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 THECiba Foundation, a unique international institution, owes
its inception to the generosity of CIBA Limited, Basle. However,
being established under British trust law, it enjoys complete
independence in practice and policy.
Under the guidance of its distinguished Trustees, the
Foundation offers accommodation to scientists from all over
the world at its home in Portland Place. Foremost in its activities
is the organization of small conferences, the proceedings of which
are published in book form in the manner of the present volume.
The Foundation convenes many other informal discussions
between research workers of different disciplines and different
nationalities and each year invites an outstanding authority to
deliver a special lecture. An exchange programme between
French and British postgraduates is conducted and a library
service is available. Furthermore, the Ciba Foundation attempts
in every other way possible to aid scientists, whether they be
Nobel Laureates or young graduates malung their first original
contribution to research.
The purpose of the Ciba Foundation, whch is to promote
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V
 THE CIBA FOUNDATION
for the Promotion of International Co-operation in Medical and Chemical Research
41 PORTLAND
PLACE, W.I.
LONDON,

Trustees
Tm RIGHTHON.LORDADRIAN,
O.M., F.R.S.
THERIGHTHON.LORDBEVERIDGE,
K.C.B., F.B.A.
Sm RUSSELL
BRAIN,BT.
THEHON.SIR GEORGE
LLOYD-JACOB
SIRRAYMONDNEEDHAM,Q.C., F.S.A.

Executive Council
SIR RUSSELL
BRAIN,BT., Chairman SIRARTHURVEREHARVEY, C.B.E., M.P.
DR. F. GROSS THEHON.SIR GEORGE LLOYD-JACOB
PROFESSORA. HADDOW, F.R.S. F. G. YOUNG,F.R.S.
PROFESSOR

Director, and Secretary to the Executive Council

DR. G. E. W. WOLSTENHOLME,
O.B.E.

Deputy Director
MR. A. v. s. DE bUCX, M.SC.

Assistant Secretary
Mrss N. BLAND

Scientific Assistant and Librarian Editorial Assistant

M r s s M. P. CAMERON,
M.A. Mrss MAEVE
O'CONNOR,
B.A.

Conference Assistant
G. SPLFFORD
MRS.NANCY
vi
 PREFACE
MEMBERS of the Biological Council’s Co-ordinating Committee
for Symposia on Drug Action have many excellent reasons to be
grateful to Sir Charles Harington, Chairman of the Committee
from its inception in 1951to 1960. The succession of conferences
jointly organized each Spring by various societies, among which
it would not be iiividious to single out the British Pharmacological
Society, have greatly extended the international range of indebted-
ness to Sir Charles for his guidance in the selection and treatment
of subjects designated by the committee for special attention. In
addition to the work of co-ordinating the conference programme
of a number of organizations, the committee has itself initiated
successful symposia on Anticholinesterases, Histamine, Hypo-
tensive Drugs, 5-Hydroxytryptamine, Quantitative Methods in
Human Pharmacology and Therapeutics,and Polypeptides which
Affect Smooth Muscles and Blood Vessels.
The Ciba Foundation has been privileged to join the Wellcome
Trust and the Wellcome Foundation, Limited, in support of these
symposia, mostly by assistance with accommodation and travelling
expenses and on social occasions; but in 1955 also by joining in the
programme for the symposium on Histamine, held in honour of
Sir Henry Dale. On that occasion, to supplementthe programme of
papers presented at the Wellcome Building, the Ciba Foundation
provided facilitiesfor two further days of more intimate discussion,
and assumed responsibility for publication of the complete pro-
ceedings. It was with pleasant memories ofthis earlier collaboration
that the Director readily agreed to a similar plan in the organiza-
tion and publication of an international symposium on “Adren-
ergic Mechanisms.”
Main responsibility for the meeting lay in the hands of a com-
mittee representing the British Pharmacological Society, with
the co-operation of the Physiological Society, the Biochemical
Vii
viii PREFACE

