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Sir Henry Hallett Dale – Nobel Lecture
Nobel Lecture, December 12, 1936
Some recent extensions of the chemical transmission of the
effects of nerve impulses
The transmission of the effects of nerve
impulses, by the release of chemical agents, first became an
experimental reality in 1921. In that year Otto Loewi published the
first of the series 1,
2, 3,
4,
5,
6
of papers from his laboratory, which, in the years from 1921-1926,
established all the principal characteristics of this newly revealed
mechanism, so far as it applied to the peripheral transmission of
effects from autonomic nerves to the effector units innervated by
them. Of the general history of this discovery, of the speculations
which preceded it, and of its more recent developments in detail in
many laboratories, as regards one aspect of it particularly by
Cannon and his co-workers in Boston, you have heard from Professor
Loewi himself. I propose to deal with a wider application of this
conception of chemical transmission, which has resulted from
researches carried out during the past three years in my own
laboratory, by a number of able investigators - J.H. Gaddum, W.
Feldberg, A. Vartiainen, Marthe Vogt, G.L. Brown, Z.M. Bacq. These
investigations have made it possible to suggest that a fundamentally
similar chemical mechanism is concerned in the transmission of
excitatory effects at the synapses in all autonomic ganglia, and at
the motor nerve endings in ordinary, voluntary muscle.
You will see that, according to this relatively
new evidence, a chemical mechanism of transmission is concerned, not
only with the effects of autonomic nerves, but with the whole of the
efferent activities of the peripheral nervous system, whether
voluntary or involuntary in function. This extension of the
principle of chemical transmission has come as a surprise to many;
the relative ease, with which the evidence justifying it can be
obtained, has been surprising to ourselves. But the basic
conception, which encouraged us to undertake experiments in this
direction, was no novelty to me; and for its origin I must ask you
to look briefly at some experiments which I had already made and
published in 19147
. My chemical collaborator at that time, Dr. Ewins8,
had isolated the substance responsible for a characteristic activity
which I had detected in certain ergot extracts, and it had proved to
be acetylcholine, the very intense activity of which had been
observed by Reid Hunt9
already in 1906. Since we had found this substance in nature, and it
was no longer merely a synthetic curiosity, it seemed to me of
interest to explore its activity in greater detail. I was thus able
to describe it as having two apparently distinct types of action.
Through what I termed its "muscarine" action, it reproduced at the
periphery all the effects of parasympathetic nerves, with a fidelity
which, as I indicated, was comparable to that with which adrenaline
had been shown, some ten years earlier, to reproduce those of true
sympathetic nerves. All these peripheral muscarine actions, these
parasympathomimetic effects of acetylcholine, were very readily
abolished by atropine. When they were thus suppressed, another type
of action was revealed, which I termed the "nicotine" action,
because it closely resembled the action of that alkaloid in its
intense stimulant effect on all autonomic ganglion cells, and, as
later appeared, on voluntary muscle fibres. I am tempted here to
quote some words which I wrote in that paper, in 1914.
"It is clear, then, that the distinction between
muscarine and nicotine activity cannot be made with
absolute sharpness... Nor is there any evidence enabling us to
regard one group of the molecule as responsible for the one type of
action, and another for the other. One can merely conclude that
there is some degree of biochemical similarity between the ganglion
cells of the whole involuntary system and the terminations of
voluntary nerve fibres in striated muscle, on the one hand, and the
mechanism connected with the peripheral terminations of craniosacral
involuntary (i.e. parasympathetic) nerves on the other."
In the same paper I had speculated on the
possible occurrence of acetylcholine in the animal body, and on its
physiological significance if it should be found there; and had
pointed out the extraordinary evanescence of its action, suggesting
that an esterase probably contributed to its rapid removal from the
blood.
