Ergebnisse der Physiologie Reviews of Physiology, Volume 63

226 Pages·1971·6.797 MB·English

by  H. O. Schild (auth.)

Ergebnisse dcr Physiologic • Reviews ~o Physiology

Ergebnisse red Physiologic
Biologischen Chemie und experimentellen Pharmakologie
Reviews of Physiology
Biochemistry and Experimental Pharmacology
63
Herausgeber / Editors
E. Helmreich, Wiirzburg • H. Holzer, Freiburg • R. Jung, Freiburg
K. Kramer, Mtinchen • O. Krayer, Boston
F. Lynen, Miinchen • P. A. Miescher, Genf. W. D. M. Paton, Oxford
H. Rasmussen, Philadelphia • A. E. Renold, Genf
U. Trendetenburg, Wiirzburg • H. H. Weber, Heidelberg
With 79 Figures
Springer-Verlag Berlin • Heidelberg • New York 1971
ISBN 3-540-053174 Springer-Verlag Berlin Heidelberg New York
1SBN 0-387-05317-4 Springer-Verlag New York Heidelberg Berlin
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Universit~itsdruckerei H. Stiirtz AG, Wiirzburg
Inhalt
Henry Hallett Dale, 1875--1968. By H. .O Schild. With t
Portrait . . . . . . . . . . . . . . . . . . . . . . .
Presynaptic Inhibitation in the Vertebrate Central Nervous Sys-
tem. By R.F. Schmidt, With 33 Figures . . . . . . . . 20
The Physiology of the Collateral Circulation in the Normal and
Hypoxic Myocardium. By W. Schaper. With 10 Figures 102
Rheological Propertfes of Human Erythrocytes and their In-
fluence upon the "Anomalous" Viscosity of Blood. By
H. Schmid-Sch6nbein, and R. E. Wells, Jr. With 36 Figures 146
Namenverzeichnis . . . . . . . . . . . . . . . . . . . . 220
Sachverzeichnis . . . . . . . . . . . . . . . . . . . . . 532
Mitarbeiter
Schaper, W., Priv.-Doz. Dr., Department fo Cardiovascular Research,
Janssen Pharmaceutica, Koninkliieke Laan 17, B-2340 eiZ Beerse
Schild, H. ,.O Prof. Dr., Department fo Pharmacology, University
egelloC London, Gower Street, London W.C.t/Great Britain
Schmid-Sch6nbein, H., Priv.-Doz. Dr., Physiologisches Institut der
Universit~it, D-8000 Mtinchen t ,5 Pettenkoferstr. 21
Schmidt, R.F., Prof. Dr. Dr., Physiologisches Institut der Univer-
sit,it, D-2300 Kiel, Olshausenstr. 40/60
Wells, R.E., Dr., Department fo Medicine, Peter Bent Brigham
Hospital and Harvard Medical School, 127 Huntington Avenue,
Boston, Mass. 02tl 5/USA
z j 1 ~
Henry Hallett Dale, I875--1968
H. O. SCHILD
"Favoured with opportunities such as few of my own generation enjoyed,
I have been able to make scientific research, on problems mainly of my own
choosing, the central activity of my working life". These introductory words
to Adventures in Physiology, a selection of DALE'S scientific writings published
in t953, emphasize the central role which scientific research has played in his
life, but they can hardly convey the feeling of passionate involvement in
scientific work which emanated from his personality. His conversation, even
in old age, was outstandingly lucid and informative. Talking to him on a
scientific subject was like wandering through a sunlit landscape in which every
detail is distinctly delineated; the clarity, intensity and confidence of his
thought adding to its impact.
DALE was one of the originators of modern physiology and almost certainly
the most influential pharmacologist since PAUL EHRLICH. His work has shaped
much of contemporary medicine and the power and fruitfulness of his thought
was such that we now tend to think within the framework of his ideas. DALE
remarked, in a paper on EHRLICH, whom he greatly admired, that a pre-
dominant line of interest and habit of thought could be traced in all his work.
This applies equally to DALE himself; in his case the idea of autoregulation in
the body, or as he himself called it, autopharmacology, provided the con-
necting link.
DALE'S scientific development was extraordinarily harmonious and seemed
to depend on certain dominating ideas which he developedm ore or less through-
out his life. The following is a brief account of his main scientific achievements.
Scientific Work
Ergot and the Dual Action of Adrenaline
DALE'S work, carried out in 1909-1912, has been the source of most sub-
sequent developments in this field, including some of the most recent. It
provides a good illustration of his approach and of his capacity to extract
fundamental notions out of scattered and often accidental experimental ob-
servations. The following is his own (abbreviated) account ofh is first important
experimental discovery. "When I accepted the appointment (to the Wellcome
Physiological Research Laboratories) Mr. WELLCOME said to me that, when I
could find an opportunity for it without interfering with plans of my own,
I Ergebnisse der Physiologie, Bd. 63
2 H.O. SCHILD"
it would give him special satisfaction if I would make an attempt to clear up
the problem of ergot, then in a state of obvious confusion. I was frankly not
at all attracted by the prospect of making my first excursion into pharmacolog-
ical research on the ergot morass, but I found GEORGE BARGER, a former
Cambridge colleague, and a very able and enterprising chemist, working in
the Wellcome laboratories, and BARGER had already prepared from ergot a
number of active substances. So I began by testing their effects on the blood
pressure of the cat. All of these compounds showed an initial pressor action
but that in itself would not have added greatly to earlier knowledge. By one