Society, and the Royal Society of Medicine. It was arranged that

there should be two days for formal presentations and brief dis-
cussion at the Wellcome Building on the 28th and 29th Maich
1960, attended by some 300 people, and two fkther days on the
30th and 3 1st March at the Ciba Foundation for unscripted discus-
sion by one-tenth of this number.
Every member and reader will wish to acknowledge the essen-
tial and notable parts played in the preparation and management of
both sections of this symposium by Dr. H. Blaschko, Dr. H. 0.
Schild, Dr. W. A. Bain, Dr. G. B. West, Dr. J. H. Gaddum and
Dr. J. R. Vane. The responsibilities of the latter as Organizing
Secretary continued into hisjoint-editorship of this volume, to the
relief and pleasure of his co-editors and the benefit of all who find
value and enjoyment in it.
 EDITORS' NOTE
THEfollowing convention has been used for identifying substituents
on the phenylethylamine skeleton:
m 0

o= ortho; m= meta; p=para.

The terms and abbreviations given below have been used; the
abbreviations therefore have not been explained every time they
appear :
adrenaline P(3,q-dihydroxypheny1)P-hydroxy N-methyl
ethylamine
noradrenaline p( 3,4-dihydroxyphenyl)p-hydroxy ethylamine
me tanephrine P(3-methoxy-4-hydroxyphenyl)@-hydroxy N-
methyl ethylamine
normetanephrine p(3-methoxy-4-hydroxyphenyl)p-hydroxy
ethylamine
ATP adenosine triphosphate
dopa P( 3,4-dihydroxyphenyl)alanine
dopamine p(3,4-dihydroxyphenyl)ethylamine
SHT 5-hydroxytryp tamine
5HTP 5-hydroxytryptophan
LSD lysergic acid diethylamide
MA0 monoamine oxidase
Where possible names approved by the British Pharmacopoeia Com-
mission have been used. Trade names are indicated by the use of a
capital letter; British trade names have been used if these differ from
American ones (Dibenyline rather than Dibenzyline).
Some sections of the discussion at the Ciba Foundation, which were
particularly relevant to papers given at the Wellcome Building, have
been transferred to the discussions after those papers,
ix
 CONTENTS
PAGE

Opening address
by SIR HENRY
DALE,O.M. . . . I

Session 1 : Formafion and lnactivation of Adrenevgic Transmitters

Chairman: SIR HENRY
DALE
Formation of adrenergic transmitters
byH.J. SCHUMANN . .
Formation of adrenaline and noradrenaline
by N. KIRSHNER . .
Discussion: BACQ,SMITH . . . .
The fate of adrenaline and noradrenaline
by J. AXELROD .
3-Methoxy-4-hydroxymandelic acid excretion in phaeochromo-
cytoma
by M. SANDLERand C. R. J. RUTHVEN .
The metabolism of [a-l4CJ(*)-adrenaline in the cat
by N. KIRSHNER . . . . . .
.
BACQ,HAGEN,KIRSHNER,
Discussion: AXELROD, KONZETT . .

Session 2: Storage of Catechol Aminer

Chairman: H. BLASCHKO
Chairman’s opening remarks . . .
Origin, development and distribution of chromaffin cells
b y J . D. BOYD .
The storage of amines in the chromaffin cell
by P. HAGENand R. J. BARRNETT . . .
Some observations on the synthesis and storage of catechol amines
in the adrenaline-containing cells of the suprarenal medulla
N. A. HILLARP
by A. BERTLER, and E. ROSENGREN . . . .
Cell types of the adrenal medulla
byO.ERiim6 .
Discussion: ANDREWS, BLASCHKO, ERiimO, HAGEN, WEST
HARPER, .
xi
Xii CONTENTS