When, therefore, some seven years later, Loewi
described his beautiful experiments, showing that stimulation of the
vagus nerve produced its inhibitor effects on the frog's heart by
the liberation of a chemical substance; and when his successive
papers provided cumulative evidence of the similarity of this
substance to acetylcholine, including its extreme liability to
destruction by an esterase, which Loewi extracted from the heart
muscle; I believe that I was more ready than most of my
contemporaries for immediate acceptance of the evidence for this
"Vagusstoff", and more eager, almost, than Professor Loewi himself,
to assume its identity with acetylcholine. There was wanting, it
seemed to me, only one item of evidence to justify certainty as to
the nature of this substance, namely, a proof that acetylcholine
itself, and not merely some choline ester of closely similar
properties, was an actual constituent of the animal body.
Professor Loewi has already mentioned the
extraction and identification of acetylcholine, as a natural
constituent of a mammalian organ, by my late and deeply lamented
colleague, H.W. Dudley, and myself10,
in 1929. He has also dealt with the general rule that
parasympathetic effects are transmitted by acetylcholine, and true
sympathetic effects by what his own most recent experiments appear
definitely to identify as adrenaline. He has mentioned also the
important exceptions to that rule. In view of such exceptions, it
seemed to me desirable to have a terminology enabling us to refer to
a nerve fibre in terms of the chemical transmission of its effects,
without reference to its anatomical origin; and, on this functional
basis, I11
proposed to refer to nerve fibres and their impulses as
"cholinergic" or "adrenergic", as the case might be. Such a
functional terminology seemed to me the more important, in view of
the evidence which was already coming from our experiments, that
acetylcholine had a much wider function as a transmitter of nervous
excitation, than that concerned with the post-ganglionic fibres of
the autonomic system, and their effects on involuntary muscle and
gland cells. For all such effects of acetylcholine, directly
analogous to those which Loewi discovered in relation to the heart
vagus, were covered by what I had termed the "muscarine" action of
acetylcholine, and were all very readily suppressed by atropine. But
there remained, as yet without any corresponding physiological
significance, the other type of action of acetylcholine, so similar
in distribution to that of nicotine, which had come to my notice
nearly twenty years earlier. Was it credible, I asked myself, that
this sensitiveness of ganglion cells, and of voluntary muscle
fibres, to the substance now known to be the transmitter of
peripheral parasympathetic effects, was entirely without
physiological meaning? I could not believe it. At the same time, it
had to be recognized that the transmission of nervous excitation at
ganglionic synapses, and at motor nerve endings in voluntary muscle,
was a phenomenon of a different order from any of those in connexion
with which the intervention of a chemical transmitter had hitherto
been demonstrated, or even considered. Acetylcholine, released at
the peripheral endings of the vagus or the chorda tympani, could be
pictured as reaching the heart cells or those of the salivary gland
by diffusion, and there inhibiting an automatic rhythm, or exciting
glandular secretion. At a ganglionic synapse or a motor ending on a
voluntary muscle fibre, on the other hand, the evidence was clear,
that a single impulse, reaching the end of the preganglionic or
motor nerve fibre, caused the passage from the ganglion cell, along
its post-ganglionic axon, of a single nerve impulse, and no more; or
caused the passage, from the motor end plate of the muscle fibre, of
a single wave of excitation, of propagated contraction, and no more.
In both cases, the phenomenon had the appearance of a direct,
unbroken conduction, to ganglion cell or muscle fibre, of the same
propagated wave of physico-chemical disturbance as had constituted
the preganglionic or the motor nerve impulse, with only a slight,
almost negligible retardation in its passage across the ganglionic
synapse or the neuromuscular junction. And, indeed, such continuity
of the conduction, in both cases, had generally been assumed, and,
in the case of the neuromuscular conduction, in particular, had been
implicit in the interpretation of a great body of detailed evidence,
which the ingenuity and the labours of two generations of
physiologists had produced.
