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Divalent cation dependence of the inhibition by phenothiazines of mediator release from mast cells.
Br J Pharmacol. 1989 Jun; 97(2):547-55.BJ

Abstract

1. The divalent cations calcium, strontium and barium--and in that order of decreasing effectiveness--were capable of supporting the stimulated release of histamine from rat peritoneal mast cells (RPMC). 2. The responsiveness of mast cells to stimulation in the presence of divalent cations was, in general, markedly enhanced when the cells were first depleted of their intracellular calcium stores. 3. The putative calmodulin antagonists, chlorpromazine, promethazine, thioridazine (phenothiazines) and W-7 (a naphthalene sulphonamide) all inhibited histamine release in the presence of divalent cations in both untreated cells and in RPMC depleted of their intracellular calcium. 4. Histamine release induced by antigen, compound 48/80 and ionophore A23187 was inhibited by this class of compounds most effectively in the presence of extracellular barium, less so in the presence of strontium and least so in calcium-containing media. 5. In the experimental situation where the extracellular calcium concentration was reduced (less than 1 mM), the phenothiazines inhibited the stimulated release of histamine more effectively. 6. In toto, these results suggest that strontium and barium, as well as calcium, can support histamine release from RPMC by directly interacting with an intracellular divalent cation-binding site that may be calmodulin. As a consequence, one mechanism by which the phenothiazines and W-7 may modulate the secretory response could reflect an antagonism of a divalent cation interaction at that same site, although other additional potential sites of inhibitory action are indicated, dependent on the stimulus employed for secretion.

Links

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Authors+Show Affiliations

Peachell PT
Department of Chemistry, University College London.
Pearce FL
No affiliation info available

MeSH

AnimalsBariumCalcimycinCalciumCationsChlorpromazineHistamine ReleaseIn Vitro TechniquesMaleMast CellsPhenothiazinesPromethazineRatsRats, Inbred StrainsStrontiumSulfonamidesThioridazinep-Methoxy-N-methylphenethylamine

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

2474349

Citation

Peachell, P T., and F L. Pearce. "Divalent Cation Dependence of the Inhibition By Phenothiazines of Mediator Release From Mast Cells." British Journal of Pharmacology, vol. 97, no. 2, 1989, pp. 547-55.
Peachell PT, Pearce FL. Divalent cation dependence of the inhibition by phenothiazines of mediator release from mast cells. Br J Pharmacol. 1989;97(2):547-55.
Peachell, P. T., & Pearce, F. L. (1989). Divalent cation dependence of the inhibition by phenothiazines of mediator release from mast cells. British Journal of Pharmacology, 97(2), 547-55.
Peachell PT, Pearce FL. Divalent Cation Dependence of the Inhibition By Phenothiazines of Mediator Release From Mast Cells. Br J Pharmacol. 1989;97(2):547-55. PubMed PMID: 2474349.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Divalent cation dependence of the inhibition by phenothiazines of mediator release from mast cells. AU - Peachell,P T, AU - Pearce,F L, PY - 1989/6/1/pubmed PY - 1989/6/1/medline PY - 1989/6/1/entrez SP - 547 EP - 55 JF - British journal of pharmacology JO - Br J Pharmacol VL - 97 IS - 2 N2 - 1. The divalent cations calcium, strontium and barium--and in that order of decreasing effectiveness--were capable of supporting the stimulated release of histamine from rat peritoneal mast cells (RPMC). 2. The responsiveness of mast cells to stimulation in the presence of divalent cations was, in general, markedly enhanced when the cells were first depleted of their intracellular calcium stores. 3. The putative calmodulin antagonists, chlorpromazine, promethazine, thioridazine (phenothiazines) and W-7 (a naphthalene sulphonamide) all inhibited histamine release in the presence of divalent cations in both untreated cells and in RPMC depleted of their intracellular calcium. 4. Histamine release induced by antigen, compound 48/80 and ionophore A23187 was inhibited by this class of compounds most effectively in the presence of extracellular barium, less so in the presence of strontium and least so in calcium-containing media. 5. In the experimental situation where the extracellular calcium concentration was reduced (less than 1 mM), the phenothiazines inhibited the stimulated release of histamine more effectively. 6. In toto, these results suggest that strontium and barium, as well as calcium, can support histamine release from RPMC by directly interacting with an intracellular divalent cation-binding site that may be calmodulin. As a consequence, one mechanism by which the phenothiazines and W-7 may modulate the secretory response could reflect an antagonism of a divalent cation interaction at that same site, although other additional potential sites of inhibitory action are indicated, dependent on the stimulus employed for secretion. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/2474349/Divalent_cation_dependence_of_the_inhibition_by_phenothiazines_of_mediator_release_from_mast_cells_ DB - PRIME DP - Unbound Medicine ER -