Experimental autoimmune myocarditis in rats and therapeutic histamine H1 - H4 receptor inhibition.

Myocarditis, a life threatening disease, is still not adequately treated. Histamine plays an important role in physiology and pathophysiology of cardiovascular system. All four histamine receptors (H1R - H4R), are present in the heart. Experimental autoimmune myocarditis (EAM) was used to investigate which histamine receptor had a greater impact on the disease's progression. EAM was evoked in Lewis rats by porcine myosin immunization. Mepyramine, ranitidine and ciproxifan were used to inhibit H1R, H2R and H3R receptors, respectively, and 2,4-diaminopyrimidines: ST994, ST1012, ST1006 were ligands of H4R. Quinapril, an ACE inhibitor, served as a reference drug. Drugs were administered daily, either from 0 - 2 weeks or from 2 to 4 weeks post EAM induction. Cardiac dysfunction developed with significant decreases in left ventricular ejection fraction and fractional shortening due to dilatation and wall thickening. EAM rats treated with mepyramine and ST994 in weeks 0 - 2 had the lowest decreases. These treated with ST994, ST1012 or quinapril performed much better the following 2 weeks without therapy than did the other groups. On autopsy their hearts were smaller, less fibrotic, histopathological changes in them of a lower grade. When the treatment started with 2 weeks' delay, the ST994-treated EAM rats showed the highest median survival. H4 receptor antagonism inhibits heart remodelling, preserves heart contractility, improves survival and may be of potent therapeutic relevance in human clinics. The blockade of H1 receptor inhibits heart dilatation but does not prolong the life.

The central histamine level in rat model of vascular dementia.

The histaminergic system plays an important role in memory and learning. Deficient histaminergic transmission in the human brain in vascular dementia (VD) has been suggested. To get a better insight into the problem, a rat model of VD based on permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion was used. Prior to the BCCAO, male Wistar rats underwent 7 days training and only those animals that positively passed the holeboard memory test were chosen for the study. The rats which were operated on were injected i.p. daily for 6 days with either a monoamine oxidase B inhibitor - PF9601N (40 mg/kg), an acetycholinesterase inhibitor - tacrine (3 mg/kg), a histamine H(3) receptor blocker - DL76 (6 mg/kg) or saline. The first retest (R1) was performed one week after the surgery while each subsequent test was 5-7 days apart. The rats were euthanized 2 or 4 weeks following the operation. The concentration of brain histamine (HA) and the activity of histamine metabolising enzymes were measured using current procedures. The BCCAO drastically increased latency and run time (p<0.001) 54 ± 30 vs. 3.4 ± 1.2 and 268 ± 18 vs. 74 ± 9, respectively, and affected working memory rather than reference memory as measured by the 1(st) retest (R1). Treatment with either PF9601N or tacrine seems to exert a positive effect on working memory. This tendency disappeared after the drug treatment stopped. Latency and run time, although they improved in R2-R4, never attained the preoperative values. The brain tissues from rats treated with PF9601N showed only 15% and 50% of untreated rat MAO B and MAO A activity, respectively, despite the drug administration having been discontinued for 3 weeks. Other drugs examined did not influence MAO enzymes. Neither did histamine N-methyltransferase activity show changes related to BCCAO nor to the treatments. The hypothalamic HA concentration was significantly reduced after BCCAO: 1.13 ± 0.1 vs. 1.91 ± 0.16. Noteworthy, the rats treated with PF9601N or DL76 had brain HA levels not significantly different from their intact counterparts. The rat vascular dementia model supports deficiency in histaminergic system in VD.

Involvement of the histaminergic system in cytidine 5'-diphosphocholine-induced reversal of critical haemorrhagic hypotension in rats.

Cytidine 5'-diphosphocholine (CDP-choline) is an endogenously synthesized mononucleotide which exerts a variety of physiological effects by altering central cholinergic transmission. Administered intracerebroventricularly (i.c.v.) or intravenously, it reverses haemorrhagic hypotension in rats, apparently by the activation of central cholinergic receptors. The study was undertaken to investigate the involvement of the central histaminergic system in CDP-choline-mediated reversal of haemorrhagic hypotension. Experiments were carried out in male ketamine/xylazine-anaesthetised Wistar rats subjected to haemorrhagic hypotension of 20-26 mmHg. CDP-choline (2 micromol; i.c.v.) administered at 5 min of critical hypotension produced a long-lasting pressor effect with increases in mean arterial pressure (MAP), heart rate (HR), and renal, hindquarters and mesenteric blood flows, resulting in a 100% survival at 2 h. The action was accompanied by approximately a 26% increase in extracellular histamine concentration at the posterior hypothalamus, as measured by microdialysis. Cardiovascular effects mediated by CDP-choline were almost completely blocked by pretreatment with H(1) receptor antagonist chlorpheniramine (50 nmol; i.c.v.), but not with H(2) receptor blocker ranitidine (25 nmol; icv) or H(3)/H(4) receptor antagonist thioperamide (50 nmol; i.c.v.). In conclusion, the present results show that he central histaminergic system, through the activation of H(1) histaminergic receptors, is involved in CDP-choline-induced resuscitating effect in haemorrhage-shocked rats.