Could the stimulating action of acetylcholine on
ganglion cells and on muscle fibres, its "nicotine" actions, be
pictured as intervening in these rapid and strictly limited
transmissions of excitation across ganglionic and neuro-muscular
synapses? We could only imagine such intervention, if we could think
of acetylcholine as appearing and disappearing in a manner entirely
different from that involved in its transmission of peripheral
parasympathetic effects. We must suppose that an impulse, arriving
at the ending of a preganglionic or a voluntary motor nerve fibre,
releases with a flashlike suddenness a small charge of
acetylcholine, in immediate contact with the ganglion cell or the
motor end plate of the muscle fibre. We must suppose that this
sudden rise in concentration of acetylcholine stimulates the
ganglion cell to the discharge of a postganglionic impulse, or
initiates a propagated wave of excitation along the muscle fibre.
And we must suppose, further, that the acetylcholine then disappears
with a suddenness comparable to that of its liberation, so that it
has vanished by the end of the brief refractory period of the
ganglion cell or the muscle fibre, which is thus left fully
responsive to another discharge of acetylcholine, by another nerve
impulse. Such a sequence of events seems to involve two things. The
first is a depot, closely related to the preganglionic or motor
nerve ending12,
in which acetylcholine may be held in some association which
prevents its action and protects it from destruction, and from which
it can be immediately liberated by the arrival of a nerve impulse.
Professor Loewi has mentioned the evidence for such storage of
acetylcholine, waiting for liberation, at parasympathetic nerve
endings; and Brown and Feldberg13,
in my laboratory, have obtained evidence that nearly the whole of
the acetylcholine, obtainable by extraction from a normal
sympathetic ganglion, disappears when the preganglionic nerve fibres
are caused to degenerate by section; so that its maintenance is, in
fact, dependent on the integrity of the preganglionic nerve endings.
The second thing required, by the suggested action of acetylcholine
in transmitting the kind of excitation we are discussing, is a
mechanism for its very rapid removal, so that it disappears
completely within the few milliseconds of the refractory period of
muscle fibre or ganglion cell. One naturally thinks of the specific
cholinesterase, first detected by Loewi in heart muscle, and since
found to be widely distributed in the blood and tissues. Even when
obtained in solution this potent enzyme destroys acetylcholine with
a quite remarkable rapidity; and if we could suppose it to be
concentrated on surfaces at preganglionic or motor nerve endings, in
immediate relation to the site of liberation and action of
acetylcholine, it might furnish an adequate mechanism for the
complete destruction of this substance, even during the very brief
interval of the refractory period. Here, again, I am permitted to
make preliminary mention of experiments which Dr. Franz Briicke, who
earlier worked under Prof. Loewi, is even now making in my
laboratory, and which have already given uniform evidence that a
large amount of cholinesterase is present in a sympathetic ganglion,
and that this, like the acetylcholine obtainable from such a
ganglion, disappears largely when the preganglionic fibres, and
their endings in the ganglion, are caused to degenerate. We have
evidence, then, that both the reserve of acetylcholine, and the
esterase required for its destruction, are in fact associated with
the preganglionic nerve endings, as our hypothesis demands. I am
departing, however, too far from the true historical order, and
presenting recent and confirmatory details of evidence, before I
have described the initial observations, which opened this new field
to our experimental exploration.
