The Relationship Between Energy Metabolism and the Action of Inhibitors of Histamine Release

Abstract

1Dextran-induced release of histamine from rat mast cells was inhibited equally in complete and glucose-free Tyrode solution by doxantrazole (0.03-3,mol/l), theophylline (0.1-3 mmol/l) and dicumarol (0.0 1-10 gmol/litre).2 Doxantrazole (3 gmol/1), theophylline (3 mmol/1) and dicumarol (10 pmol/1) did not reduce the adenosine 5'-triphosphate (ATP) content of mast cells in glucose-free medium. Higher concentrations of dicumarol (56-100 gmol/1) markedly reduced the cellular ATP content. This reduction was reversed by glucose. 3 Papaverine was a more potent inhibitor of histamine release from mast cells incubated in glucosefree solution than in complete Tyrode solution (dose-ratio = 20). Like antimycin A (1 ,umol/l), papaverine (3 Amol/l) caused a depletion of mast cell ATP that was greater in the absence (85%) than in the presence (25%) ofextracellular glucose. 4 These results suggest that dicumarol, like doxantrazole and theophylline, inhibits histamine release without affecting mast cell energy metabolism. In contrast, papaverine probably inhibits release by depleting ATP that is required for exocytosis. SInhibition of histamine release by dibutyryl cyclic adenosine 3,5'-monophosphate (1-3 mmol/l) was significantly greater when cells were incubated in complete rather than in glucose-free medium.

Immunopharmacological Studies on TBX, a New Antiallergic Drug (2) Inhibitory Effects on Histamine Release from Peritoneal Mast Cells and Lung Fragments of Rats

“…Almost the same inhibition of anaphylactic histamine release by TBX was observed in glucose-free medium in which metabolic inhibitors such as 2-deoxyglucose (13, 14), antimycin A (15) and papaverine (16) were found to display higher degrees of inhibition of histamine release, compared with the use of the complete medium. The results demonstrating that the inhibitory ac tivity of TBX on histamine release was hardly modified in glucose-free medium strongly suggest that this agent exerts little influence on energy metabolism.…”

“…The results demonstrating that the inhibitory ac tivity of TBX on histamine release was hardly modified in glucose-free medium strongly suggest that this agent exerts little influence on energy metabolism. Indeed, doxantrazole (16), one of the potent antiallergic drugs whose properties differed entirely from the antimetabolites is known to inhibit IgE mediated histamine release from rat mast cells in glucose-free medium to the same extent as in complete medium, showing no modification of the cellular ATP content. On the other hand, the inhibition of histamine release by 10-7 g/ ml of TBX was found to be slight in Ca2+ depleted medium containing no chelating agents such as EDTA or EGTA.…”

Cyclic AMP Levels during Stimulation and Inhibition of Histamine Release from Rat Mast Cells by the Calmodulin Inhibitor Trifluoperazine

“…A signifi cant correlation has been found between the lipophil ic nature of these agents and their histamine-releasing activity [Frisk-Holmherg and Kleijn, 1972], Histamine release from rat mast cells, incubated in a glucose-free medium, is more susceptible to inhibi tors of oxidative metabolism such as antimycin A, than is release from cells in glucose-containing media [Peterson, 1974;Diamant et al, 1974]. Furthermore, antimycin A (I uM) reduces the ATP content to very low levels, this reduction being largely counteracted if the cells are incubated in a glucose-containing medi um [Garland and Johansen, 1977], The trifluopera zine-induced histamine release observed in the pres ent investigation at high concentrations, and during prolonged incubations, was not affected by preincu bation with I ¡.tM antimycin A (in a glucose-free me dium). These results suggest a mechanism of hista mine releasing action of trifluoperazine which does not require energy under such circumstances.…”

“…Antimycin A, at a final concentration of I pM, was included in one series of experiments [Garland and Johansen, 1977]. The cells were preincubated with this agent for 10 min at 37°C in a glucosefree BSS-B.…”

Na+‐K + pump activity in rat peritoneal mast cells: inhibition by extracellular calcium

“…The ouabain-resistant uptake was determined in cells equilibrated at various pH for 15 min in the presence of ouabain, 1.0 mmol 1-P'. almost completely blocked by incubation of the cells with 2-deoxyglucose and antimycin A, agents which are known to inhibit glycolytic and mitochondrial adenosine 5'-triphosphate (ATP) production in mast cells (Diamant et al, 1974;Garland & Johansen, 1977;Johansen, 1980). In addition, the activity of this uptake mechanism was dependent on temperature and pH.…”