histidine-PLP complex did not influence enzyme activity. The possible mechanisms of the inhibitory action of PLP on histidine decarboxylase activity are discussed.     

Phosphopyridoxal complexes with histamine and histidine. (4) The kinetics of complex formation between histidine and pyridoxal 5' -phosphate in the presence of bacterial histidine decarboxylase.

The dynamics of the complex formation between pyridoxal 5'-phosphate (PLP) and histidine in the presence of bacterial histidine decarboxylase was examined. Since PLP is able to form a cyclic product with histidine and histamine, the possibility of complex formation between PLP and histamine formed during a decarboxylation reaction was examined too. It was found that the cyclization reaction between PLP and histidine is equimolecular and the rate of cyclic product formation is not significantly influenced by the presence of enzyme. In the presence of bacterial histidine decarboxylase both the cyclization reaction and cyclic product formation were observed. Predominance of histamine or cyclic product formation was dependent on pH and substrate concentration. In the presence of histidine and enzymatic protein, histamine formed during the decarboxylation reaction was unable to form a cyclic product with PLP.     

The gastric antisecretory activity of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide).

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide) possesses potent gastric antisecretory activity in a number of animal species. It causes a marked inhibition in the volume and concentration of basal and chemically-stimulated gastric acid secretion in the conscious rat and guinea-pig, and of chemically-stimulated secretion in the anaesthetised cat, dog and monkey. Marked activity is also seen in conscious Heidenhain-pouch dogs, against secretion stimulated by betazole and gastrin tetrapeptide. In the pylorus-ligated rat preparation, the antisecretory effect of 30 mg/kg tiquinamide persists for 8-9 h. The possible mode of action of this drug, in view of its wide non-selective antisecretory profile, is discussed.     

The effects of 4-imidazolyl-3-amino-2-butanone (McN-A-1293), a specific histidine decarboxylase inhibitor, on the expression of morphine tolerance and physical dependence in mice

McN-A-1293, a specific histidine decarboxylase inhibitor administered intracisternally in the 'withdrawal' phase, significantly suppressed the expression of morphine tolerance. Severity of withdrawal, assessed by percentage body weight loss, was significantly enhanced although incidence of jumping was unaltered. The opposite effects of this compound on morphine tolerance and withdrawal suggest that tolerance and physical dependence are based on different underlying mechanisms.     

Autoradiography of 3H-alpha-fluoromethyl histidine in mice: correlation with the kidney histidine decarboxylase activity

Tritium-alpha-fluoromethyl histidine (3H-alpha-FMH), designed as a kcat-inhibitor of mammalian histidine decarboxylase (EC 4.1.1.22), was administered intravenously in male and pregnant female mice of the NMRI strain and the distribution of tritium in the body recorded by whole-body and microautoradiography. The results showed penetration of radioactivity into most tissues within 5 min. after the injection. After 4 hrs the highest levels of radioactivity were present in the intestinal content and in the kidneys. In the pregnant animal there was also a high labelling of the foetal tissues. When whole-body sections were washed in TCA prior to the autoradiographic exposure to retain only protein-bound radioactivity, a distinct labelling pattern was seen in the kidneys of the pregnant female mice but not in those of the male mice. Microautoradiography of the kidneys showed that the cells involved were located within the proximal convoluted tubuli. In several mouse strains, including the NMRI, the activity of kidney histidine decarboxylase is low in the males but high in females during a transient period of pregnancy. Incorporation of tritium into kidney protein after treatment with 3H-alpha-FMH, was correlated to a loss in histidine decarboxylase activity. The isotopic labelling was confined mainly to a component which cofractionated with histidine decarboxylase in polyacrylamide gel electrophoresis (PAGE) under non-denaturing conditions. Our data indicate that the cells described above represent the location of kidney histidine decarboxylase.     

Effect of H2 receptor antagonists on histidine decarboxylase activity in rat gastric mucosa

Histidine decarboxylase activity in the gastric mucosa of the rat stomach is markedly increased by the H₂ receptor antagonists, burimamide and metiamide. The increase in enzyme activity is reduced by cycloheximide but not by actinomycin D. An inhibitor of histidine decarboxylase, 4-imidazolyl-3-amino-2-butanone (McN-A-1293), is also effective in reducing the enzyme activity stimulated by the H₂ receptor antagonists. The time course and the magnitude of the response of the enzyme with maximum doses of burimamide are similar to those obtained with pentagastrin. The histamine content of the mucosa is also reduced by burimamide and the data are discussed in relation to the hypothesis that H₂ receptor antagonists increase histidine decarboxylase activity through the release of endogenous gastrin.     

The effect of submaximal doses of pentagastrin on gastric acid secretion, histamine and histidine decarboxylase in rats

In Lai-rats gastric mucosal histamine and histidine decarboxylase were estimated after stimulation of gastric acid secretion by intravenous infusions of submaximal doses of pentagastrin for 1 or 2 h. Pentagastrin produced a dose-dependent acid response with a maximum of 26 μ equiv H⁺ per 10 min at a dose of 2.56 μg kg^?1 min^?1. There was a linear relation between the log dose of pentagastrin and the activation of gastric histidine decarboxylase. The highest dose of pentagastrin yielded a histidine decarboxylase activity of 200% of the unstimulated level when infused for 1 h and of 290% when infused for 2 h. No reduction of gastric mucosal histamine could be detected whatever the dose of pentagastrin or the duration of infusion. It was concluded (1) that stimulation of gastric histidine decarboxylase is a physiological function of gastrin-like peptides, (2) that a reduction of gastric mucosal histamine by gastrin or pentagastrin is a pharmacological rather than a physiological effect, and (3) that no negative feedback relation exists beween gastric mucosal histamine and the activation of histidine decarboxylase.     

Effect of a decarboxylase inhibitor (Ro 4-4602) on 5-HTP induced muricide blockade in rats

The effect of N'-(dl-seryl)-N²(2,3,4-trihydroxybenzyl)-hydrazine (Ro 4-4602) on the blockade in the rat of muricidal behaviour caused by 5-hydroxytryptophan (5-HTP) was investigated. It had been previously reported that Ro 4-4602 exhibited dual actions on the antagonism by DOPA of reserpine effects on motor activity. This dual effect was also observed in the present study where 5-HTP and mouse killing behaviour are employed. Lower doses (2.5–10 $\text{mg}\text{kg}$) of Ro 4-4602 enhanced while the dose of 25 $\text{mg}\text{kg}$ of Ro 4-4602 decreased the blockade of the muricidal behaviour due to 5-HTP. The biochemical interaction of Ro 4-4602 and 5-HTP in the periphery and in the brain are speculated upon in an attempt to explain the data.