Although from the time when it first became
clear that Loewi's Vagusstoff was acetylcholine, I had begun to
consider the possible significance of its "nicotine" actions, it was
long before the possibility of its intervention as transmitter at
ganglionic synapses, or at voluntary motor nerve endings, seemed to
be accessible to investigation. Experiments on the ganglion came
first in order. Chang and Gaddum14
had found, confirming an earlier observation by Witanowski, that
sympathetic ganglia were rich in acetylcholine. Feldberg, just
before he returned to my laboratory for a stay of some years, had
observed, with Minz and Tsudzimura15,
that the effects of splanchnic nerve stimulation are transmitted to
the cells of the suprarenal medulla by the release of acetylcholine
in that tissue. Now these medullary cells are morphological
analogues of sympathetic ganglion cells, and Feldberg, continuing
this study in my laboratory, found that this stimulating _ action of
acetylcholine on the suprarenal medulla belonged to the "nicotine,
side of its actions. Clearly we had to extend these observations to
the ganglion; and a method of perfusing the superior cervical
ganglion of the cat, then recently described by Kibjakov16,
made the experiment possible. Feldberg and Gaddum17,
though unable to reproduce effects obtained by Kibjakow with pure
Locke's solution, found that, when eserine was added to the fluid
perfusing the ganglion, stimulation of the preganglionic fibres
regularly caused the appearance of acetycholine in the venous
effluent. It could be identified by its characteristic instability,
and by the fact that its activity matched the same known
concentration of acerylcholine in a series of different
physiological tests, covering both "muscarine" and "nicotine"
actions. It appeared in the venous fluid in relatively high
concentrations, so strong, indeed, that reinjection of the fluid
into the arterial side of the perfusion caused, on occasion, a
direct stimulation of the ganglion cells. It was clear that, if the
liberation took place actually at the synapses, the acetylcholine
liberated by each preganglionic impulse, in small dose, indeed, but
in much higher concentration than that in which it reached the
venous effluent, must act as a stimulus to the corresponding
ganglion cells. Feldberg and Vartiainen18
then showed that it was, in fact, only the arrival of preganglionic
impulses at synapses which caused the acerylcholine to appear. They
showed, further, that the ganglion cells might be paralysed by
nicotine or curarine, so that they would no longer respond to
preganglionic stimulation or to the injection of acetylcholine, but
that such treatment did not, in the least, diminish the output of
acetylcholine caused by the arrival of preganglionic impulses at the
synapses. There was, in this respect, a complete analogy with the
paralysing effect of atropine on the action of the heart vagus,
which, as Loewi and Navratil had shown many years before, stops the
action of acetylcholine on the heart, but does not affect its
liberation by the vagus impulses.
My colleagues have added other chapters of
interest to this story of chemical transmission at the synapses in
the ganglion. I may just mention Brown and Feldberg's13
observation that potassium ions, the mobilization of which is so
intimately connected with the nervous impulse, will liberate
acetylcholine from its depot in the ganglion, in a manner closely
recalling the effect of preganglionic impulses; and their more
recent finding19
that, with prolonged preganglionic stimulation, the ganglion sheds
into the fluid perfusing it several times as much acetylcholine as
can be obtained from a similar, unstimulated ganglion by artificial
extraction. The effects of eserine, on the transmission of
excitation in the ganglion, are complicated by a paralyzing action
of this alkaloid on the ganglion cells, and still need further
elucidation. I can more usefully pass to our recent work on
voluntary muscle, in which such effects are much clearer.
The difficulty facing us in the case of the
voluntary muscle was largely a quantitative one. In a sympathetic
ganglion, the synaptic junctions, at which the acetylcholine is
released by the incident preganglionic impulses, form a large part
of the small amount of tissue perfused. In a voluntary muscle the
bulk of tissue, supplied by a rich network of capillary blood
vessels, is relatively enormous in relation to the motor nerve
endings, of which only one is present on each muscle fibre. The
volume of perfusion fluid necessary to maintain functional activity
is, therefore, relatively very large, in relation to the amount of
acerylcholine which the scattered motor nerve endings can be
expected to yield when impulses reach them. With the skilled and
patient co-operation of Dr. Feldberg and Miss Vogt20,
however, it was possible to overcome these difficulties, and to
demonstrate that, when only the voluntary motor fibres to a muscle
are stimulated, to the complete exclusion of the autonomic and
sensory components of the mixed nerve, acetylcholine passes into the
Locke's solution, containing a small proportion of eserine, with
which the muscle is perfused. If, by calculation, we estimate the
amount of acetylcholine thus obtained from the effect of a single
motor impulse, arriving at a single nerve ending, the quantity is of
the same order as that similarly estimated for a single
preganglionic impulse and a single ganglion cell; in both cases
10-15 gram, which corresponds to about three million
molecules of acetylcholine. We found that, if the muscle was
denervated by degeneration, direct stimulation, though evoking
vigorous contractions, produced no trace of acetylcholine. If, on
the other hand, the muscle was completely paralysed to the effects
of nerve impulses by curarine, stimulation of its motor nerve fibres
caused the usual output of acerylcholine, though the muscle remained
completely passive. Again there is a complete analogy with Loewi's
observations on the heart vagus and atropine.
