Table Of ContentIonic Transport in
Hypertension:
New Perspectives
Edited by
Antonio Coca, M.D., Ph.D.
Hypertension Unit
Department of General Internal Medicine
Hospital Clinic
University of Barcelona
Barcelona, Spain
Ricardo P. Garay, M.D., Ph.D.
INSERM Unit 2
Faculte de Medicine
Creteil, France
Boca Raton London New York
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PREFACE
There is increasing evidence that primary hypertension, both in animal models
and humans, emerges as a result of a particular confluence of genetic and envi-
ronmental factors. Among the latter, excess sodium intake, and low potassium or
calcium intake have been proposed as pathogenetic factors in primary hypertension.
Such ion-hypertension hypotheses assume that all subjects are similarly susceptible
to diet. However, for a significant fraction of hypertensive patients, salt restriction
or potassium- or calcium-rich diets do not lower blood pressure. Though the en-
thusiasts of the ion-hypertension hypothesis suggest that even these latter are subjects
in whom high blood pressure was irreversibly induced by diet factors, what is
undeniable is the existence of individual variations in ion sensitivity in relation to
blood pressure.
The structural complexity of the vessel wall and other relevant organs for
hypertension and the difficulty in obtaining blood vessel samples from patients has
determined the use of circulating blood cells as a cellular model for the clinical
investigation of membrane ion transport in hypertension. Therefore, red blood cells
from essential hypertensive patients have been extensively investigated during the
last fifteen years. The emerging picture has been extremely complex and frequently
controversial. However, all authors seem to agree on at least two points: (1) red
cell ion transport is abnormal in essential hypertension and (2) different ion transport
abnormalities can be found in different subsets of essential hypertensive patients
and strains of spontaneously hypertensive rats.
It took more than twenty years for Laragh and his colleagues to persuade the
scientific community that measurement of plasma renin activity can distinguish two
forms of essential hypertension i.e., low and normal (or high) renin hypertension.
If instead of looking at the plasma we investigate the red cell membrane, we may
detect at least seventeen ion transport abnormalities. Each of them should be in-
tegrated with other biochemical and clinical parameters in order to provide a clear,
comprehensive picture of each form of essential hypertension, and they may indeed
prove useful for identifying salt-sensitivity, or calcium-sensitivity, in subjects ge-
netically predisposed to the development of hypertension. More importantly, easy
and precise red cell tests should be introduced in the near future for the diagnosis
and specific treatment of the different forms of essential hypertension.
Beyond our basic aim to present a "state-of-the-art" discussion of membrane
transport in hypertension, the ambition of the present volume is to anticipate and
set up the scientific background of what could be clear technological progress in
the diagnosis and treatment of essential hypertension. We sincerely hope to see the
accomplishment of such work in the coming years.
Antonio Coca
Barcelona, Spain
Ricardo P. Garay
Paris, France
THE EDITORS
Antonio Coca M.D., Ph.D., is Chief, Hypertension Unit, Department of
General Internal Medicine, Hospital Clinico, School of Medicine, University of
Barcelona, Spain.
Dr. Coca obtained his M.D. in 1974 from the School of Medicine at the
University of Barcelona, Spain. In 1983 he obtained his Ph.D. (summa cum laude)
from the University of Barcelona. He served as an Associate Professor at University
of Barcelona from 1975 to 1986, as a Research Associate Professor at the Laboratory
of Cardiovascular Physiology and Pharmacology (INSERM, CNRS, Hospital Necker,
Paris, France) in 1986, and as a Professor of Medicine at the School of Medicine,
University of Barcelona from 1986. It was in 1992 that he assumed his present
position as Chief of the Hypertension Unit at the Hospital Clinico, University of
Barcelona, Spain.
Dr. Coca is member of the International Society of Hypertension, American
Society of Hypertension, European Society of Hypertension, Research Society on
Alcoholism, and the International Society of Internal Medicine. He has served on
the Spanish Society of Hypertension since 1992 and as President of the Hypertension
Research Foundation of the Catalan Community Hospitals since 1992.
