The Croonian Lecture, 1964 The release and fate of the transmitter liberated by adrenergic nerves

Abstract

It is customary for Croonian lecturers, after expressing their thanks to the President and Council for the honour that they have received in being asked to give this lecture, to devote some time to a justification of their subject in terms of Mrs Croone’s suggestion that the lecture should deal with the advancement of natural knowledge on local motion. The first of these tasks, Mr President, I perform humbly and with deep gratitude, but at the same time with some surprise that Council in its wisdom should have chosen one so ill-fitted for the honour you have laid upon him. The second task is easier since my lecture will deal with the nerves which control the muscles surrounding the hollow organs of the body, blood vessels and bowels, and further justification as a theme dealing with local motion the most captious critic could not desire. Three years ago my former colleague Bernard Katz gave the Croonian Lecture on ‘ Transmission of impulses from nerve to muscle’ in which he described our present knowledge of the mechanism of the chemical mediation interposed between nerve and skeletal muscle and summarized his own brilliant contributions to this, to me, fascinating subject. Today I am dealing again with transmission from nerve to muscle, but in a different system and, I am afraid, at a quite different and lower intellectual level than that of Katz. The idea of chemical transmission from nerve to effector cell came first to T. R. Elliott in 1904 as a result of his observation, in an extensive comparative study, of the close similarities between the actions of adrenaline injected intravenously and the effects of stimulating nerves belonging to the sympathetic system. These nerves we should now call in Dale’s (1933) terminology the adrenergic nerves, those transmitting their effects whether excitatory or inhibitory by the liberation at their endings of a ‘minute charge’ of the catecholamine adrenaline or one of its analogues. The cells upon which these nerves exert their action are the smooth muscle cells controlling the movements of the hollow viscera, intestines, reproductive tract and so on, and of the muscle cells of the vascular system that regulate the diameter of the blood vessels. These are processes that do not demand high precision of timing nor do they apparently require the instant turning on and off of transmitter action with which we have grown familiar in the junction between nerve and skeletal muscle. At this junction, as Katz showed, liberation and action of acetylcholine and its inactivation by the specific enzyme cholinesterase are over in a few milliseconds, and there is no reason to believe that the liberated transmitter in the untreated junction can ever diffuse more than a few microus from its site of action. It is hemmed in by barriers of specific cholinesterase, and these are reinforced by barriers of the non-specific enzyme in blood and tissue fluids. This narrow coarctation of the transmitter acetylcholine in space and time seems, however, to be confined to places where precise timing is required, such as at the neuromuscular junction and in the ganglionic and central nervous synapse. When it is liberated as the transmitter from nerves to blood vessels, or to secretory glands, it can escape some way from its site of liberation and persist long enough to be detected by skeletal muscles sensitized by denervation, as is seen in the Sherrington, Rogowitz and Vulpian-Heidenhain phenomena. I have laboured a little this question of diffusion and action at a distance of transmitter because it constitutes prima facie one of the most striking differences between the adrenergic and the cholinergic transmitters in at least the mammalian body. It was indeed because the liberated adrenergic transmitter escaped into the blood stream and could be detected by another tissue or organ, sometimes, but not necessarily, specially sensitized, that W. B. Cannon and his colleagues in the 30’s were able to add so much to our knowledge of sympathetic innervation. Nevertheless, in spite of the relative stability of the adrenergic transmitter and its ready detection in the blood stream, little had been discovered about the quantitative aspects of its liberation and metabolism some 50 years after its existence had been postulated, whereas we now have, and have had for 30 years, quite reasonably complete information about the liberation, storage and metabolism of the unstable and ephemeral acetylcholine.