With this demonstration, that acetylcholine was
liberated at the endings of motor nerve fibres in voluntary muscle,
in immediate relation to the motor end plates of the muscle fibres,
only one side of our problem had been solved. Acetylcholine,
injected into the vessels of a ganglion, could be shown to stimulate
the ganglion cells to the discharge of postganglionic impulses. In
the case of normal voluntary muscle, on the other hand, the evidence
before us suggested only that certain muscles of frogs, reptiles and
birds responded to the application of acetylcholine, not by quick,
propagated contractions like those evoked by motor nerve impulses,
but by slow, persistent contractures, of low tension. As for the
normal muscles of mammals, on which our evidence of acetylchohne
liberation had been obtained, these were supposed, on evidence
provided by myself among others, to give no response at all to
acetylchohne, except in large doses, and then only irregularly. The
denervated mammalian muscle was known to be highly sensitive to
acetylcholine, but the evidence, again from myself among others,
suggested that its response was of the nature of a contracture, and
not of a quick, propagated contraction.
Considering the manner in which acetylcholine
must reach the motor end plates of the muscle fibres, if it were
indeed the transmitter of motor nerve excitation - that it must
appear with a flash-like suddenness, in high concentration,
simultaneously at every nerve ending - we concluded that the
ordinary method of injecting acerylcholine, so that it reached the
muscle by slow diffusion from the general circulation, could not
possibly reproduce this abrupt appearance at the points responsive
to its action. We attempted a nearer approach to these supposed
conditions of its natural release, by a method which enabled us,
after a brief interruption of the arterial blood supply, to inject a
small dose of acetylcholine, in a small volume of saline solution,
directly and rapidly into the empty blood vessels of the muscle21.
The responses which we thus obtained were of an entirely different
kind from any which had previously been recorded. A dose of about 2
gamma of acetylcholine, thus injected at close range into the
vessels of a cat's gastrocnemius, produced a contraction with a
maximal tension equal to that of the twitch produced by a maximal
motor nerve volley, and of a rapidity but little less than that of
the motor nerve twitch. We have direct evidence that only a small
part of the acetylcholine so injected actually reaches the muscle
end plates by diffusion from the vessels; and we argued that, in any
case, it could not reach them simultaneously, but only in rapid
succession; so that the response, in spite of its superficial
resemblance to a rather slow twitch, must actually be a brief,
asynchronous tetanus. My colleague, G.L. Brown, using a strictly
localized electrical lead from the muscle, involving only a few
fibres, has obtained clear evidence that the response has, indeed,
that nature. It is a brief burst of unsynchronized and repetitive
responses of the individual muscle fibres; but these individual
responses are, without doubt, quick, propagated contractions, and
there is no semblance of contracture about the phenomenon. Unlike
the response of the denervated muscle to acetylcholine, this quick
response of normal mammalian muscle is suppressed with great ease by
curarine.
At this point I must briefly refer to some
observations made only in the past few weeks, and still in progress.
The normal mammalian muscle had seemed to present us initially with
the greatest difficulty, being supposed not to react to
acetylcholine at all. This difficulty being removed by a more
adequate technique, we had to face the fact that the function of
acetylcholine, as transmitter of voluntary motor nerve impulses,
could not be confined to the case of mammalian muscle. The muscle of
the frog, the classical object of innumerable studies of
neuromuscular conduction, had been found to respond to
acetylcholine, indeed, but only by contractures of low tension, and
not by propagated contractions comparable to those evoked by
nerve-volleys. Here again, we reflected that the method which had
been used for the application of acetylcholine, the immersion of the
excised muscle in a suitable dilution of the substance, could hardly
be expected to reproduce that rapidity of access to the appropriate
points on the fibres, which its simultaneous liberation at all nerve
endings would achieve. The patient skill of my colleague, G.L.
