New approaches to the physiology of histamine.

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Abstract
The biogenesis of tissue histamine was established employing various approaches. The amine is endogenous in origin, and there is no evidence that exogenous histamine is held in tissues. In the female rat fed a histamine-free diet the urinary excretion of free histamine parallels the rate of endogenous histamine formation, thus affording a nonisotopic method to determine in vivo the rate of histamine formation and changes therein. This simple nonisotopic means made possible the discovery of a singularly high rate of histamine formation, e.g. in the rat embryo and wound tissue. For determination of the histamine-forming capacity of individual tissues and for studies on the catabolism of histamine, Schayer''s radioactive methods, as currently employed, stand unequaled in sensitivity, specificity, and meaningful results so far obtained. A specific, nontoxic inhibitor of histamine formation in vitro and in vivo, a-methylhistidine was discovered. Histidine decarboxylase is defined as the enzyme responsible for endogenous histamine formation, the enzymic activity of which is strongly inhibited by a-methylhistidine but not by a-methyl-DOPA, and requiring pyridoxal phosphate as a cofactor. Histamine-forming enzymes not complying with these criteria should not be referred to as histidine decarboxylase, even under the reservation of a prefix, such as "nonspecific". Inhibition studies led to a distinction in several aspects between mast-cell and non-mast-cell histamine, at present only the latter having been shown to be concerned in physiological phenomena. A feedback relation between tissue histamine content and HFC [histamine-forming capacity] was discovered, mobilization of preformed histamine evoking a concurrent and longlasting elevation of HFC. High HFC was revealed as a part of certain types of normal and malignant tissue growth and cell multiplication; inhibition of histamine formation results in retardation of growth whereas artificial elevation of HFC promotes the type of growth studied. The histamine operating in the processes of growth is referred to as "nascent histamine", believed to be part of anabolic-metabolic pathways. Physical exercise evokes elevation of HFC in most tissues in mice, but not in rats. Species differences in histamine metabolism are emphasized. Various chemical agents, among them catecholamines, incite accelerated rate of histamine formation. This finding opens a new field of study, the pharmacology of HFC. On stimulation (by secretory nerves, gastrin, or distent ion) of the gastric hydrochloric acid secretion, a steep and prolonged increase in the rate of histamine formation in the parietal-cell-containing region of the mucosa is a consistent and prominent event in each of several species studied. In hypersensitivity reactions histamine is newly formed in most tissues. The elevation of HFC persists for long periods, up to days, and is not correlated with the mast-cell density of the tissues. These facts appear to explain, in part, the long duration of hypersensitivity reactions and the limited effect of antihistaminic drugs. There is evidence that an elevation of tissue HFC is a part of the machinery designed to sustain homeostasis. The physiological significance of elevated tissue HFC lies in various spheres, the most important being possibly metabolic in nature.