Dr. Coca has been the recipient of many research grants from the Spanish
National Research Institutes (Fondo de Investigación Sanitaria, Comisión Asesora
de Investigación Científica y Técnica) and private industry from 1982 to the present.
He has published more than 100 papers and has presented over 40 invited lectures
at national meetings and universities. His current research interests include the
cellular pathogenesis of salt-induced hypertension and alcohol-induced hypertension
and the molecular pathogenesis of left ventricular hypertrophy in essential hyper-
tension.
Ricardo P. Garay, M.D., Ph.D., is Director of Research, INSERM Unit 2,
School of Medicine of Créteil, France.
R. P. Garay was born in San Fernando, Argentina in 1943. He graduated with
an M.D. degree from the University of Buenos Aires School of Medicine in 1966.
In 1971 he graduated from the University of Buenos Aires School of Sciences with
a Ph.D. in Chemistry. He then worked with Professor P. J. Garrahan in the De-
partment of Biochemistry, School of Pharmacy at this university and studied the
kinetics of the sodium pump in human red blood cells.
From 1974 through 1976, R. P. Garay worked with Professor R. Lefever in
Belgium at the Service de Chimie Physique II (Faculte de Sciences, Université
Libre de Bruxelles) directed by Professor I. Pngogine, 1977 Nobel Prize winner
in Chemistry. There he studied thermodynamics and kinetics of biochemical phe-
nomenon, including membrane transport reactions.
In 1976, R. P. Garay was nominated Attaché de Recherche at CNRS (French
National Council of Research) to investigate membrane sodium transport in primary
hypertension at INSERM Unit 7/CNRS URA 318, Hôpital Necker, Paris. In 1978,
he became Charge de Recherche and in 1982, Director of Research.
R. P. Garay published several scientific articles from 1979 to the present on
membrane ion transport in erythrocytes from essential hypertensive patients. He
has also published over 240 articles in various international scientific journals. He
is a member of four scientific societies and the organizer of eight international
scientific meetings. R. P. Garay has also been the editor of several books and special
issues of scientific journals.
CONTRIBUTORS
Arantxa Arrázola, Sc.D. Jean R. Cusson, M.D., Ph.D., FRCPC
Senior Researcher Senior Researcher
Laboratory of Cellular Transport and Centre de Recherche
Hypertension Hôtel-Dieu de Montreal
Department of Internal Medicine Montreal, Canada
Center for Biomedical Research and Associate Researcher
School of Medicine Department of Pharmacology
University of Navarra Université de Montreal
Pamplona, Navarra, Spain Montreal, Canada
Alejandro De la Sierra, M.D.
Abraham Aviv, M.D.
Attending Physician
Professor and Director
Hypertension Unit
Hypertension Research Center
Department of General Internal Medicine
University of Medicine and Dentistry of
Hospital Clinic
New Jersey
School of Medicine
Newark, New Jersey
University of Barcelona
Barcelona, Spain
Giuseppe Bianchi, M.D., Ph.D.
Professor of Nephrology Javier Diez, M.D., Ph.D.
Department of Nephrology, Dialysis, and Chief
Hypertension Laboratory of Internal Medicine
S. Raffaele Hospital Professor of Internal Medicine
Milan, Italy Department of Internal Medicine
Center for Biomedical Research
Sylvie Cavalier, M.Sc. School of Medicine
INSERM Unit 2 University of Navarra
Faculté de Medicine Pamplona, Navarra, Spain
Créteil, France and Professor of Medicine
Department of Medicine
University of Zaragoza
Josep Closas, M.D.
Zaragoza, Spain
Attending Physician
Department of Internal Medicine
Patrizia Ferrari, B.S., Ph.D.
