Table Of ContentDrugs, Enzymes and Receptors of the
Renin-Angiotensin System
The Victor Cha11g Molecular Cardiology Series
A serie of books forming a y tematic approach to cardiova cular mechani ms, development, di -
ea e and treaunent at the molecular level.
Edited by Ahsan Hu ain and Robert M. Graham, Victor Chang Cardiac Re earch In titute, Sydney,
Au tralia.
Volume 1:
Drugs, Enzyme and Receptor of the Renin-Angioten in System:
Celebrating a Century of Di covery
edited by A. Husain and R. M. Graham
Thi book i part of a erie . The publi her will accept continuation order whlch may be cancelled
any time and which provide for automatic billing and hipping of each title in the eries upon pub
lication. Please write for detail .
Drugs, Enzymes and Receptors of the
Renin-Angiotensin System
CELEBRATING A CENTURY OF DISCOVERY
Edited by
Ah an Hu ain
Enzyme Research Unit, Victor Chang Cardiac Research InstitLIIe
Sydney, Australia
and
Robert M. Graham
Molecular Cardiology Unit, Victor Chang Cardiac Research InstitLIIe
Sydney, Australia
harwood academic publi her
he Australia • Canada • France • Germany • india • Japan
ap Luxembourg • Malay ia • The etherlands • Rus ia
Singapore • Switzerland
Copyright© 2000 OPA (Over ea Publi her A ociation) N.Y. Publi hed by licen e
under the Harwood Academic Publishers imprint, part of The Gordon and Breach
Publi hing Group.
All rights reserved.
No part of this book may be reproduced or utilized in any form or by any mean , elec
tronic or mechanical, including photocopying and recording, or by any information tor
age or retrieval y tern, without permi ion in writing from the publisher. Printed in
Singapore.
Am teldijk 166
1 t Floor
1079 LH Am terdam
The Netherlands
British Library Cataloguing in Publication Data
A catalogue record for thi book i available from the Briti h Library.
ISB 90-5823-038-4
ISSN 1561-4409
Dedication
This volume is dedicated to the memory and achievements of Edgar Haber, MD, whose contributions to this
area of cardiovascular research and to many others spanned over four decades.
Born in Berlin on February I, 1932 he emigrated to the US at age seven. He received his undergraduate
training (A.B. (Philosophy), 1952) at Columbia College, NY and his medical training (MD, 1956) from
Columbia College of Physicians and Surgeons. After an internship and first-year re idency at the Massachusetts
General Hospital, he worked as a Research Associate in the laboratory of Dr Christian Anfin en from 1958 to
1961. His work there established that the three-dimensional structure of the enzyme ribonuclease is determined
by information in the linear sequence of the amino acids forming the protein. This finding, which Edgar subse
quently showed also applied to antibody molecules, formed the basis for Anfinsen's 1972 Nobel Prize in
Chemistry. After a year of clinical training in cardiology at StGeorge's Hospital, London, Edgar returned to the
Massachusetts General Ho pita! (MGH) in 1963, and one year later assumed the position of Chief, Cardiac
Unit of the Medical Services, MGH and Associate Professor, Harvard Medical School. This marked the begin
ning of a rapid rise through the academic ranks of Harvard Medical School. He became a Professor of Medicine
in 1971 and was named Higgins Professor of Medicine in 1982. Over the next 24 years he transformed the
Cardiac Unit into a world-renowned research facility staffed by 90 MDs and a PhD. Of those trained during this
time, I 0 are now Department Chairs or Institute Directors, 35 Division Directors and 48 are Full Professors. In
1988, Edgar left Harvard to become President of the Squibb Ln titute for Medical Research and sub equently
President of Bristol-Myers Squibb Pharmaceutical Research Institute. In 1991, he returned to academia as the
Elkan R. Blout Professor and Director, Division of Biological Sciences; Head, Cardiovascular Biology
Laboratory and Founder, Center for the Prevention of Cardiovascular Diseases at the Harvard School of Public
Health.
During his four decades in science Edgar Haber served as a personal mentor to more than I 00 graduate
students and post-doctoral fellows. In addition, he amassed an extensive list of accomplishments including the
University Medal of Excellence from Columbia University, the Research Achievement Award and Special
Citation for Distingui hed Service to Research from the American Heart Association, the Otsuka Award for
Outstanding Research from the International Society for Heart Research, the Franz Volhand Award from the
International Society of Hypertension, and the Arthur Corcoran Lectureship and CIBA Award from the Council
for High Blood Pressure Research, American Heart Association. He also served as a member of the Albert
Lasker Medical Research Awards Jury and was a member of the Institute of Medicine of the National Academy
of Sciences and fellow of the American Academy of Arts and Sciences. From 1984-1988, Edgar Haber served
as Editor-in-Chief of Hypertension.
In addition to some 70 papers on the renin-angiotensin system, Edgar Haber's more than 550 papers
detailed major contributions to many other areas including cardiology, basic immunology and molecular biolo
gy. Perhaps few know that one of his major contributions to cardiology, made in collaboration with his wife
Carol, was the development of an ECG monitoring device, an achievement for which he was awarded a patent
and which was the forerunner of coronary care units.
On a personal note Edgar Haber served as a role model for generations of young investigators. Much
admired and respected by both students and colleagues, he was often perceived initially as being somewhat
reserved, if not aloof. To those who came to know him better, however, he clearly became much beloved if not
appearing omewhat larger than life, and his vitality and enthusiasm were no more apparent than when he lec
tured and taught.
