Wacław Kazimierczak

The action of local anaesthetics on histamine release

Abstract The effect of the local anaesthetics lidocaine, procaine and tetracaine on compound 48/80-induced histamine release from isolated rat mast cells has been investigated. They inhibited histamine release in a dose-dependent manner; at a concentration of 20 mM there was almost total inhibition of histamine release by lidocaine and about 75% inhibition by procaine. Tetracaine exerted a biphasic effect: at concentrations below 1 mM it inhibited, but at concentrations above 1 mM it potentiated histamine release. The inhibitory effect of lidocaine on compound 48/80-evoked histamine release was dependent upon the time of preincubation of mast cells with this anaesthetic and it persisted after washing the cells and resuspension in a lidocaine-free medium. An increase of calcium ions antagonized the inhibitory action of lidocaine. These results can be explained by (1) blockade of membrane receptors for calcium binding which leads to a decrease in intracellular calcium concentration and (2) increase of cellular cyclic AMP content which subsequently inhibits the releasing process.

Histamine release from mast cells by compound 48/80. The membrane action of zinc.

The influence of both zinc chloride and unsaturated zinc: 8-Hydroxyquinoline (Zn: 8-HQ) complex on histamine release induced by compound 48/80 have been investigated. It was found that the inhibitory action of Zn: 8-HQ complex which is known to be unable to penetrate into the cells and acts on mast cell membrane was more pronounced than the action of zinc alone.These results suggest the membrane mechanism of zinc action. The inhibitory action of zinc depends on compound 48/80 concentration when the 2 chemicals act simultaneously but it is not dependent on 48/80 concentration when zinc was added before the liberator. Zinc potentiated the histamine releasing effect of compound 48/80 when it was added after mast cells degranulation. This effect supports the hypothesis of the ionic binding of histamine in mast cells granules.

Failure of acetylcholine to release histamine from rat mast cells

The action of various salts of acetylcholine on isolated mast cells from Wistar and F1 hybrids of Wistar and August rats was investigated.None of the acetylcholine salts within the concentration range 10−12M to 10−2M was able to release histamine either from Wistar or from hybrid mast cells. Compound 48/80, used as a control, was active in both cases.The results obtained are in opposition to some recent reports. The possible reasons for these contradictions are discussed.

The mechanism of the inhibitory action of zinc on histamine release from mast cells by compound 48-80,.

peritoneal mast cells, and in vivo on passively sensitized rat skin. Homocytotropic antibodies were produced in F1 hybrids of August and Wistar rats after immunization with 500 [zg of egg albumin in 1 ml of aluminium hydroxide gel (60 mg AI(OH)3 per ml) given subcutaneously into the back and into the foot-pads. The sensitizing antibodies, detectable in serum after 7-8 days (PCA titre 1:40-1:160) have properties of the IgE class of immunoglobulins. The peritoneal mast cells of actively sensitized rats released histamine when exposed to egg albumin in vitro at 37~ Nicotinamide, 10 z M, preincubated with peritoneal mast cells for 15 minutes before challenge, inhibited spontaneous, and antigeninduced, histamine release; at 4 x 10-z M, inhibition was complete. 60% of inhibition was obtained in 1 minute of preincubation. Increasing incubation time to 10 or 15 minutes produced complete inhibition. In vivo the homologous PCA reaction was produced in Wistar rats with antiserum in dilutions 1 : 20, 1 : 40 and 1 : 80; reaction intensity was determined by Evans blue extraction with formamide. Nicotinamide in i.p. doses of 100 and 200 mg/kg, 30 minutes before challenge with antigen, reduced the PCA reaction 15-45% (antiserum dilution 1:20); 200 mg/kg i.v. 10 minutes before antigen provoked a 25% reduction of PCA (antiserum dilution 1:20). In all cases the per cent of PCA inhibition was higher in antiserum dilution 1:40 and reached 100% in dilution 1:80. It is evident that nicotinamide inhibits the rat anaphylactic reaction both in vivo and in vitro, but high doses are required. Nicotinamide, 5--40 m M is a potent inhibitor of cAMP phosphodiesterase in vitro [4]. Possibly our high concentrations of nicotinamide were required for influencing intracellular levels of cAMP through inhibition of phosphodiesterase activity.

