K. Sasiak

Effect of Pargyline on Brain N‐tele‐Methylhistamine in Portocaval‐Shunted Rats: Relation to Amine Neurotransmitters

Abstract: HPLC determination of histamine, serotonin, dopamine, and noradrenaline in the brain tissue of rats with portocaval anastomoses (PCA) has revealed a selective increase in histamine concentration. In the posterior hypothalamus, the steady‐state level of the amine metabolites showed an inverse pattern; N‐tele‐methylhistamine(t‐MeHA), as estimated by gas chromatography‐mass spectrometry, was not changed significantly by portocaval shunting, whereas 5‐hydroxyindoleacetic acid (5‐HIAA) and homovanillic acid were more than doubled. Interestingly, the net increase in t‐MeHA concentration in response to pargyline (80 mg/kg i.p.) was almost the same for PCA and sham‐operated rats. This implies that the great enhancement of the histamine level in this area might be a consequence of the persistent stimulation of its synthesis and the unchanged activity of histaminergic neurons. In the rest of the brain, on the other hand, the steady‐state level of t‐MeHA was higher after PCA (3.8‐fold), as were the levels of 5‐HIAA and homovanillic acid. Surprisingly, t‐MeHA remained unchanged after monoamine oxidase blockade. Of the pargyline‐induced alterations in the concentrations of indoles and catechols, the most pronounced were those in the serotonin level; serotonin was elevated more than twofold in hypothalamus and more than 12‐fold in the rest of the brain, with a concomitant 80% decrease in 5‐HIAA. The dopamine and, to a much smaller extent, noradrenaline levels were also increased, and the levels of homovanillic acid and 3,4‐dihydroxyphenylacetic acid fell below the detection limit. The study suggests that at least two different mechanisms operate in the brains of PCA rats to counteract the excessive synthesis of neuromediators, e.g., increased deposition and increased metabolism.

Histamine and its catabolism in tumour-bearing rat and mouse.

The hypothesls that fallure of histamine (Hi)-mediated inter and intracellulary cell-cell communication may be involved in the control of cellular growth has been tested in leukaemia-bearing mice and fibrosarcoma-bearing rats.In all examined tissues of mice bearing leukaemia L1210 cells and rats bearing methylcholanthrene fibrosarcoma histamine content was higher than in controls.Tissues of fibrosarcoma-bearing rats more intensively metabolized14C-Hi and oxidative pathway was predominat. Histamine metabolic activity as well as histamine catabolic pathways do not differ in leukaemic mice as compared with the controls.

Phosphopyridoxal complexes with histamine and histidine. (3) The influence of presumed complex on activity of rat intestinal histaminase.

Histamine in high concentration inhibits the rat intestinal histaminase (diamine oxidase E.C. 1.4.3.6). The apparent Km is approximately 4.2×10−5 M. This inhibition can be reversed by an addition of PLP.It was also found that excess of PLP inhibits enzyme activity. It is competitive inhibition.Histamine and other amines which were associated with enzyme inhibition form spectrophotometricaly demonstrable complex with PLP. The possible mechanism of the inhibitory action of PLP and complex with histamine and other amines on rat intestinal histaminase activity are discussed.

Phosphopyridoxal complexes with histamine and histidine (1) the kinetics of complex formation between pyridoxal 5′-phosphate and histamine

Amines and amino acids are able to form cyclic compounds with pyridoxal 5′-phosphate (PLP). The quantitative relationship between histamine and PLP in the cyclization reaction were examined. It was found that one mole of amine reacts with one mole of coenzyme. The velocity of complex formation increased with an excess of either histamine or PLP, without any change in molar ratios. The formation of cyclic compound was confirmed by the use of isotopic method. The separation of cyclic compound from histamine, but not from PLP, was achieved by paper chromatography.

In vivo formation of histamine phosphopyridoxal cyclic compounds

A possibility of in vivo formation of cyclic compounds between histamine (Hi) given i.p. and endogenous pyridoxal (PL) or pyridoxal 5′-phosphate (PLP) has been studied. Cyclic compounds of Hi with PL or PLP were found in all tissues examined. Although an increase in Hi levels in tissues enhances the formation of cyclic compounds, no simple relationship between the rate of formation and Hi concentration has been observed. The reaction seems to be limited by endogenous PLP. The cyclic products Hi-PL and HI-PLP were discovered in urine. It is suggested that the process of cyclic compound formation may reduce PLP resources, resulting in a modification of PLP-enzyme activities.

