Abstract
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.