A protective action of disodium cromoglycate against the contraction of guinea-pig ileum induced by various pharmacological stimulants

The effect of disodium cromoglycate (DSCG) on the contraction of isolated guinea-pig ileum induced by histamine, acetylcholine and serotonin has been investigated. DSCG protected ileum against all agents tested. The action of DSCG at concentrations of 10−3 to 10−2M was both dose- and time-dependent. Furthermore, DSCG inhibited compound 48/80-induced histamine release from isolated mast cells over the same range of concentrations.The anti-histaminic action of DSCG was reversible and after 2 h the ileum responded normally to histamine.DSCG-induced inhibition of the contractile response to histamine could be overcome by increasing concentrations of histamine but not by extracellular calcium.A mechanism of the action of DSCG, either against the contraction of ileal smooth muscle or against histamine release from mast cells, is discussed with a view to the inhibition of the utilization of calcium ions by both cells.

New light on the mechanism of action of disodium cromoglycate.

Disodium cromoglycate (DSCG) shows a prolonged protective effect against histamine on the smooth muscle of guinea pig ileum. Preventing allergen-induced mediator release from mast cells as well as protection of smooth muscle against mediators already released can both explain a beneficial effect of DSCG in the treatment of bronchial asthma and food allergy. It is believed that disappointing clinical trials with many new anti-allergic drugs, e.g. RS 7540, can be explained by the lack of a protective effect on the smooth muscle of target organs.

A modulation of the anaphylactic basophil histamine release by selective H2 histamine agonists.

Two selective H2-histamine agonists, dimaprit and impromidine, have been tested for their action on histamine release from human basophils and rat mast cells.IgE-mediated basophil histamine release was inhibited by stimulation of histamine H2-receptors. However, differences between the actions of both dimaprit and impromidine were noticed. Both impromidine and dimaprit had no specific effect on 48/80-induced histamine release from rat mast cells, although the latter in higher concentrations either slightly increased spontaneous histamine release or non-specifically inhibited compound 48/80-induced release.The results are consistent with the view that activation of adenylate cyclase via H2-histamine receptors might be an important regulatory mechanism of histamine release from human basophils but not from rat mast cells.

On the mechanism of histamine release from sodium fluoride-activated mouse mast cells

We have found that sodium fluoride-induced histamine release from mouse mast cells occurs in two separate steps, activation in the presence of fluoride and absence of calcium, and secretion triggered by calcium. The amount of released histamine was dependent either on the time of cell exposure to fluoride or on the final fluoride concentration in the incubation medium.The secretory step depends on the concentration of extracellular calcium; it increased as the concentration of calcium was increased. However, a substantial part of the release was both calcium and energy independent. This part, probably cytotoxic, increased markedly at the highest concentration and with extended times of cell exposure to fluoride.Among other divalent cations tested only strontium could partly substitute calcium to trigger secretion. The activating action of fluoride slowly decayed with time and addition of calcium for up to 2 h caused histamine release. Both steps were dependent on temperature and pH and were inhibited by antimycin A, suggesting that the reaction was enzymatic.The action of fluoride on mouse mast cells closely resembles its action on rat mast cells; however, some differences were also observed.

The participation of H1 and H2 histamine receptors in vascular skin permeability induced by some imidazoles

ConclusionsThe inhibitory action of both types of histamine receptor antagonists on imidazole-induced skin vascular permeability suggests that histamine receptors are involved in this phenomenon.The mechanism of the action of imidazoles on skin vessels may be related to the endogenously released histamine [7] which subsequently stimulates its receptors and/or directs stimulation by imidazoles of both types of histamine receptors present in the vascular tree.

The pharmacological inhibition of the heterologous PCA reaction by histamine antagonists and chloropromazine

ConclusionThe experiments with the passive sensitization of rat skin by mouse IgE show that this heterologous PCA reaction may be modulated (similarly to homologous reaction) by antihistaminic and antiserotonic drugs. It supports the concept of a role of both histamine and serotonin in rat and mouse anaphylaxis.