PAGB

Session 3: The Adrenergic Neurone

Chairman: J. H. GADDUM
Chairman’s opening remarks . . . . . . . I11

Release of sympathetic transmitter by nerve stimulation

by G. L.BROWN . . . . . . .
116
Discussion: AXELROD,BACQ,BROWN,DORNHORST, FURCHGOTT,
HAGEN,
HUTTBR, KIRSHNER,KOSTERLITZ, PATON . . . .
124
Interference with the release of transmitter in response to nerve
stimulation
byW.A.B” . . . . . I31
The effects of bretylium and allied agents on adrenergic neurones
by A. F. GREEN . . . . . . . . .I48
The persistence of adrenergic nerve conduction after TM 10 or
bretylium in the cat
byK.A.Exu~ . . . . . . IS8
Some pharmacological properties of guanethidine
by H. J. BBIN . . . . . . . . . . 162
Discussion: CHRUSCIEL,
FURCHGOTT,KOSTERLITZ,Zms . . . 171

Session 4: Adrenergic Mechanisms in Man

Chairman: W. D. M. PATON
Effects of adrenaline, noradrenaline and isopropylnoradrenaline in
man
and A. F. COBBOLD .
b y J 6 A ~GINSBURG . . I73
Effects of catechol amines on consecutive vascular sections
by B. FOLKOW . . . . . . . 190
Discussion: ARIENS,BACQ,BARCROFT, BURN,DALE,FOLKOW, HARPER,
HILTON . . . . . . . . . . . 198
Clinical effects of drugs which prevent the release of adrenergic
transmitter
by D. R. LAURsNCB and M. L. ROSENHEIM . . . . . 201

Bretylium
byR.W.D.TuRNeR . . . . . . . 209
Discussion: BROWN, DOLLERY,
VON EULER,FOLKOW, GILLIS,HARPBR,
HUNT,LOWB, PATON,ROSENHEIM, TAYLOR,
TURNsR . . . 213
 CONTENTS xiii
PAGE

Session 5 : Actions of Adrenaline and

Noradrenaline on the Efector Cell
Chairman: H. 0. SCHILD
Chairman's opening remarks: The concept of receptors . . 220

Relationships between agonists, antagonists and receptor sites

by B. BELLEAU . . . 223

Receptors for sympathomimetic amines

byR.F.FuRcH~ow . . . 246

Sympathomimetic drugs and their receptors

by E. J. ARI~NS . . 253

Various types of receptors for sympathomimetic drugs

by E. J. ARIENS . . . 264
Discussion: BELLEAU, CHAPMAN, JAMES . . . . . . 270

Biophysical changes produced by adrenaline and noradrenaline

by EDITHBULBRING. . . . * 275

Effect of adrenaline on depolarized smooth muscle

b y H . 0. SCHILD . . . . . . . 288
Discussion: BACQ,BROWN,BULBRING, DALE . . . . . 292

The relation of adenosine-j',j'-phosphate to the action of catechol

amines
by E. W. SUTHERLAND and T. W. FULL . . . * 29.5

The action of adrenaline on carbohydrate metabolism in relation

to some of its pharmacodynamic efficts
by L. LUNDHOLM and ELLAMOIIME-LUNDHOLM . . .
Discussion: COBBOLD,
HAGEN,HILTON,LUNDHOLM, Sum- .

Session 6: Mechanism of Action of Other

Sympathortiimetic Amines
Chairman: U. S . VON EULER
Chairman's opening remarks .
Tyramine and other amines as noradrenaline-releasing substances
byJ.H. BURN. . . . . . . . .
XiV CONTENTS

PAGE
Some observations on the effects of tyramine
by P. A. NASMYTH. . . . . . . . .337
Discussion: ANDREWS,AXELROD,BACQ, BURN, DALE, VON EULER,
FARRANT, FURCHGOTT,LOCKETT, PATON,SCHUMANN, Z m s 344
VARAGI~,
The actions of sympathomimetic amines on tryptamine receptors
b y J . R. VANE . . . . . . . . .356
The depolarizing and blocking action of amphetamine in the cat's
superior cervical ganglion
by H. REINERT . . . . . ' 373
Discussion: BLASCHKO, VANE,ZAIMIS .
FURCHGOTT, . 379

