Reviews of Physiology, Biochemistry and Pharmacology, Volume 87

232 Pages·1980·4.818 MB·English-German

by  Giuseppe Moruzzi (auth.)

Reviews of
78 ~3goloisyhP
Biochemistry and
ygoloca,.mrahP
Editors
R. H. Adrian, Cambridge E. • Helmreich, Wiarzburg
H. Holzer, Freiburg • R. Jung, Freiburg
O. Krayer, Boston" R. J. Linden, Leeds
F. Lynen ,-[- Miinchen • .P A. Miescher, Genrve
J. Piiper, Grttingen • H. Rasmussen, New Haven
A. E. Renold, Genrve • U. Trendelenburg, Wflrzburg
K. Ullrich, Frankfurt/M. • W. Vogt, Grttingen
A. Weber, Philadelphia
With Figures 26
Springer-Verlag
Berlin Heidelberg New York 1980
Reviews of Physiology, Biochemistry and Pharmacology
formerly
Ergebnisse der Physiologie, biologischen Chemie und
experimentellen Pharmakologie
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ISBN 0-387-09944-1 Springer-Verlag New York Heidelberg Berlin
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Contents
In Memoriam Lord Adrian (1889- 1977).
By G. Moruzzi, Pisa/Italy. With 1 Figure
Wilhelm Steinhausen (1887 - 1954).
Von D.E.W. Trincker, Bochum/Bundes-
republik Deutschland. Mit 1 Abbildung 52
A Kinetic Analysis of the Extraneuronal Uptake
and Metabolism of Catecholamines.
By U. Trendelenburg, Wt~rzburg/Federal
Republic of Germany. With 22 Figures 33
Angiotensin Stimulation of the Central Nervous
System. By J. T. Fitzsimons, Cambridge/
United Kingdom . . . . . . . . . . . . 711
The Cellular Processing of Lysosomal Enzymes
and Related Proteins. By L.D. Strawser and
O. Touster, Nashville, Tennessee/USA.
With 2 Figures . . . . . . . . . . . . . 961
Author Index . . . . . . . . . . . . . . . 112
Subject Index . . . . . . . . . . . . . . . 227
Indexed in Current Contents
Rev. Physiol. Biochem. Pharmacol., Vol. 87
© by Springer-Verlag 1980
nI mairomeM droL nairdA (1889-1977)
GIUSEPPE MORUZZI *
* Istituto di Fisiologia della Universitfi di Pisa, Via S. Zeno 31, I-56 t 00 Pisa.
2 .G izzuroM
Edgar Douglas Adrian was born on 30 November 1889 in Hampstead,
London. He was the son of Alfred Douglas Adrian, legal adviser to the Lo-
cal Government Board. His mother was born Flora Lavinia Barton.
In the personal records of the Fellows of the Royal Society, Adrian
noted that his family was of French or Flemish Huguenot descent and
came to England in 1572 after the massacre of St. Bartholomew. Various
members of the family were at Cambridge University. Adrian's father,
grandfather, and great grandfather were in the civil service, the latter hav-
ing been clerk to the House of Parliament.
Adrian's childhood was spent in London, where he went to the West-
minster School. He received a classical education, but moved to a modern
curriculum 2 years before leaving the school. In 1908 he went to Trinity
College, Cambridge, with a scholarship in science. In t 1 19 he started work
at the Institute of Physiology in collaboration with Keith Lucas, with
whom he published his first paper in 1912. From 1912 to 1914 Adrian
worked alone,with guidance from his teacher, Keith Lucas, who died in an
airplane accident in 1916. Adrian, who had left Cambridge 2 years previ-
ously, was under the direct influence of Keith Lucas for only 3 years.
However, in the handwritten notes mentioned above, Adrian states that
Keith Lucas decided his career and made a physiologist out of him.