of my greatest strokes of good fortune, however, this work was to give me
an opportunity of making a mistake of my own--a really shocking 'howler'.
I was finishing one of these experiments on a spinal cat to which I had given
successive doses of one of BARGER'S ergot preparations when a sample of
dried suprarenal gland substance was delivered to me from the Burroughs
Wellcome factory, with a request that I would test it for the presence of
adrenaline. Successive injections of the extract elicited, to my surprise, only
falls in arterial pressure, and with the confidence of inexperience I condemned
the sample without hesitation. And then by another and almost incredibly
fortunate coincidence, the same sequence of events was repeated in detail a
week later. Again I was finishing an experiment on a cat heavily dosed with
an ergot preparation when a sample of suprarenal gland substance was delivered
for testing. The result was the same as on the earlier occasion and by reference
to my notes now raised the question whether the cat's response to adrenaline
might have been so altered by ergot that the normal pressor action had been
reversed."
DALE'S following paper deals with a detailed analysis of the interaction
between ergot and adrenaline. He concluded that ergot paratysed the motor
/unctions of the sympathetic and of adrenaline, leaving inhibitory /unctions
unaffected. Although DALE was aware of LANGLEY'S postulated receptor sub-
stance on which adrenaline supposedly acted, he makes no reference to receptors
either in this or in later papers. He suggests instead that sympathetic nerves
might contain some fibres connected to purely inhibitory and others to purely
motor myoneural junctions, or alternatively that myoneural junctions may
themselves be composite, containing both motor and inhibitory elements. DALE
also observed that the actions of adrenaline on the heart were much more
difficult to antagonise by ergot than its actions on blood vessels, thus anti-
cipating in this early paper the modern subdivision into adrenergic e- and/%
receptors.
Sympathomimetic Amines and Noradrenaline
DALE and BARGER'S study of over fifty sympathomimetic amines is a
comprehensive investigation of the relation between chemical constitution and
Henry Hallett Dale 3
pharmacological action. They introduced the term citemimohtapmys to denote
a range of compounds which "simulate the effects of sympathetic nerves with
varying intensity and varying precision." It is characteristic of DALE'S way
of thinking to have adopted this rather open definition; he was generally
averse to rigid formulations, preferring to use a more pragmatic approach.
Their main conclusions were that the more substances resembled adrenaline
in structure the more active they became, and that all typical sympathomimetic
compounds were primary or secondary amines whilst tertiary and quaternary
bases had nicotine-like actions.
Retrospectively, perhaps the most interesting aspect of their paper is its
discussion of noradrenaline. DALE investigated noradrenaline showing that it
had greater stimulant and less inhibitory activity than adrenaline and he
points out in the discussion that the actions of noradrenaline correspond more
closely to sympathetic stimulation than those of adrenaline. He explicitly
rejects ELLIOTT'S earlier suggestion that the similarity between the effects of
adrenaline and sympathetic nerves may be due to the latter liberating adrenaline
at nerve endings, giving as his main reason the lack of parallelism between
adrenaline and sympathetic stimulation; but he fails to conclude that nor-
adrenaline might occur as such in the body and be a better candidate than
adrenaline of ELLIOTT'S postulated transmitter substance. DALE himself mar-
velled later at his failure to "jump to the truth". In this connection I can
recall when working with DALE in 1933 and finding a consistent discrepancy
between physiological and colorimetric estimates of the adrenaline content of
suprarenal glands that it did not seem to occur to either of us that the dis-
crepaa~cy might be due to the adrenal gland containing noradrenaline as well
as adrenaline. It remained for the later work by HOLTZ and voN EULER to
establish clearly the occurrence and function of noradrenaline in the body.
Histamine
DALE had a lifelong attachment to histamine, which he discovered (with
)WALDIAL in ergot extracts and whose pharmacological actions he first de-
scribed. He used histamine as a tool for a deep-going analysis of capillary
function under normal and pathological circumstances. In the course of this
analysis he introduced the concept of a "locally acting chemical stimulant",
distinguishing between true hormones in the Bayliss and Starling sense and
other physiologically active substances whose effects were restricted to the
immediate neighbourhood of their liberation. The problem of capillary tone
had become of central interest through the work of AUGUST KROGH, and DALE
thought that substances with "histamine-like" action played an important
part in its regulation. He argued that the capillary epithelium must be con-
stantly exposed to products with vasodilator activity which arose in tissues
and whose production was accelerated by excitatory or injurious influences.