Causal relationship between a tumour growth and the changes in histamine metabolism in tissues of sarcoma-bearing rat

The relationship between malignancy and histamine metabolism in the liver and the small intestine has been examined in sarcoma-bearing Wistar rats two weeks after subcutaneous implantation of a transplantable methylcholanthrene sarcoma Sa1828 and on the 3, 7 and 14th days after tumour extirpation. Two weeks after tumour implantation, the histamine level was increased by 100% and 50% in the liver and the small intestine, respectively. On the 3rd day after extirpation of the tumour the level of histamine had returned to the control values and remained unchanged during the next 10 days. Neither of the histamine catabolizing enzymes, diamine oxidase with a putrescine as a substrate or histamine methyltransferase were influenced by the existing tumour or by its extirpation except on the 14th day where a high increase in diamine oxidase activity was found. Some changes in the distribution of histamine metabolites suggest an involvement of an oxidative pathway of histamine catabolism as well as the aldehyde catabolizing enzymes in tumour development.

Phosphopyridoxal cyclic compounds with histamine and histidine. 7: The properties of pyridoxal and phosphopyridoxal cyclic compounds with histamine and histidine.

Cyclic compounds synthesized from histamine (Hi) or histidine (His) with pyridoxal (PL)-[Hi-PL, His-PL] and Hi or His with pyridoxal 5′-phosphate (PLP)-[Hi-PLP, His-PLP] were tested for stability in buffer, acid and base solutions, crude homogenates of various tissues and in the presence of enzymes which metabolize Hi or His. The cyclic pyridoxal compounds were stable in all experimental conditions, whereas phosphopyridoxal cyclic products were degraded by rat intestinal DAO and rat intestine homogenate, apparently enzymatically. In acidic and basic solutions changes in migration velocity and u.v. absorption spectrum occur. The characteristic fluorescence of these cyclic compounds is described.

Hepatocyte transplantation reverses the effect of portocaval shunt on rat brain histamine.

Rats with portocaval anastomosis (PCA) serve as experimental models of hepatic encephalopathy associated with chronic liver dysfunction in man. Portocaval shunt is connected with an exaggerated amine production in the central nervous system. The excess histamine produced is largely deposited in neurons, in contrast to serotonin which undergoes catabolism [1, 2]. Experiments with the suicidal histidine decarboxylase inhibitor, a-fluoro-methylhistidine administered few months after the shunt operation have suggested that the accumulated histamine can be mobilised from its neuronal deposits/stores [3]. In the present study, we strengthened these data by using PCA rats in which the substantially reduced hepatic function was improved by hepatocyte transplantation. The therapeutic use of hepatocyte transplantation in chronic liver failure has recently been proposed [4].

Polyamine system in developing rat eye and an animal model of retinopathy of prematurity

Abstract · Background: In experimental models of retinopathy of prematurity (ROP), a vasoproliferative disorder of the retina, retinal lesions are usually assessed by morphological examination. However, studies suggest that the polyamine system may be useful in monitoring proliferation processes. For this reason, polyamine concentrations in rat erythrocytes (RBC) and the regulation of polyamine system in rat eyes under the conditions relevant to ROP were investigated. · Methods: Newborn Wistar rats were reared in room air (control) or exposed first to hyperoxia (60% or 80% oxygen, 2 weeks) and then to normoxia (relative hypoxia, 1 or 2 weeks). Blood was collected from orbital vessels at 2 weeks of age and before death. Polyamine system-related enzyme activities were measured in retina and lens with radioassays. Polyamines were quantified by fluorometry after extraction, dansylation and HPLC separation. · Results: Oxygen (80% only) significantly decreased RBC polyamine concentrations, which then markedly increased after rats were transferred for a week to normal air, suggesting retardation of growth processes and compensatory stimulation, respectively. However, polyamine system changes in the rat eye were not so pronounced. Enzyme activities and polyamine concentrations tended to be lower in retina after hyperoxia and were only slightly higher, with the exception of ornithine decarboxylase, after a subsequent 1 week of normoxia. In litters subjected to normoxia for longer periods no changes were found. · Conclusion: The transient and short-lived alteration in polyamine metabolism, especially in the eye, suggests that exposure of newborn rats to high oxygen supplementation followed by normoxia does not necessarily result in marked retinopathy.

The effect of an ICV H3-agonist on plasma prolactin in portocaval shunted and sham operated rats

Portocaval shunt (PCA) in the rat results in a high synthesis and accumulation of histamine in the central nervous system (CNS) [1]. It is thought that hypothalamic histamine participates in the regulation of anterior pituitary hormone release and evidence is available that plasma hormone levels are influenced by manipulation of the cerebral histamine concentration [2]. However, while i.p. administration ofthe histamine H3 receptor antagonist thioperamide decreases the brain histamine concentration, it does not alter plasma levels of adrenocorticotrophic hormone (ACTH) or prolactin either in PCA or in sham rats [3]. On the other hand, Navarro et al. [4] reported that activation of H 3 receptors by i.c. v. application of R( )alfamethylhistamine elicits prolactin release in male rats, and suggested the involvement of postsynaptic H3 receptors. Since not only histaminergic but also serotoninergic and dopaminergic systems are affected in PCA rats [5], we have now examined how in these animals the stimulation of H3 receptors with a selective agonist influences plasma prolactin and brain neurotransmitter levels.