Satiety signalling histaminergic system and brain-gut peptides in regulation of food intake in rats with portocaval anastomosis.

Brain histamine plays a regulatory role in feeding behaviour, acting as an inhibitory modulator. Portocaval anastomosis (PCA) is associated with cerebral aminergic systems alterations, including high histamine accumulation and release from neurons. Despite that, the rats with PCA eat significantly more, their body mass being lower than sham-operated animals. To disclose underlying regulatory mechanisms, food intake was measured before and after treatment with antagonists of histamine H(1) and H(2), orexin type 1 (OX(1)) and cannabinoid type 1 (CB(1)) receptors in adult male Lewis rats 6 months following the end-to-side PCA or sham operation. Hypothalamic concentrations of orexin A and histamine as well as serum concentrations of leptin, insulin and cholecystokinin (CCK) were analysed. PCA rats with body mass lower by 30%, have consumed more feed and water 150% and 200%, respectively. The modifying effects of pyrilamine, ranitidine, SB 334867 and rimonabant were less pronounced in PCA compared with sham-operated rats. Hypothalamic orexin A and histamine concentrations were higher in PCA rats than in the control group with intact portocaval system. In PCA rats, serum concentrations of CCK were higher, leptin concentrations lower, while there were no differences between the groups in insulin levels. In conclusion, the adaptive mechanisms efficiently render PCA rats less sensitive to peripheral and central anorexigenic signals. Orexin A appears to be involved in the counteracting mechanisms preventing further body mass loss in PCA rats.

High voluntary alcohol consumption, in experimental liver cirrhosis is hardly responsive to opioid antagonist treatment.

BACKGROUND: Rats with liver cirrhosis, evoked by chronic administration of thioacetamide (TAA), consumed voluntarily more alcohol than their healthy counterparts. Seeking the mechanisms underlying this phenomenon, the opioid system was screened for involvement and alterations. In vivo, the influence of chronically administered Naloxone and Naltrexone, non-specific opioid receptor antagonists, on alcohol intake was examined in free choice tests between 10% alcohol and tap water and ex vivo receptor binding studies were performed on cerebral membrane preparations. METHODS: TAA rats, selected for the study, had confirmed liver insufficiency: their plasma bilirubin concentrations were about 3 times higher, the prothrombin time was 50% longer and they consumed voluntarily 3 times more alcohol than the control animals. The drugs were given s.c. for five days, at the beginning of the dark phase of a 24h cycle, in a daily dose of 10 mg per kg body mass. Throughout the treatment, the rats were kept individually in metabolic cages with a free access to water, alcohol solution and food. Feed and fluid consumption, as well as the urine outputs, were recorded on the 2h, 4h, 6h and 24h after the drug administration. The mu opioid ligand - [(3)H]-(D-Ala(2), -N-MePhe(4), Glyol(5)) Enkephalin was used to obtain binding characteristics of the control and TAA rat brain membranes. RESULTS: The drugs, if modified drinking behaviours, they did it transiently; alcohol, water and thus the total fluid intake by the cirrhotic and control rats was significantly less after 2h - 6h from either naloxone or naltrexone administration. Both drugs decreased general fluid consumption as such rather than the consumption of alcohol only, as observed from the recordings related to TAA rats. The binding data: K(d) of 2.62 +/- 0.98 nM and B(max) of 43.71 +/- 6.12 fmol/mg protein for cirrhotic rats, versus K(d) of 4.63 +/- 1.98 nM and B(max) 95.61 +/- 18.33 fmol/mg protein for the control ones, suggest that while the affinity of radioligand to cerebral mu receptors was similar for the two groups, there was a lower density of those receptors in the cirrhotic rats. CONCLUSIONS: The results indicate some disturbances in the opioid system in cirrhotic rats. However, the low response to opioid therapy suggests that the opioid system may have only be partly involved in the development of the observed increased alcohol drinking in the rats with liver cirrhosis.

Histamine in food: is there anything to worry about?

Biogenic mono-, di- and poly-amines are widely distributed among living organisms. The amines fulfil many important functions in the human body both in the periphery and brain. Some authors suggest that foods rich in biogenic amines, especially histamine, present high health hazards for consumers. However, this is conditional on a range of other factors. The alimentary tract is well equipped with enzymes that inactivate amines and the blood-brain barrier prevents them entering the brain from the circulation. Oxidative deamination, methylation, acetylation and transglutamylation are the degradation pathways which operate efficiently in the stomach, intestines and liver. Particularly important is oxidative deamination. Food histamine poisoning or cheese reaction, manifested itself in patients treated with drugs that inhibit amine oxidases or in patients showing an enterocytic diamine oxidase deficit. It is rather food allergy, which should worry us more, as endogenous histamine release from mast cells is more dangerous. Preventive measures should be undertaken against increases in food allergies.