Brown, has now made it possible to apply acetylcholine to the frog's
muscle by direct injection of a small dose into its empty blood
vessels, in a manner quite analogous to that which produced such
significant results in the mammalian muscle. If 1 gamma of
acetylcholine, for example, dissolved in 0.1 cc of Ringer's
solution, is thus injected suddenly into the artery supplying the
frog's gastrocnemius, the surface of the muscle, covered with its
glistening aponeurosis, shows immediately the ripple and shimmer of
innumerable, unsynchronized contractions, propagated along the
fibres and fascicles of the muscle; at the height of the effect a
tension of several hundred grams is developed; and the electrical
record gives decisive evidence that this response is an irregular,
asynchronous tetanus, and not a contracture. With larger doses this
tetanus is cut short and extinguished by the contracture - the only
effect of acetylcholine on frog's muscle which earlier work had
recognized.
From the study of the mammalian muscle we have
also obtained what seems to be clear evidence concerning a mechanism
by which acetylcholine, suddenly liberated at the nerve ending to
transmit the excitatory effect of a motor impulse to the muscle
fibre, may, with a comparable suddenness, be removed completely
during the refractory period. If this removal is due, as we have
suggested, to the destructive action of cholinesterase, concentrated
on surfaces at the nerve ending, we should expect that eserine, with
its depressant effect on the action of the cholinesterase,
discovered by Loewi and Navratil, would delay the disappearance,
from the neighbourhood of the motor end plates of the muscle fibres,
of the acetylcholine liberated by a single nerve volley, and would
thereby modify the response of the muscle. The effect is easy to
demonstrate. Eserine causes, in fact, a great increase of the
maximum tension attained by the contraction of the muscle in
response to a maximal nerve volley. The all-or-none principle
forbade us to suppose that such a potentiated response was a single
twitch; and the electrical records showed that it was, indeed,
repetitive, and had the nature of a brief, diminishing tetanus21.
The eserine has so depressed the action of the
esterase at the nerve endings, that the acetylcholine liberated by a
single nerve volley lingers there, and reexcites the muscle at each
emergence from successive refractory periods, until the
concentration falls at last below the stimulation threshold. Bacq
and Brown22
have more recently extended these observations to a series on
artificial eserine analogues, and have found that the potentiating
action on the response of mammalian muscle to single nerve volleys
is, in fact, proportional, in the different compounds of the series,
to the anticholinesterase action, as independently determined.
There are many other aspects of these phenomena,
some of them still under active investigation in my laboratory. I
must be content today to have presented the main headings of the
evidence, which, as it seems to me, is forcing upon us the
conclusion, in spite of the preconceptions which made the idea
initially so difficult to entertain, that acetylcholine does
actually intervene as a chemical transmitter of excitation, in the
rapid and individualized transmission at ganglionic synapses and at
the motor endings in voluntary muscle; that, in the terminology
which I have proposed, the preganglionic fibres of the autonomic
system, and the motor nerve fibres to voluntary muscle, are also
"cholinergic".
You will see that we are thus led to the
conclusion that nearly all the efferent neurones of the whole
peripheral nervous system are cholinergic; only the postganglionic
fibres of the true sympathetic system are adrenergic, and not even
all of these. As I have earlier pointed out, on more than one
occasion12,
23,
before the evidence for the cholinergic function of voluntary motor
nerves was nearly as strong as it has now become, this new
classification of nerve fibres, by chemical function, renders at
once intelligible the formerly puzzling evidence as to the
functional compatibility of different types of nerve fibre, in
replacing one another in experimental regeneration. The whole of the
evidence of such replacement, obtained by Langley and Anderson early
in the present century, can now be summarized by the simple
statement that any cholinergic fibres can replace any other
cholinergic fibres, and that adrenergic fibres can replace
adrenergic fibres, but that no fibre can be functionally replaced by
one which employs a different chemical transmitter. The chemical
function, as I have expressed it, seems to be characteristic of the
neurone, and unchangeable. In that connexion, particular interest
appears to me to attach to the recent observations of Wybauw24,
which seem to provide clear evidence that the antidromic
vasodilatation, generally believed to be produced through peripheral
axon branches from sensory fibres, also employs a cholinergic
mechanism. If this is substantiated, and if my suggestion holds good
that the chemical mechanism is characteristic of the neurone, the
question at once presents itself, whether at transmission of
excitation will be found.