Hospital San Lorenzo
Head of Cellular Pharmacology
Viladecans, Spain
Department of Cellular Pharmacology and
Biology
Antonio Coca, M.D., Ph.D. Prassis Sigmatau Research Institute
Chief Milano, Italy
Hypertension Unit
Department of General Internal Medicine Ricardo P. Garay, M.D., Ph.D.
Hospital Clinic Director of Research
School of Medicine INSERM Unit 2
University of Barcelona Faculté de Medicine
Barcelona, Spain Créteil, France
Kenneth A. Gruber, B.A., Ph.D. Andrea Semplicini, M.D.
Professor of Physiology Associate Professor of Therapeutics
Department of Physiology and Biophysics Institute of Clinical Medicine
University of Puerto Rico University of Padua
San Juan, Puerto Rico Padua, Italy
Patrick A. Hannaert, Ph.D.
Nathalie Senn
INSERM Unit 2
INSERM Unit 2
Faculté de Medicine
Faculté de Medicine
Créteil, France
Créteil, France
Kent Hermsmeyer, Ph.D.
Professor Javier Sobrino, M.D.
Oregon Regional Primate Research Center Attending Physician
Beaverton, Oregon Department of Internal Medicine
Hospital del Espiritu Santo
Steven C. Hunt, Ph.D. Santa Colona de Gramanet, Spain
Professor
Cardiovascular Genetics, Department of
Internal Medicine Alvaro Urbano-Márquez, M.D., Ph.D.
University of Utah School of Medicine Professor of Medicine
Salt Lake City, Utah Department of Internal Medicine
School of Medicine
Pierre Larochelle, M.D., Ph.D., FRCPC University of Barcelona
Director of Clinical Research Barcelona, Spain
Centre de Recherche and Chairman
Hôtel-Dieu de Montreal Hospital Clinic
and Professor Barcelona, Spain
Department of Pharmacology
University of Montreal
Roger R. Williams, M.D.
Montreal, Canada
Professor and Director
Cardiovascular Genetics, Department of
Jean-Pierre Ollivier
Internal Medicine
INSERM Unit 2
University of Utah School of Medicine
Faculté de Medicine
Salt Lake City, Utah
Créteil, France
Nancy J. Rusch, Ph.D. Lily L. Wu, Ph.D.
Associate Professor Associate Professor
Departments of Physiology and Cardiovascular Genetics, Department of
Cardiothoracic Surgery Pathology
Medical College of Wisconsin University of Utah School of Medicine
Milwaukee, Wisconsin Salt Lake City, Utah
TABLE OF CONTENTS
Chapter 1
The Erythrocyte as a Cellular Model for the Clinical Investigation of
Essential Hypertensive Patients 1
Antonio Coca and Ricardo P. Garay
Chapter 2
Genetic Abnormalities of the Na-K-Cl Cotransport in Experimental
and Primary Hypertension 25
Patrizia Ferrari and Giuseppe Bianchi
Chapter 3
The [Na+,K+,C1~] Cotransport System: Relevance in Essential
Hypertension 45
Ricardo P. Garay, Sylvie Cavalier, and Patrick A. Hannaert
Chapter 4
Kinetic Abnormalities of the Na+,K+ Pump in Essential
Hypertension 57
Javier Diez and Arantxa Arrázola
Chapter 5
The Li+/Na+ Countertransport in Hypertension 89
Andrea Semplicini
Chapter 6
The Na+/H+ Antiport: Its Role in Cellular Metabolism and in the
Pathophysiology of Essential Hypertension 119
Abraham Aviv
Chapter 7
The C1"/HC0 " Anion Exchanger in Hypertension 133
3
Javier Diez and Arantxa Arrázola
Chapter 8
Endogeneous Digitalis-Like Factors: Past Progress and Future
Prospects 157
Kenneth A. Gruber
Chapter 9
Atrial Natriuretic Peptide, Sodium Transport Systems and Essential
Hypertension 183
Josep Ciosas, Jean R. Cusson, and Pierre Larochelle