Mammary histidine decarboxylase vulnerability to enzyme antisense oligonucleotides: histamine and polyamine systems cross-talk.

Histamine system is suggested to have a role in mammary gland growth regulation, differentiation and functioning during pregnancy and lactation. Histidine decarboxylase activity undergoes significant changes during pregnancy and lactation. Pregnancy associated elevation of HDC activity and mRNA transcript in mouse mammary gland was successfully affected by enzyme antisense oligonucleotides treatment. The enzyme activity of resting mammae was unaffected as it lacked inducible pool of HDC. The short-term mammary histamine shortage evoked influenced the mRNA expression of histamine receptors (H1 and H2) and ornithine decarboxylase during pregnancy. There were essentially no morphological changes in the mammary gland upon the treatment, however, adipocytes neighbouring alveolar structures were more pronounced. These findings further substantiate the role of histamine in mammary gland physiology and emphasise presence of common motifs of biogenic amines and polyamine metabolism as well as mutual interferences implicating observed "cross-talk" phenomenon.

Mouse mammary epithelial histamine system.

Histamine is suggested to play a role in mammary gland growth regulation, differentiation and functioning during pregnancy and lactation. Two pools of histamine are thought to be involved in these processes: mastocyte- and epithelial cell related histamine. In the present study we focused on epithelial cells. Immunohistochemistry has shown that the epithelial cells positive for histamine and L-histidine decarboxylase (HDC), the primary enzyme regulating histamine biosynthesis, were mainly found in cells forming alveolar structures in the mammary gland. Cultured primary mouse mammary epithelial cells (MMEC) expressed strong HDC immunoreactivity, especially dividing cells and non-differentiated ones. Histidine decarboxylase activity undergoes significant changes during pregnancy and lactation. Pregnancy associated intensive growth of the mammary gland coincided with an increase and the first days of lactation with a decrease of HDC protein expression. Binding studies with mammary tissue membranes and epithelial cell membranes revealed the presence of H1 and H3 but not H2 receptors. Summarizing, our data have shown that mammary epithelial cells are capable of synthesizing and excreting histamine and they bear histamine receptors. These findings further substantiate the role of histamine in mammary gland physiology.

Effects of human growth hormone (hrGH) treatment on amine metabolism in rats subjected to extensive small bowel resection.

The effect of human recombinant growth hormone (hrGH) on intestinal adaptation in rats subjected to massive small bowel resection has been followed by monitoring changes in the tissue polyamine system and in red blood cell (RBC) polyamine levels. In parallel, the activities of monoamine oxidase A and B and diamine oxidase, the enzymes that catalyse one of the major routes of biogenic amine metabolism, oxidative deamination, were also examined. The results suggest that whilst hrGH treatment accelerates adaptive intestinal hyperplasia evoked by the resection, it has no significant effect on RBC polyamine level or gut mucosal DNA concentration as measured 3 weeks post surgery. hrGH treated operated rats exhibited significantly lower amine oxidase activities which implies that GH may alter biogenic amine systems.

Neuronal storage of histamine in the brain and tele-methylimidazoleacetic acid excretion in portocaval shunted rats.

Rats with portocaval anastomosis (PCA), an animal model of hepatic encephalopathy (HE), have very high brain histamine concentrations. Our previous studies based on a biochemical approach indicated histamine accumulation in the neuronal compartment. In this study, immunohistochemical evidence is presented which further supports the amine localization in histaminergic neurons. These neurons become pathological in appearance with cisternae frequently seen along histaminergic fibres in many brain areas, including the hypothalamus, amygdala, substantia nigra and cerebral cortex. Such formations were not observed in sham-operated animals. The neuronal deposition is predominant, and unique for histamine. It serves as a mechanism to counterbalance excessive brain neurotransmitter formation evoked by PCA. However, there are other mechanisms. The data provided here show that there is also a significant increase in histamine catabolism in the shunted rats, as reflected by both the higher brain N-tele-methylhistamine (t-MeHA) concentration and urinary excretion of N-tele-methylimidazoleacetic acid (t-MelmAA), a major brain histamine end product. The stomach, in addition to the brain, is a site of enhanced histamine synthesis in portocavally shunted subjects. After gastrectomy or food deprivation to eliminate the contribution of the stomach, shunted rats excrete significantly more t-MelmAA, implying the role of the CNS. This last finding suggests that under strictly defined conditions, namely in parenterally fed HE patients with abnormal plasma L-histidine, the measurement of urinary t-MelmAA might provide valuable information concerning putative brain histaminergic activity.