Session 7: Central Adrenergic Mechanisms

Chairman: MARTHE
VOGT
Chairman's opening remarks . . . . . 382
Some central actions of adrenaline and noradrenaline when ad-
ministered into the cerebral ventricles
by F. R. DOMERand W. FELDBERG . . 386
Intervention of an adrenergic mechanism during brain stem
reticular activation
by P. DELL . . * 393
Electrophysiological evidence relating to the r6le of adrenaline in
the central nervous system
by P. B. BRADLEY . . . . 410
The passage of catechol amines through the blood-brain barrier
by H. WEE-MALHERBE . . . . 421
Release of an adrenaline-like substance by electrical stimulation of
the brain stem
b y E . MARLEY . . . . . . . 424
Discussion: BARCROFT, CROSS,DELL, FELDBERG, RADOUCO-THOMAS,
VOGT,WBIL-MALHERBE, WILSON. . . . . 427
O n the biochemistry and possible functions of dopamine and nor-
adrenaline in brain .
by A. CARLSSON, MARGITLINDQVIST and T. MAGNUSSON . . 432
Awakening actions of derivatives of phenylalanine
by T. L. CHRU~CIEL . . . . . . ' 440
Discussion: CARLSSON, SPINKS, WEIL-~~ALHERBB,ZAIMIS . . . 443
 CONTENTS xv
PAGE
Clinical effects of amine oxidase inhibitors
by R. T. C. PRATT . . . . . . .q46
Clinical results with monoamine oxidase inhibitors in psychiatry
by A. VOELKEL . . . . 454 .
.
f

Disnrssion: DEWHURST, TODRICK .

SINCLAIR, . 459

Session 8: General
Chairman:J. H. BURN
Short communication
Specific antagonism of Dibenamine to ergometrine
by H. KONZETT . . . * . . * . 463
Short communication
Adrenergic mechanisms in inflammation .
by D. A. WILLOUGHBY
and W. G. SPECTOR . . . 466
Short communication
Thermoregulation in newborn animals
byR.E. MOORE , 469
Chairman’s closing remarks . 472

Ciba Foundation Sessions on Periphernl

Adrenergic Mechanisms
Chairman: H. BLASCHKO
Chairman’s opening remarks . . , * 473
Short communication
Some problems concerning the storage of catechol amines in the
adrenal medulla
by N. 19. HILLARP. . . . 481
Discussion: BACQ, BAIN, BEIN, BELLEAU,BLASCHKO,
BOYD, BROWN,
BURN, DALE,ERANKO,VON ELJLER,FURCHGOTT, HAGEN,HILLARP,
KONZETT, PATON,SCHUMANN, WEST.
SUTHERLAND, . 486 .
Short commuriication
A new adrenergic mechanism
byJ.H. B U R N . . . . . . . .so2
Discussion: ARIENS,AXELROD,BACQ,BAIN,BEIN, BELLEAU,
BLASCHKO,
BROWN,B~LBRING, BURN, DALE,VON EULER,EXLEY, FELDBERG,
FURCHGOTT, GRAHAM,GREEN,HAGEN,
KONZETT,LUNDHOLM, SCHILD,
SUTHERLAND, VANE,WEST . . . . . so7 . . .
mi CONTENTS

PACE

Ciba Foundation Sessions on Central

Adrenergic Mechanisms
Chairman: J. H. GADDUM
Short communication
Observations on the localization of noradrenaline in homogenates
of dog’s hypothalamus
by T. L. CHRUSCIEL . . 539
Short comtnunication
Synthesis of catechol amines in the depleted brain
byH.Wm-MAmm~ . . . . . 544
Discussion: AXELROD,BACQ, BEIN, BELLEAU,BLASCHKO, BRADLEY,
BULBRING, CARLSSON,
CHANCE, CHRU~CIEL,DALE,DELL,VON EULER,
FELDBERG, FURCHGOTT, GADDUM, HAGEN,KIRSHNER, PATON,PRATT,
SCHILD,SCHUMANN, SUTHERLAND, VANE,VOGT,WEIL-MALHERBE,
WEST,ZAIMIS . . . f 548
Chairman’s summary . * 588
Epilogue
by S ~ H E N RDALE
Y . . . ’ 59s
 List of those presenting papers or contributing to
the discussions on Adrenergic Mechanisms
held at
the Wellcome Budding and at the Ciba Foundation,
28th-3 1 s t March 1960

