Further studies on the histidine‐histamine relationship in vivo: effects of endotoxin and of histidine decarboxylase inhibitors

1. Mice were injected with ((14)C)-L-histidine, killed at various intervals, and tissues assayed for ((14)C)-histamine. In some cases free ((14)C)-L-histidine and total ((14)C) were also determined.2. Removal of stomach, the most active histamine-forming tissue, failed to reduce the ((14)C)-histamine content of any tested tissue; ((14)C)-histamine concentrations in lung and muscle of gastrectomized mice were higher than in shamoperated controls.3. In mice pretreated with endotoxin and subsequently injected with ((14)C)-L-histidine, the ((14)C)-histamine content of liver, lung and muscle was markedly higher than in controls. The increased concentrations of ((14)C)-histamine in endotoxin-pretreated mice seemed to reflect a greater rate of formation; they could be attributed neither to changes in tissue concentration of ((14)C)-L-histidine, to increased uptake from other tissues, nor to impaired ability to inactivate histamine.4. Results of studies on in vivo effectiveness of several histidine decarboxylase inhibitors are reported.5. The following conclusions are supported by the evidence presented: (a) in stressed mice, those tissues which show activation of histidine decarboxylase also show increased ability to form histamine in vivo; (b) tissue histamine is largely formed locally; (c) histidine decarboxylase inhibitors are highly effective in blocking histamine formation in mast cells and in stomach, but do not normally reach the locus of an inducible form of histidine decarboxylase; (d) the inducible form of histidine decarboxylase in liver may be located in phagocytic microvascular endothelial cells; (e) in conditions favouring near-maximal activation of histidine decarboxylase, the histamine-methylating enzyme of liver and diamine oxidase of intestine showed no inducible characteristics; (f) blood histamine concentrations do not accurately reflect changes in tissue histamine formation.