In 1913 Adrian had won a fellowship at Trinity College with a thesis
on the conduction of the impulse in the nerve. In 1914 he went to St. Bar-
tholomew's Hospital in London, where he took his medical degree in 1915.
During the war Adrian worked at the National Hospital in Queen Square
and at the Connaught Medical Hospital, Aldershot. During this period he
published some papers of interest in the field of clinical neurology. These
investigations were undoubtedly prompted by his work as a medical
officer, but the roots of his clinical interests were probably deeper. In his
handwritten notes he states that had he not come under the influence of
Keith Lucas he might have turned to clinical medicine, and acknowledges
his debt to Professor Walshe at Queen Square and to Dr. Abrahams at the
Connaught Hospital for the medical training he received during this period
of his life. His medical training appears particularly important in the ap-
proach of his physiological experiments on man.
After the end of the war, in 1919, Adrian returned to Cambridge to
take over Keith Lucas' laboratory. He later became University lecturer,
was Foulerton Research Professor of the Royal Society from 1929 to
1937, and professor of physiology after the retirement of Sir Joseph
Barcroft. He resigned in 1951, when he was elected Master of Trinity Col-
lege, a position which he held until 1965.
During the last 20 years of his life Adrian held the highest academic
positions. He was Chancellor of Leicester University from 1957 to 1971,
Vice-Chancellor of Cambridge from 1957 to 1959, and Chancellor of
In Memoriam Lord Adrian 3
Cambridge from 1968 to 1976. Adrian had been awarded the Order of
Merit in 1942, was President of the Royal Society from 1950 to 1955,
and President of the Royal Society of Medicine in 1960-1961. He was
made a peer in 1955.
In 1923 Adrian married Hester Agnes Pinsent, related on her father's
side to David Hume. She was Justice of the Peace and did much social
work. They had three children. Anne Keynes, Jennet Campbell, and
Richard Hume Adrian, FRS, who succeeds to his father's title. After his
wife's death in 1967, Adrian lived in Trinity College until his last weeks.
He died on 4 August 1977, at the age of 87.
The Early Studies on the Physiology of the Nerve
When Adrian started to work with Keith Lucas in the Physiological Labo-
ratory at Cambridge in 1911, most of the information available on the
functions of the nerve were based on indirect evidence. The frog's nerve-
muscle preparation was still utilized as a biologic recording apparatus, as a
natural device that was more sensitive and reliable than the physical instru-
ments available in those days. A number of ingenious experiments, com-
bined with the insight of outstanding investigators, had permitted good
progress with this simple technical approach, which had been introduced
by Galvani at the end of the eighteenth century.
Two years previously, in 1909, Keith Lucas had utilized a preparation
containing a small number of motor nerve fibres and provided the final
proof of the all-or-none contraction of the amphibian skeletal muscle fibre.
This fundamental work undoubtedly prompted Adrian's attempt (1912)
to measure what Keith Lucas called the "propagated disturbance" of the
nerve fibre by the capability to travel across a narcotized region of the
nerve. Simply by observing the muscle twitch, hence with an indirect
method, Adrian (1914) came to the correct conclusion that "... there is
an all-or-none relation between the strength of the stimulus and the size
of the propagated disturbance which follow it" (1.c.p. 472).
Twenty years later, in a review article written for Ergebnisse der Physio-
logie (1933), Adrian summarized these experimental conclusions in a
statement of the all-or-none principle:
The facts are these (a) that the beat of the heart which results from a single brief
stimulus cannot be varied in any way by changing the strength of the stimulus, (b) that
the wave of contraction which travels down a striated muscle fibre is also incapable of
variation by changing the strength of the stimulus and (c) that the impulse which
travels down a nerve fibre is similarly invariable. The facts enumerated above can be
condensed into a single statement, namely that in nerve fibre, skeletal muscle fibre and
4 G. Moruzzi
in the heart the intensity of the propagated disturbance at any point is determined
solely by the local conditions at that point (1.c. pp 745).
