Cardiovascular Pharmacology: Heart and Circulation

339 Pages·2010·4.98 MB·English

by  Paul M. Vanhoutte (Eds.)

CARDIOVASCULAR

PHARMACOLOGY:

HEART AND CIRCULATION

Edited by
Paul M. Vanhoutte
Department of Pharmacology and Pharmacy
University of Hong Kong
Hong Kong, PR China
Serial Editor
S. J. Enna
Department of Molecular and Integrative Physiology
Department of Pharmacology, Toxicology and Therapeutics
University of Kansas Medical Center, Kansas City, Kansas, USA
ADVANCES IN
PHARMACOLOGY
VOLUME 59

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Contributors

Numbers in parentheses indicate the pages on which the authors’ contributions begin.
Takeshi Adachi (165) First Department of Internal Medicine, Division of
Cardiology, National Defense Medical College, Saitama, Japan
Sarfaraz Ahmad (197) Hypertension and Vascular Disease Research Center,
Wake Forest University School of Medicine, Winston Salem, North
Carolina, USA; Department of General Surgery, Wake Forest University
School of Medicine, Winston Salem, North Carolina, USA
Jean-Luc Balligand (135) Pole of Pharmacology and Therapeutics, Institute
of Experimental and Clinical Research, Université catholique de Louvain,
Brussels, Belgium
Chantal Dessy (135) Pole of Pharmacology and Therapeutics, Institute of
Experimental and Clinical Research, Université catholique de Louvain,
Brussels, Belgium
Ming-Qing Dong (93) Department of Medicine, Li Ka Shing Faculty
of Medicine, the University of Hong Kong, Hong Kong Special
Administration Region, China
Carlos M. Ferrario (197) Hypertension and Vascular Disease Research
Center, Wake Forest University School of Medicine, Winston Salem,
North Carolina, USA; Department of General Surgery, Wake Forest
University School of Medicine, Winston Salem, North Carolina, USA
Ingrid Fleming (235) Institute for Vascular Signalling, Centre for Molecular
Medicine, Johann Wolfgang Goethe University, Frankfurt am Main,
Germany
Erik W. Holy (259) Cardiovascular Research, Physiology Institute and
Centre for Integrative Human Physiology, University of Zurich, and
ix
x Contributors
Cardiology, Cardiovascular Centre, University Hospital Zurich, Zurich,
Switzerland
JaNae Joyner (197) Hypertension and Vascular Disease Research Center,
Wake Forest University School of Medicine, Winston Salem, North
Carolina, USA; Department of General Surgery, Wake Forest University
School of Medicine, Winston Salem, North Carolina, USA
Alexander Kushnir (1) Department of Physiology and Cellular Biophysics,
Clyde and Helen Wu Center for Molecular Cardiology, College of
Physicians and Surgeons of Columbia University, New York, NY, USA
Gui-Rong Li (93) Department of Medicine, Li Ka Shing Faculty of Medicine,
the University of Hong Kong, Hong Kong Special Administration Region,
China; Department of Physiology, Li Ka Shing Faculty of Medicine, the
University of Hong Kong, Hong Kong Special Administration Region,
China
Xinyan Li (31) Zensun Science and Technology Co. Ltd., Shanghai, China
Xifu Liu (31) Zensun Science and Technology Co. Ltd., Shanghai, China
Andrew R. Marks (1) Department of Physiology and Cellular Biophysics,
Clyde and Helen Wu Center for Molecular Cardiology, College of
Physicians and Surgeons of Columbia University, New York, NY, USA;
Department of Physiology and Cellular Biophysics, Russ Berrie Medical
Sciences Pavilion, New York, NY, USA
Voahanginirina Randriamboavonjy (235) Institute for Vascular Signalling,
Centre for Molecular Medicine, Johann Wolfgang Goethe University,
Frankfurt am Main, Germany
Felix C. Tanner (259) Cardiovascular Research, Physiology Institute and
Centre for Integrative Human Physiology, University of Zurich, and
Cardiology, Cardiovascular Centre, University Hospital Zurich, Zurich,
Switzerland
Catherine Thollon (53) Cardiovascular Department, Institut de Recherches
Servier, Suresnes, France
Jasmina Varagic (197) Hypertension and Vascular Disease Research Center,
Wake Forest University School of Medicine, Winston Salem, North
Carolina, USA; Department of General Surgery, Wake Forest University
School of Medicine, Winston Salem, North Carolina, USA
Jean-Paul Vilaine (53) Cardiovascular Department, Institut de Recherches
Servier, Suresnes, France
Yabei Xu (31) Zensun Science and Technology Co. Ltd., Shanghai, China
Mingdong Zhou (31) Zensun Science and Technology Co. Ltd., Shanghai,
China
Foreword

