New Approaches to the Physiology of Histamine

NEW APPROACHES TO THE PHYSIOLOGY OF HISTAMINE GEORG KAHLSON* Histamine formation has been recognized as part of various types of normal and malignant rapid tissue growth. The function ofhistamine in normal physiology has long been obscure, but a place for it in physiological processes may now have been found. This is a very recent development. Haifa century has passed since Henry Dale and his colleagues discovered histamine in an extract ofergot and made the first detailed examination of its intense actions when injected into an animal. At that time, to cite Sir Henry's own reminiscent words (i), "much interest in circles concerned with experimental pathology was centred on the syndrome of the anaphylactic reaction [and] . . . you can imagine that Laidlaw and I had to discipline our eagerness as we examined one by one the actions of histamine on the different organs and systems ofthe dog and the guinea-pig in particular, and found them fitting neatly, like units of ajigsaw puzzle, into the contrasting pictures of the anaphylactic reactions in those two species." With the stage so fascinatingly set by the father ofthe histamine story, the mobilization and participation ofhistamine in the anaphylactic reaction soon became widely and firmly established. It appears that in response to diverse kinds ofinjury the histamine normally formed in and held within tissue cells escapes, and this extracellular histamine accounts in partfor the reactions in blood vessels, smooth muscle, and glands following tissue damage. The reservation, in part, should be emphasized, since a multitude ofagents are now known to be concerned in the reactions ofthese effector cells. This aspect of histamine merits a separate tale within the realm ofpathology. * Professor of Physiology, University of Lund, Sweden. This article is the Block Fund Lecture delivered at the University ofChicago January 17, 1961; the substance was also presented in lectures and symposia at the Mayo Foundation, the University ofVirginia, and the University ofCalifornia, Los Angeles. This work has in part been supported by U.S. Public Health Service Grant No. H-4961. I79 Extracellular histamine released by tissue cells appears, from observations ofits actions when injected, to be designed to participate in the control ofnormal functional activity ofsmall blood vessels, plain muscle, and the gastric glands secreting hydrochloric acid. Nevertheless, despite innumerable attempts by highly skilled investigators, clear proof of the participation ofhistamine in any such control has not been obtained. This has been taken to mean that the release ofhistamine is not ofphysiologic importance at all, but ofpurely pathologic significance. This interpretation is largely the outcome ofinformation obtained from determinations ofthe histamine content ofvarious tissues and fluids draining normal or anaphylactically reacting tissues. Subsidiary evidence has been derived from the use ofantihistamine drugs that antagonize some of the known effects ofhistamine. It now appears that none ofthe methods and approaches available until very recently, however ingeniously applied, would have revealed the function of histamine which forms the niain theme ofthis paper. This function is metabolic and concerns intracellular histamine. A steep increase in the enzyme histidine decarboxylase, which forms histamine from histidine, has been recognized as associated with certain types ofrapid tissue growth. I. Informationfrom Germ-free Animals The studies which eventually led to the discovery ofa connection between rate ofhistamine formation and certain types ofrapid tissue growth began in attempts to understand more clearly the origin ofhistamine in the body. Until very recently it was thought (and current textbooks still present this view) that the tissue histamine is derived from two sources— onepart being absorbedlike a vitaminfrom the intestinallumen, where the amine is formed by bacteria, the other part being formed endogenously within the tissue cells. According to this dual theory, the urinary excretion ofhistamine would not be likely to reflect faithfully the rate ofendogenous histamine formation and changes therein, because ofthe complication introduced by the absorbed fraction. Nevertheless, our approachto the problem was sustained by the supposition that the capacity oftissues to form histamine (its histamine-forming capacity: H.F.C.) might be related to physiological events, even though determinations of the histamine content had rather tended to minimize the participation of histamine in physiological processes. 1 80 Georg Kahlson · Physiology ofHistamine Perspectives in Biology and Medicine · Winter 1962 It thus became necessary...