These principles now appear self-evident. But the statement could be
so lucid and rigorous because of the experimental evidence provided by
Adrian himself in the twenties by means of electrophysiological recording,
i.e., by direct methods. It is interesting to compare this statement with
that of Keith Lucas in the lectures he gave at University College of London
in the spring of 1914. These lectures were published by Adrian in 1917,
one year after the death of his teacher 1. At that time the experimental
evidence had been mainly obtained with indirect methods, and the task of
the investigator appeared terribly difficult, because the direct approach
was outside the range of the techniques that were then available.
The first problem of conduction is whether the nervous impulse is a variable quan-
tity, or whether in each unit fibre of the nervous system it is always of like strength.
The investigation of this question is one of singular difficulty because the impulse is so
intangible. If we stimulate a motor nerve and record the contraction of the muscle in-
nervated, we conclude that a nervous impulse has passed from the seat of excitation to
the muscle; but how are we to come to closer contact with the nervous impulse, to
learn something more about it than the mere fact that it has or has not passed along
the nerve? That we can measure its rate of passage we lla know, but that does not help
us much; we want to know how the impulse varies in intensity, whether it si stronger if
the stimulus is stronger, whether it si weakened by passing a region of partial obstruc-
tion such sa the junctional tissue between nerve and muscle. It is only when we can
measure the nervous impulse that we begin to learn the elements of conduction.
It might appear at first sight that we could learn something of the intensity of the
impulse from the magnitude of the effect which it produces. If a large contraction
results from stimulation of the motor nerve we might infer an increase in the intensity
of the nervous impulse. This method si open to two fatal objections. Any nerve with
which we can experiment is comprised of many unit fibres, and a larger contraction
might result with equal probability either from an increase of intensity in each nerve
fibre, or from an increase in the number of fibres brought into action. And even if this
difficulty were overcome by the use of a single nerve fibre, there would remain the ob-
jection that we should be measuring the intensity of the impulse in terms of the mag-
nitude of contraction, whereas we have no knowledge whatever of the function relat-
ing these quantities. If we turn to a process which seems more intimately connected
with conduction, the electric response of nerve, and attempt, as many physiologists
have done, to measure the nervous impulse in terms of the magnitude of the accom-
panying electric response, we are still no nearer to the truth; here again an alteration in
the number of fibres may be mistaken for an alteration in intensity. In fact every at:
tempt of this kind is doomed to failure... (1.c. pp. 4, 5).
Keith Lucas had clearly envisaged what was the main problem in nerve
physiology: the recording from a single fibre. But we must agree with him
that "every attempt of this kind is doomed to failure" when only direct
methods based on the observation of the contraction of the muscle are
available. It remained for his pupil to record for the first time the action
potentials from a single sensory fibre. This historic achievement became
possible only 10 years later, through a major technical advance.
1 Lucas K (1917) The conduction of the nerve impulse. Longmans, Green, London
In Memoriam Lord Adrian
First Attempts at Direct Eleetrophysiologie Recording
Some of the studies which Adrian carried out immediately after the war,
such as his work on the recovery process of excitable tissues (1920, 1921),
are obviously related to the approach he had learned from Keith Lucas.
Adrian was aware, however, that only by direct electrophysiologic record-
ing was there hope of making this area of work fertile. With Forbes, in
1922, he utilized the string galvanometer for the study of the all-or-none
response of sensory nerve fibres; with Olmsted, in 1922, and with Sybil
Cooper, in 1923 and 1924, he adopted the same recording technique for
investigating spinal reflexes. But the very fact that he tried several ap-
proaches in such a short period shows that Adrian was not satisfied with
these attempts. It is interesting to learn directly from him the reasons for
his attempts to find a new way and how he was led to the discovery of the
methods of single unit recording.
