Metabolism of histamine and its role in certain pathological processes

At the Ciba Foundation Symposium on Histamine, many aspects of the cellular metabolism, tissue distribution and physiological function of histamine in particular tissues were discussed. It became clear that little was kno:'.n about the physiological dissemination of exogenous or endogenous histamine in the intact animal. At the end of the symposium Feldberg suggested that the mode of action of histamine could form the subject for another symposium (Ciba Foundation Symposium, 1956). Perhaps he made this suggestion because references to its function in pathological conditions had been scanty; yet the anti -histamines are well used therapeutic weapons of the present day, employed for treatment of conditions attributed to the pathological action of histamine. It is clear that the body's control of the dissemination of histamine through the tissues will determine the extent to which histamine can produce physiological, and indeed, pathological effects. In particular areas of the body, circumstantial evidence suggests that histamine may play a part in producing local changes and possibly pathological conditions. Reference was made to this evidence at the Ciba Symposium by Terry when he referred to the possible function of histamine in the skin and by Whelan when he referred to its vasodilator properties. Code has accused endogenous histamine of being responsible for the production of gastric ulcers, since he has stated that it is undoubtedly responsible for acid gastric secretion, (Ciba Foundation Symposium, 1956), and both he and other workers have said that acid is responsible for the production of ulcers. Histamine may produce sighs and symptoms not only by its general effects throughout the body, but also by its local tissue effects. Investigation of the role of histamine in pathological conditions will depend upon knowledge of the rate and extent of its metabolism in the intact animal, and on examination of its local tissue concentrations and actions in particular conditions. In the present experiments, these aspects of the metabolism and pathological characters of histamine have been investigated with reference to the damage sustained by animals during irradiation, and with reference to local gastric damage. In these conditions, the physiological actions and pathological effects which could be attributed to histamine are not unconnected. There is evidence that changes occur in the normal blood concentrations of histamine following irradiation, and that irradiated animals become more sensitive to infusion of histamine. Toxic products are believed to be liberated during irradiation from the alimentary canal; it is possible that one of these products could be endogenous histamine. The alimentary canal contains high concentrations of histamine, which, in the stomach at any rate, it has been suggested can play a pathological role. Irradiation causes a break -down in the continuity of skin surfaces,and tissue damage in the intestine. Gastric ulceration can be defined as a break -down in the continuity of the gastric mucosa associated with local tissue damage. It seems unlikely that such break -downs in the continuity of surface coverings, and local tissue damage are completely unconnected; it is possible that the local release of histamine could play some part in their initiation. This suggestion is supported by the observation that exogenous histamine can produce local tissue damage in the stomach and profound local changes in the skin. Why should endogenous histamine in abnormal circumstances not play a similar role? The experiments described in this thesis attempt to find an answer to this question. The pharmacological actions of histamine are well -known, and the details of its tissue metabolism have been extensively investigated. The use of this knowledge and the development of further experimental methods have enabled part of the answer to the question to be obtained. however, in all research, the answer to any question always provides several further problems. The way in which the problems, which have been raised in the present investigations, might be solved is suggested in the discussion in each chapter. In the final chapter, the initial experiments which have been performed in an attempt to find an answer to one of the problems have been briefly discussed