Hitherto the evidence concerning a chemical
transmission in the central nervous system, of the type which we
have found prevailing at all peripheral synapses, is scattered and
insufficiently uniform in its indications. The basal ganglia of the
brain are peculiarly rich in acetylcholine, the presence of which
must presumably have some significance; and suggestive effects of
eserine and of acetylcholine, injected into the ventricles of the
brain, have been described. I take the view, however, that we need a
much larger array of well authenticated facts, before we begin to
theorize. It is here, especially, that we need to proceed with
caution; if the principle of chemical transmission is ultimately to
find a further extension to the interneuronal transmission in the
brain itself, it is by patient testing of the groundwork of
experimental fact, at each new step, that a safe and steady advance
will be achieved. The possible importance of such an extension, even
for practical medicine and therapeutics, could hardly be
overestimated. Hitherto the conception of chemical transmission at
nerve endings and neuronal synapses, originating in Loewi's
discovery, and with the extension that the work of my colleagues has
been able to give to it, can claim one practical result, in the
specific, though alas only short, alleviation of the condition of
myasthenia gravis, by eserine and its synthetic analogues.
1. O. Loewi, Pflügers
Arch. Ges. Physiol., 189 (1921) 239.
2. O. Loewi, Pflügers
Arch. Ges. Physiol., 193 (1921) 201.
3. O. Loewi, Pflügers
Arch. Ges. Physiol., 203 (1924) 408.
4. O. Loewi and E.
Navratil, Pflügers Arch. Ges. Physiol., 206 (1924) 123.
5. O. Loewi and E.
Navratil, Pflügers Arch. Ges. Physiol., 214 (1926) 678.
6. O. Loewi and E.
Navratil, Pflügers Arch. Ges. Physiol., 214 (1926) 689.
7. H.H. Dale, J.
Pharmacol., 6 (1914) 147.
8. A.J. Ewins, Biochem.
J., 8 (1914) 44.
9. R. Hunt and M. Taveau,
Brit. Med. J., 2 (1906) 1788.
10. H.H. Dale and H.W.
Dudley, J. Physiol., 68 (1929) 97.
11. H.H. Dale, J.
Physiol., 80 (1933) 10 P.
12. H.H. Dale, Dixon
Memorial Lecture, Proc. Roy. Soc. Med., 28 (1935) (Sect.
Therapeutics and Pharmacology, pp. 15-28).
13. G.L. Brown and W.
Feldberg, J. Physiol., 86 (1936) 290.
14. H.C. Chang and J.H.
Gaddum, J. Physiol., 79 (1933) 255.
15. W. Feldberg, B. Minz,
and H. Tsudzimura, J. Physiol., 81 (1934) 286.
16. A.V. Kibjakov,
Pflügers Arch. Ges. Physiol., 232 (1933) 432.
17. W. Feldberg and J.H.
Gaddum, J. Physiol., 81 (1934) 305.
18. W. Feldberg and A.
Vartiainen, J. Physiol., 83 (1934) 103.
19. G.L. Brown and W.
Feldberg, J. Physiol., 86 (1936) 40 P.
20. H.H. Dale, W.
Feldberg, and M. Vogt, J. Physiol., 86 (1936) 353.
21. G.L. Brown, H.H. Dale,
and W. Feldberg, J. Physiol., 87 (1936) 394.
22. Z.M. Bacq and G.L.
Brown, J. Physiol., 89 (1937) 45.
23. H.H. Dale,
Nothnagel Lecture, No. 4., Vienna: Urban and Schwarzenberg
(1935).
24. L. Wybauw, Compt.
Rend. Soc. Biol., 123 (1936) 524.
From
Nobel Lectures, Physiology or Medicine 1922-1941.
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1935