At a scientific session held in connection with the formal opening of
The Charles H. Best Institute, some distinguished scientists were asked
"which of your scientific investigations has given you the most satisfaction
and pleasure?" Adrian's reply is important not only because this was one
of the few instances in which he agreed to report a personal experience,
but also in view of the fact that he gave an account of his typical way of
directing questions to nature. Adrian's reply was published in Diabetes in
1954, and for this reason probably escaped the attention of several neuro-
physiologists. The article was quoted however by Hodgkin, in the obituary
he wrote for Nature 2.
It was in the early 20's. I had taken up electrophysiological research on the central
nervous system and had spent a great deal of time making string galvanometer records
of action currents in the hope of being able to find out exactly what was coming down
the nerve fibres when the muscle contracted. We knew then that nerves sent down
nerve impulses as signals, but we didn't know anything about the way in which the im-
pulses would follow one another. We didn't know whether they came at a high fre-
quency, or at a steady frequency. We didn't know whether the frequency varied or not.
In fact, we didn't know at all how the nervous signals were controlled. Alexander
Forbes had been working with me in Cambridge and I had learned a great deal from
him about string galvanometers and about-mammalian preparations, but the experi-
ments I had startet became more and more unprofitable. You know the sort of thing
that happens - they became more and more complicated and the evidence more in-
direct, and after a time it was quite clear that I was getting nowhere at all. But it was
fairly clear at that time that the valve amplifier was going to make it very much easier
to record action potentials, particularly very small ones, and there had been various
descriptions of valve amplifying arrangements. In particular, Gasser and Newcomer had
used a three-stage one to record action potentials in the phrenic nerve. I had rigged up
a single valve one, but it wasn't much good, so having decided that I was getting no-
where, I wrote to Gasser for the details of the arrangement he was using for the
phrenic. He was then beginning his studies with the cathode-ray oscillograph on the
2 Hodgkin AL (1977) Lord Adrian, 1889-1977. Nature 269:543-544
6 G. Moruzzi
action potentials of nerve fibres of different sizes, but he gave me a full description of
the amplifier that he and Newcomer had used, and I built one to much the same pat-
tern. I knew very little about it and was rather afraid of all the complications in it.
When it was ready, I decided to test it using the capillary electrometer which was in
the laboratory, built by Keith Lucas about fifteen years before. I used the capillary
electrometer because, although it wasn't as sensitive as the stringg alvanometer, it had
the great advantage of being more foolproof in that it wasn't so easy to break the
string if you overloaded it. The amplifier had to be treated with great respect, as in
those days the valves were terribly microphonic. The arrangement I had gave a magnifi-
cation of about 2000, so I set up a pair of non-polarizable electrodes in a shielded
chamber, and put the normal accompaniment of physiological research, the frog's
nerve-muscle preparation, on the electrodes, to see whether I could get a steady base
line. Well, I was distressed, but not very greatly surprised, to find that the base line
wasn't a bit steady. It was oscillating rapidly all the time. As soon as the circuit was
open there was this constant rapid oscillation going on and I naturally suspected that I
was picking up an artifact from somewhere and that I should have to pull the whole
apparatus down and stick it all together again and go on for another month or so, get-
ting no results.
I began re-adjusting the apparatus, and then I found that sometimes the oscillation
was there (it was a fine, rapid affair) and sometimes the base line was quite steady.
There was a ray of hope, and after trying various arrangements, I found that this little
oscillation was only there when the muscle was hanging down quite freely, from the
knee joint of the frog's nerve-muscle preparation. If the muscle was supported on a
glass plate there was no oscillation at all and the base line was quite steady. The ex-
planatiosnu ddenly dawned on me, and that was a time when I was very pleased indeed.
A stretched muscle, a muscle hanging under its own weight, ought, if you come to
think of it, to be spending sensory impulses up the nerves coming from the muscle
spindles, signalling the stretch on the muscle. When you relax the stretched muscle,
when you support it, those impulses ought to cease.
