Interdependence of histamine and methylhistamine kinetics: modelling and simulation approach.

In the article a model of histamine kinetics is described. A motivation of this project was to investigate the hypothesis that methylhistamine may be a marker of histamine appearance in plasma. A model has been made to support the hypothesis. Since metabolic and transport pathways of histamine and methylhistamine are complex and not very well known, the relationship between histamine and methylhistamine should be elucidated by mathematical modelling. From experimental data and the information in the literature, a nonlinear and time-varying four-compartment model is proposed. Extensive release of histamine from mast cells when methylhistamine is injected, is modelled as histamine to methylhistamine ratio control loop.

Effects of an anaesthetic on plasma levels of histamine and tele-methylhistamine in the cat.

The effects of intravenous injection of ketamine on plasma levels of histamine (Hi) and its metabolite, tele-methylhistamine (MeHi) were studied in the cat. The results showed that the anaesthetic, given in doses which prolonged anaesthesia in the cat (2.5-7.5 mg/kg) caused Hi release, which raised the concentrations of Hi in plasma up to 1600%. It was followed by a slower and also significant increase of plasma MeHi levels (up to 1200%). When urethane was used as an anaesthetic no changes of plasma levels were noticed. However, about 50% of i.v. injections of Ringer-Locke solution were followed by a transient increase of plasma Hi and MeHi concentrations.

The effect of adrenocorticotropin on histamine and 5-hydroxytryptamine secretion from rat mast cells.

Characteristics of histamine (Hi) and 5-hydroxytryptamine (5-HT) release from rat peritoneal mast cells in response to the polypeptide adrenocorticotropin (ACTH) were studied. During a 15 min incubation at 37 degrees C, ACTH evoked Hi as well as 5-HT release from rat mast cells at concentrations of 1 X 10(-4) M-1 X 10(-3) M. The release was dose-dependent and very rapid. After 15 sec the amount of the amines released was the same as after 4.5 min. In most experiments, the percentage of Hi release was slightly but significantly higher than the percentage of 5-HT release. Hi and 5-HT release induced by ACTH also took place in a calcium-free medium. However, the release of the amines was decreased when calcium was omitted. Comparison of the effects of ACTH, compound 48/80 and substance P on mast cell secretion showed that ACTH is about 100 times less active then substance P which was in turn about 100 times less active than compound 48/80. When both ACTH and compound 48/80 were used together as liberators , the release was significantly higher than with either liberator alone. Our results indicate that there are receptor sites for the endogenous polypeptide ACTH on the mast cell membrane which mediate Hi and 5-HT release. This release was found to resemble that evoked by the basic secretogogue compound 48/80 but in some aspects to be different from that evoked by substance P.

Histamine and tele-methylhistamine in cat plasma after intravenous injection of histamine.

The effects of increased plasma histamine (Hi) on plasma tele-methylhistamine (MeHi) levels and the kinetics of Hi and MeHi elimination from plasma were studied in the cat. Hi (40 or 50 micrograms/kg) was injected intravenously and then Hi and MeHi were assayed by HPLC. Hi injection was followed by a significant increase in plasma MeHi levels, being maximal at 2-4 min. In most animals, maximal MeHi levels exceeded Hi itself. The half-lives (t1/2) of injected Hi were 0.6 and 13.3 min (mean values) in the alpha- and beta-phases, while the corresponding values for MeHi were 1.1 and 15.4 min. The t1/2 of exogenous MeHi (64 micrograms/kg, i.v.) was in the same range. Inhibitors of histamine-N-methyltransferase diminished the elimination rate of both amines studied. Plasma MeHi can thus serve as a marker for increased plasma Hi in the cat particularly because of its noticeable and delayed elevation after the rise in Hi itself.

Compound 48/80 and substance P induced release of histamine and serotonin from rat peritoneal mast cells.

The effect of substance P and compound 48/80 on histamine and serotonin release from not isolated and isolated mast cells have been compared in experiments in vitro. The response of not isolated and isolated mast cells were virtually identical. The release of both amines, in response to 48/80 and substance P, was dose-dependent. The percentage of histamine released by 48/80 was significantly higher than the percentage of serotonin, the difference being higher at lower concentrations of compound 48/80 after 15 min of incubation. Substance P also showed a tendency to higher efficiency for histamine than for serotonin release. In contrast to 48/80, the dose-response curves for histamine and serotonin release were parallel. These results support the view that the ratio between histamine and serotonin release depends on the liberator used. They also showed that this ratio can depend on the concentration of the agent inducing secretion. The results indicate that substance P as well as 48/80 act rather selectively as histamine liberators and that there is some difference in releasing properties of 48/80 and substance P.

The degradation of histamine in some animal species.

The aim of this work was 1. determine the major [3H]-metabolites of histamine in vivo by using the musculus gracilis of the dog, and in vitro in different tissues of the cat, 2. determine the endogenous levels of histamine and N tau-methylhistamine in some tissues of the cat and the rat. [3H] histamine injection into arterial supply of the muscle of the dog: after 60 minutes the content of [3H] histamine in the muscle was 1.9 +/- 0.6% and the content of [3H] N tau-methylhistamine and [3H] 'Acid metabolites' was 47 +/- 6.7% and 51.0 +/- 6.5%. The cat tissues in vitro showed the following t1/2 for exogenous histamine: submandibular gland, 95.9 min, parotid gland, 36.1 min, stomach pylorus, 39.5 min, thyroid gland, 28.3 min, liver, 23.7 min. Endogenous levels of histamine and N tau-methylhistamine were determined in the cat and the rat. In general, the contents of endogenous histamine and N tau-methylhistamine were similar to the data obtained with labelled [3H] histamine. In both species submandibular gland was among the richest tissues in N tau-methylhistamine content. The provenience of N tau-methylhistamine in mast cells is discussed.

Pyrethroid insecticides influence the signal transduction in T helper lymphocytes from atopic and nonatopic subjects.

OBJECTIVE AND DESIGN: Pyrethroids are claimed to have a low human toxicity with some neuro- and immunotoxicity. The objective of this study was to investigate the immunotoxicological properties of six commercially used pyrethroids, including natural pyrethrum and synergist piperonyl-butoxide (PBO). MATERIAL AND METHODS: PHA-stimulated cultures of T-helper lymphocytes and blood basophil incubates from nonatopic and atopic patients (IgE > 1000 IU) provided cytokine and histamine determination. Western blot analysis was used for the measurement of Th2-specific signal transducer and activator of transcription-6 (STAT6). Pyrethroids and xenobiotics were added 4 h post-plating. RESULTS: We demonstrated that interferon-gamma (IFN-gamma) production and expression was correlated with lymphocyte proliferation, however, interleukin-4 (IL-4) was down-regulated at the end of the 3 day culture. Atopics showed significantly higher IL-4 activity than nonatopics. Pyrethroids inhibited IFN-gamma and IL-4 in both groups at around 10(-5) M. Only fenvalerate and S-bioallethrin combined with 10-fold PBO in the atopic-enriched blood basophil incubates caused a weak but significant increase in histamine release. Histamine acted bidirectionally on STAT6, but pyrethroids inhibited the intracellular Th2-specific STAT6 more effectively in atopics than in nonatopics. CONCLUSION: It can be suggested that pyrethroids inhibit signal transduction in human lymphocytes ex vivo, and do not act via lymphocyte-influencing histamine release.