The twentieth century has witnessed immense progress in preventing
and treating cardiovascular disease. This has been fostered by improvements
in lifestyle (exercise, diet) and the introduction of new therapeutics (anti­
hypertensive and lipid-lowering drugs). Nonetheless, cardiovascular disease
remains a major cause of death and disability in developed countries and,
increasingly so, in the developing world. This is driven in part by demo­
graphics and the increase in longevity, and the obesity-metabolic syndrome­
diabetes-atherosclerosis continuum that is reaching pandemic proportions.
The hopes to address these issues using gene therapy have faded over the
past decade. Stem cell therapy, while scientifically exciting, is still in its
infancy, so will be, in the near-term, a treatment for the privileged. Given
its cost, this approach is likely to be inaccessible to most patients with
cardiovascular disease, in particular those in the emerging countries.
Accordingly, the discovery of novel targets involved in cardiovascular dis­
ease, and the design of small molecules or biologics that interact with these
sites, still holds the greatest promise for treating large numbers of indivi­
duals afflicted with these conditions.
Presented in this first volume of Cardiovascular Pharmacology are some
of the most promising possibilities in that regard. Included are chapters on
the treatment of heart failure. While current medications prolong life, they
do little to improve its quality. As described in this volume, attempts to
address this issue are centered on improving cardiac contractility. Other
contributions focus on potassium channels and the manner in which their
pharmacological manipulation can control heart rhythm and function. This
is an area of compelling need, particularly in the wake of the CAST study.
Other chapters describe new findings on the catecholamines, the major
drivers of cardiovascular function and crucial factors in regulating the
actions of calcium in vascular smooth muscle.
xi
xii Foreword
The emerging importance of angiotensin-converting enzyme 2 in coun­
terbalancing the contributions of the renin-angiotensin system in the devel­
opment and maintenance of hypertension and vascular disease is described
in this work.
Contributors also consider new concepts relating to the impact of
diabetes on platelet function. Presented in the volume is a summary of the
evidence that tissue factor is crucial, not only for initiating the coagulation
cascade but also for laying the groundwork for the atherosclerotic process.
I thank the contributors, all of whom are internationally recognized
experts in the field, for their efforts in making this volume possible. Together
with them, I sincerely hope these reports will be a source of inspiration,
instruction, and ideas for graduate students, cardiovascular scientists, and
physicians interested in the function and dysfunction of the heart and the
blood vessel wall. Attainment of these goals will not only be personally
satisfying for us but will hopefully provide a stimulus for further advances in
this important area.
Paul Vanhoutte, M.D., Ph.D.

Department of Pharmacology and Pharmacy,

Li Ka Shing Faculty of Medicine,

The University of Hong Kong,

Hong Kong, China

Alexander Kushnir� and Andrew R. Marks�,†
�Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for
Molecular Cardiology, College of Physicians and Surgeons of Columbia University, New
York, NY, USA
†Department of Physiology and Cellular Biophysics, Russ Berrie Medical Sciences Pavilion,
New York, NY, USA
The Ryanodine Receptor in Cardiac
Physiology and Disease
Abstract
According to the American Heart Association it is estimated that the
United States will spend close to $39 billion in 2010 to treat over five million
Americans suffering from heart failure. Patients with heart failure suffer
from dyspnea and decreased exercised tolerance and are at increased risk
for fatal ventricular arrhythmias. Food and Drug Administration -approved
pharmacologic therapies for heart failure include diuretics, inhibitors of the
renin–angiotensin system, and b-adrenergic receptor antagonists. Over the
past 20 years advances in the field of ryanodine receptor (RyR2)/calcium
release channel research have greatly advanced our understanding of cardiac
physiology and the pathogenesis of heart failure and arrhythmias. Here we
Advances in Pharmacology, Volume 59 1054-3589/10 $35.00
© 2010 Elsevier Inc. All rights reserved. 10.1016/S1054-3589(10)59001-X
2 Kushnir and Marks
review the key observations, controversies, and discoveries that have led to
the development of novel compounds targeting the RyR2/calcium release
channel for treating heart failure and for preventing lethal arrhythmias.
I. Introduction
In 1883 Sydney Ringer discovered that calcium (Ca2+) is required for
cardiac contraction (Ringer, 1883). Twenty four years later Locke and
Rosenheim (1907) observed that Ca2+ is responsible for linking myocardial
excitation with contraction. Following these seminal discoveries important
advances have been made toward understanding the molecular determinants
of cardiac Ca2+ regulation and its role in determining cardiac function.
In cardiomyocytes Ca2+ is stored in an intracellular vesicular network
called the sarcoplasmic reticulum (SR) (Hasselbach & Makinose, 1961,
1963; Martonosi & Feretos, 1964) and is available for immediate release
into the cytosol, where it binds to Troponin C and enables actin–myosin
binding and sliding of the myofilaments that results in sarcomere shortening
and myocardial contraction (Ebashi & Lipmann, 1962; Otsuka et al., 1964;
Weber, 1959). The key roles that cyclical SR Ca2+ release and reuptake play
in cardiac contraction underscore the importance of exquisite regulation of
the proteins involved in these processes.
Cardiac contraction can be divided into electrical (excitation) and con­
tractile phases. The electrical phase begins with depolarization of the sinoa­
trial node (SAN), situated near the junction of the superior vena cava and
the right atrium, which causes a wave of depolarization to spread via the
conduction system through the atria and ventricles. On the cellular level
current flows between a depolarized cardiomyocyte and its resting neighbor
through specialized low-resistance channels called gap junctions
(Weidmann, 1952) causing depolarization of the membrane potential of
the resting cell (Rohr, 2004). As the membrane potential of the resting cell
increases from –90 mV (Draper & Weidmann, 1951) to –70 mV voltage-
gated Na+ channels (SCN5A) begin to open allowing an influx of sodium
ions into the myocyte, further depolarizing the cell to ~+10 mV (Gibbons &
Zygmunt, 1992). As the membrane potential rises above –40 mV L-type
calcium channels (Cav1.2) on the sarcolemma begin opening leading to an
influx of Ca2+ into the myocyte (Bean, 1985; Gibbons & Zygmunt, 1992).
At ~0 mV voltage-gated K+ channels (e.g., KCNH2 and KCNQ1) open
allowing K+ to efflux from the cell (Oudit et al., 2004). The influx of Na+
and Ca2+ balanced by the efflux of K+ causes the membrane potential to
plateau at ~0 mV. Na+ channels and L-type calcium channels inactivate as a
function of time, membrane potential, and [Ca2+] (Campbell et al., 1988)
which reduces inward current leaving the unopposed efflux of potassium to
repolarize the membrane to resting potential.