I don't think it took more than an hour or so to show that that was what the little
oscillations were. I was able to make photographic records of them, and within about a
week I was nearly certain that many of these oscillations were action potentials coming
up sensory fibres in the nerve, and what was more, that many of them came from
single nerve fibres and that by some extension of the technique it ought to be possible
to find out exactly what was happening in single nerve fibres when the sense organs at-
tached to them were stimulated.
That particular day's work, I think, had all the elements that one could wish for,
The new apparatus seemed to be misbehaving very badly indeed, and I suddenly found
that it was behaving so well that it was opening up an entire new range of data. I'd
been bogged down in a series of very unprofitable experiments and here suddenly was
the prospect of getting direct evidence instead of indirect, and direct evidence about
all sorts of problems which I had set aside as outside the range of the techniques that
one could use. The other point about it was that, as I said, it didn't involve any partic-
ular hard work, or any particular intelligence on my part. It was one of those things
which sometimes just happens in a laboratory if you stick apparatus together and see
what results you get (1.c. pp. 26-27).
Everybody will agree with Hodgkin's comment (l.c., 1977, p. 544) con-
cerning the last sentence, that "... when most people stick apparatus to-
gether and look around they do not make discoveries of the same impor-
tance as those of Adrian's."
In Memoriam Lord Adrian
Single Unit Discharges in Sensory and Motor Fibres
A revolutioia in technique thus made it possible '".. to record the impulses
which are set up in sensory nerve fibres by the appropriate stimulation of
their sense organs, to determine the actual message transmitted to the
brain, and to see how it is related to the stimulus which produces it." This
quotation from Adrian's first monograph (1928; p. 14) summarizes the
reasons which justify the title of the book The Basis of Sensation. In only
2 years it had become clear
that the messages from our sense organs era lla made up of a common vocabulary of
the simplest kind. They consist of a series of brief impulses in fibre; nerve each lla the
impulses era very much alike, whether the message si destined to arouse the sensation
of light, of touch, or of pain; if they era crowded closely together the sensation si in-
tense, if they era separated by long intervals the sensation si correspondingly feeble
(1.c.p. .)5
In their first study of the responses of a single end-organ Adrian and
Zotterman (1926) followed the approach which had been utilized by
Keith Lucas (1909) for demonstrating the all-or-none response in the
single muscle fibres. The sterno-cutaneous muscle of the frog is innervated
by only 12-25 nerve fibres and only a few of them are sensory in nature.
There are generally three of more end-organs, but they may be reduced to
one or two by cutting successive strips from the muscle. The frequency of
the response to stretch of a single end-organ increased with the load of the
muscle, and there was an all-or-none relation between the size of the elec-
tric response in the nerve fibre and the strength of the stimulus.
In their second paper Adrian and Zotterman (1926) showed that the
skin pressure receptors of the cat's foot behaved in the same way, but that
their rate of adaptation was much more rapid. This observation led to the
classical distinction between "postural" (slow adapting) and "phasic" (fast
adapting) end-organs. At the end of the same year Adrian (I 926) extended
the study to the skin pain receptors, which turned out to differ very little
from the other receptors.
Meanwhile, Adrian's pupil, B.H.C. Matthews, had developed a new
oscillograph (1928) 3 which he utilized for his classical studies on the dis-
charge of single stretch receptors (1931, 1933) . 4 This was a major tech-
3 Matthews CHB (1928) A new electrical recording system for physiological work.
J Physiol (Lond) 65:225-242
4 Matthews CHB (1929) Specific nerve impulses. J Physiol (Lond) 67:169-190
Matthews CHB (1931) The response of a single end organ. J Physiol (Lond) :17
64-110
Matthews CHB (1931) The response of a muscle spindle during acctoinvter action
of J a muscle. Physiol (Lond) 72:153-174
Matthews CHB (1933) Nerve endings in mammalian muscle. J Physiol (Lond) 78:
1-33