Evidence is presented that mammals possess an inducible form of histidine decarboxylase, associated anatomically with the microcirculation, which synthesizes histamine at a rate determined by the needs of the tissues for blood under various environmental conditions. Some supporting evidence is: a) microcirculatory changes and histidine decarboxylase activation follow the same stimuli, occur at the same anatomical sites, have parallel time relationships, and are both essentially autonomous; b) histamine can reproduce all the microcirculatory changes of the slow phase of inflammation; c) the inducible enzyme has been found in every tested vascular tissue of the mouse; d) such diverse stimuli as increased room temperature, infection, and injection of reticuloendothelial system activators elicit changes in histidine decarboxylase activity consistent with microcirculatory homeostasis; e) certain poorly understood observations on the glucocorticoids, e.g., their vasoconstrictive action and the increased need for them during inflammation or infection, are compatible with the existence of a vasodilator substance, associated with small blood vessels, which may be produced at an increased rate either locally or systemically.
Abstract— The formation of histamine in brain was studied in mice injected with l‐[14C]‐histidine (ring 2‐14C) intravenously (i.v.) or intracerebrally; [14C]histamine appeared rapidly and exhibited a rapid rate of turnover. Drugs known to block various pathways of histamine catabolism were tested for effects on brain–[14C]histamine and [14C]‐methyl‐histamine in mice given (1) [14C]histamine i.v., (2) [14C]histamine intracerebrally, and (3) l‐[14C]histidine i.v. Blood‐borne histamine did not enter brain; brain histamine was formed locally by decarboxylation of histidine Methylhistamine did cross the blood‐brain barrier. Methylation was the major route of histamine catabolism in mouse brain and some of the methylhistamine formed was destroyed by monoamine oxidase. No evidence for catabolism by the action of diamine oxidase was found.
The activity of histidine decarboxylase of various mouse tissues is increased by stress, by epinephrine and by endotoxins. Enzyme activity reaches a maximum in about 6 hours following a stimulus and returns essentially to normal within 1 day. In mice given a lethal dose of endotoxin, enzyme activity is at its highest observed level when the animals become moribund. Evidence is presented that the elevated enzyme activites reflect an increased rate of histamine synthesis in the living animal. The hypothesis of a homeostatic relationship between newly synthesized histamine and the catecholamines, which during intense stress can suffer imbalance, affords a reasonable explanation for the events observed in the small blood vessels during development of shock, for the damaging effects of epinephrine in endotoxin-treated animals and for a number of other phenomena related to shock.
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