Edgar Haber died from multiple myeloma on October 13, 1997. He is succeeded by his companion and
wife of 38 years, Carol Avery Haber, RN, and his three children Ju tin, Graham and Eben.
Robert M. Graham
Foreword
Drugs, Enzymes and Receptors of the Renin-Angiotensin System: Celebrating a Cen111ry of Discovery repre
sents the first of several volumes comprising The Victor Chang Molecular Cardiology Series.
This particular volume, edited by Drs Ahsan Husain and Robert Graham from the Victor Chang Cardiac
Research Institute, represents a timely and comprehensive review of the renin-angiotensin system (RAS). The
editors have brought together luminaries from both the basic and clinical sciences to share their views on the
current dogma, controversies and future perspectives. It is important to recognize that the combined expertise of
the editors, ranging from clinical medicine to physiology to biochemistry to molecular biology. is a paradigm
renected in the composition of the current book.
The RAS wa once thought to be the weaker sister of other imp rtant neurohormonal regulatory mecha
nisms, particularly the sympatho-adrenal axis. However, over the past quarter century the RAS has been
demonstrated to be at least an equal partner in regulating a variety of physiological and pathological mecha
ni ms, particularly cardiovascular and renal function under normal physiological conditions and in the patho
genesis of hypertension and heart failure.
This volume is dedicated to the late Edgar Haber, MD, who was one of Dr Graham's mentors, as well as
one of mine during our tenure at Harvard Medical School. Dr Haber provided many seminal contributions to
the understanding of the RAS. It is interesting that one of his most widely quoted arbeits 'Application of a
radioimmunossay for angiotensin I to the physiologic measurements of pia rna renin activity in normal human
ubjects, E. Haber et a/., J Clin Endocrino/ Me tab 1969;29: 1349-1355' was not considered by !tim his most
imp rtant contribution. However, since that work permitted so many others to study the RAS, it did indeed
have extraordinary significance. It was also irksome to Dr Haber to see his technique quoted almost universally
as a modification of the Haber assay, if another author made even the most inconsequential change.
The RAS first gained prominence in cardiovascular physiology and pathology as a unique cause of hyper
tension. However, it was the later findings of its role in the pathogenesis of heart failure and also in myocardial
remodeling following myocardial infarction that made this system and its antagonism by ACE inhibition so
very important to clinical medicine, in the treatment of patients with congestive heart failure and myocardial
infarction.
As ably documented in this book, the understanding of the molecular basis for angiotensin regulation has
broad significance, allied to, but potentially of even greater importance than in its role in hypertension and heart
failure. This refers to the impact of these molecular signaling studies in unraveling the mysteries of cell growth
and of the cell cycle, which, although fundamental to this system's action in inducing hypertrophy and remod
eling, is also of a universal nature such that many of the same signaling pathways are shared by other regulatory
systems.
In summary, this important and timely book is the most comprehensive text on this subject available to
date. The broad scope of this volume makes it required reading for clinicians, physiologists and molecular biol
ogists, who are seeking the current frontiers of the RAS in basic science and clinical medicine.
Stephen F. Vatner, M.D.
Director, Cardiovascular and Pulmonary Research In titute
Allegheny University Health Science Center
Pittsburgh
and
Editor-in-Chief
Circulation Research
Table of Contents
Foreword vii
Preface xi
Contributors xiii
list of Abbreviations xvii
Part I Physiology of Angiotensin II
Chapter 1 The Renin-Angiotensin System and Cardiovascular Homeostasis 3
M.C. Chappell, E.A. Tallant, D./. Diz and C.M. Ferrario
I a Commentary 23
E.K. Jackson
Chapter 2 Angiotensin ll Receptors in Central Nervous System Phy iology 27
M.l. Phillips
2a Commentary 45
D./. Diz
Chapter 3 Current Opinions on the Involvement of Angiotensin ll in Hydromineral Balance 53
P.J. Mulrow
3a Commentary 63
J.J. Kelly and J.A. Wlritwortlr
Chapter 4 Angioten in ll Effects on Reproductive Biology: Physiology or Pharmacological Curiosity? 67
E.R. Lumbers
4a Commentary
E.M. Symonds
Chapter 5 Physiological Insights Derived from Mapping the Distributions of Angiotensin Receptors 93
A.M. Allen, J. Zlwo, C. Marie, S. Y. Cftai and F.A. 0. Mendelsohn
5a Commentary 109
J.M. Saavedra and 0. Johren
Part II Molecular Basis for Angiotensin II Receptor Structure, Function and Regulation 115
hapter 6 Conformational Theories on Receptor Activation from Studies of the AT Receptor 117
1
S.S. Kamik
6a Commentary 131
B.K. Kobilka
Chapter 7 Control of Angiotensin II Action Through Receptor Regulation 137
W.G. Thomas
7a Commentary 153
K.M. Baker
Part Ill Elucidation of Pathophysiological Mechanisms Through ACE Inhibition, 157
AT1 Receptor Antagonism and Gene Knockouts
Chapter 8 Clinical Applications and Limitations in the use of AT -Receptor Antagonists 159
1
B. Waeber and H.R. Brwmer
8a Commentary 171
G. Macdonald