W. H. H. ANDREWS Dept. of Pharmacology, St. Mary’s Hospital

Medical School, London
E. J. MNS. Pharmacologisch Laboratoriurn, R.K. Univer-
siteit, Nijmegen, Holland
J. AX~LROD . Dept. of Health, Education and Welfare, National
Institutes of Health, Bethesda, Maryland
Z.M.Bacq . Laboratoire de Pathologie et Thtrapeutiques
Gtntrales, Universitk de Litge
W.A.Bm . Smith Kline & French Research Institute, Welwyn
Garden City, Herts.
H. BARCROPT. Sherrington School of Physiology, St. Thomas’s
Hospital, London
H.J. BEIN . CIBA Limited, Basle
B. BELLEAU . Faculty of Pure and Applied Science, University
of Ottawa
H. BLASCHKO. Dept. of Pharmacology, University of Oxford
J.D. BOYD . Anatomy School, University of Cambridge
P.B.BRADLEY . Dept. of Experimental Psychiatry, The Medical
School, University of Birmingham
SIRLINDORBROWN Laboratory of Physiology, University of Oxford
EDITHBULBRING Dept. of Pharmacology, University of Oxford
J. H. BURN . Oxford
A. CARLSON . Dept. of Pharmacology, University of Gothen-
burg, Sweden
M. R. A. CHANCE Dept. of Medical Biochemistry and Pharmaco-
logy, University of Birmingham
N. B. CHAPMAN Dept. of Chemistry, The University, Hull
.
T. CHRUSCIEL Dept. of Pharmacology, Silesian School of Medi-
cine, Zabrze, Poland
A. F. COBBOLD. Sherrington School of Physiology, St. Thomas’s
Hospital, London
xvii
xviii L I S T OF P A R T I C I P A N T S

B. A. CROSS Dept. of Veterinary Anatomy, University of

Cambridge
SIRHENRYDALE,O.M. The Wellcome Trust, London
P. DELL . Laboratoire de Neurophysiologie, HBpital Henri-
Rousselle, Paris
W. G. DEWHURST Children’s Dept., Maudsley Hospital, London
.
C. T. DOLLBRY Dept. of Medicine, Postgraduate Medical School,
London
A. C. DORNHORST St. George’s Hospital Medical School, London
O.ER;imil . Dept. of Anatomy, University of Helsinki
U. S. VON EULER Fysiologiska Institutionen, Karolinksa Institutet,
Stockholm
K.A.ExLEY . Dept. of Pharmacology, University of Leeds
J. FARRANT . Dept. of Pharmacology, School of Pharmacy,
London
W. S. FELDBERG National Institute for Medical Research, Mill Hill,
London
B. U. G. FOLKOW Dept. of Physiology, University of Gothenburg
R. F. FURCHGOTT Dept. of Pharmacology, College of Medicine,
State University of New York
J. H. GADDUM. A. R. C. Institute of Animal Physiology, Babra-
ham, Cambridge
C. N. GILLIS . Dept. of Physiology and Pharmacology, Univer-
sity of Alberta
JEAN GINSBURG Dept. of Medicine, St. Thomas’s Hospital Medical
School, London
J. D. P. GRAHAM Dept. of Materia Medica and Pharmacology,
Welsh National School of Medicine, Cardiff
A. F. GREBN . Wellcome Research Laboratories, Beckenham,
Kent
P. B. HACEN . Dept. of Biochemistry, University of Manitoba,
Winnipeg
R. M. J. HARPER North Devon Infirmary, Barnstaple
N. .
A. H~LLARP Dept. of Histology, Division of Endocrinology,
University of Lund
S. M. HILTON. National Institute for Medical Research, Mill Hill,
London
J. N. HUNT . Physiological Laboratory, Guy’s Hospital, London
0. F. HUTTER. Dept. of Physiology, University College, London
G. W. L. JAMES . Dept. of Materia Medica and Pharmacology,
Welsh National School of Medicine, Cardiff