Pharmacological Control of Calcium and Potassium Homeostasis: Biological, Therapeutical, and Clinical Aspects

279 Pages·1995·15.58 MB·English

by  Karen S. De Jongh

PHARMACOLOGICAL CONTROL OF CALCIUM
AND POTASSIUM HOMEOSTASIS
BIOLOGICAL, THERAPEUTICAL, AND CLINICAL ASPECTS
Medical Science Symposia Series
Volume 9
The titles published in this series are listed at the end of this volume.
Pharmacological Control of
Calcium and Potassium
Homeostasis
Biological, Therapeutical, and Clinical Aspects
Edited by
T. Godfraind
Laboratory of Pharmacology, Catholic University ofLouvain, Brussels, Belgium
G. Mancia
Center of Physiology, Hypertension Clinic, University of Milan, Milan, Italy
M. P. Abbracchio
Institute of Pharmacological Sciences, University of Milan, Milan, Italy
L. Aguilar-Bryan
Baylor College of Medicine, Houston, Texas, U.S.A.
and
S. Govoni
Institute of Pharmacology, University ofPavia, Pavia, Italy
SPRINGER SCIENCE+BUSINESS MEDIA, B.V.
Fondazione Giovanni Lorenzini, Milan, Italy
Giovanni Lorenzini Medical Foundation, Houston, U.S.A.
Library of Congress Cataloging-in-Publication Data
Pharmacological control of calcium and potassium homeostasis ;
biological, therapeutical, and clinical aspects / edited by T.
Godfra ind ... let a 1.].
p. cm. — (Medical science sy-oosla series ; v. 9)
"Presented at the 6th International Symposium on Pharmacological
Control of Calcium and Potassiura Homeostasis: Biological,
Therapeutical, and Clinical Aspects. 1n Florence (Italy) on October
4-6, 1994"— Pref.
Includes Index.
ISBN 978-94-010-4056-3 ISBN 978-94-011-0117-2 (eBook)
DOI 10.1007/978-94-011-0117-2
1. Calcium—Antagonists—Congresses. " 2Caicium--Metabo 1ism-
-Effect of drugs on—Congresses. 3. Potassium—Metabolism—Effect
of drugs on--Congresses. 4. Potassium—Agonists—Congresses.
5. Cardiovascular system—Diseases—Chemotherapy—Congresses.
6. Calcium—Channels—Congresses. 7. Potassium—Channels-
-Congresses. I. Godfraind, T. (Theophile) II. International
Symposium on Pharmacological Control of Calcium and Potassium
Homeostasis: Biological, Therapeutical, and Clinical Aspects (6th :
1994 : Florence, Italy) III. Series.
[DNLM: 1. Cardiovascular System—metabolism—congresses.
2. Cardiovascular Diseases—drug therapy—congresses. 3. Calcium-
-physlolagy—congresses. 4. Calclu»—antagonists & mhtbitors-
-congresses. 5. Potassium—metabolism—congresses. 6. Potassium
Channels—physiology—congresses. 7. Homeostasis—congresses. W1
ME46R0 v.9 1995 / WG 102 P536 19951
RC684.C34P46 1995
616. 1*06--dc20
DNLM/DLC
for Library of Congress 95-19895
ISBN 978-94-010-4056-3
Printed on acid-free paper
All Rights Reserved
© 1995 Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 1995
Softcover reprint of the hardcover 1st edition 1995
No part of the material protected by this copyright notice may be reproduced or
utilized in any form or by any means, electronic or mechanical,
including photocopying, recording or by any information storage and
retrieval system, without written permission from the copyright owner.
Contents
Preface ix
List of Contributors xi
I. MOLECULAR BIOLOGY AND PHARMACOLOGY OF CELL CALCIUM
AND POTASSIUM
1. cAMP-Dependent Phosphorylation of the L-Type Calcium Channel: Biochemical
Characterization and Physiological Regulation
K.S. De Jongh, E.!. Rotman, A. Sculptoreanu, BJ. Murphy, T. Scheuer, and W.A.
Catterall
2. Integration of Plasmalemmal and Sarcoplasmic Reticular Ca2+ Transport in Smooth
Muscle
Q. Chen, D. Haynes, I. Laher, and C. van Breemen 9
3. Oligomeric and Subunit Structures of Voltage-Gated Potassium Channels
O. Pongs, S.H. Heinemann, J. Rettig, S. Sewing, and O. Dolly 17
4. Modulation of K+ Channels: Pharmacological and Therapeutic Aspects
U. Quast, J.-M. Guillon, and I. Cavero 23
II. CALCIUM AND POTASSIUM REGULATION IN CARDIOVASCULAR
PATHOPHYSIOLOGY
5. Calcium Channels and Regulation of Vascular Tone in Hypertension
T. Godfraind and N. Morel 43
6. Calcium and Calcium Channel Regulation in Cardiac Function
R. Ferrari, M. Benigno, and A. Boraso 57
7. Adenosine and ATP-Regulated Ion Currents in Cardiomyocytes
L. Belardinelli and Y. Song 65
8. Endothelium-Dependent Hyperpolarization and Potassium Channels
M. Nakashima, M. F616tou, and P.M. Vanhoutte 73
9. Potassium Channels in the Regulation of Vascular Smooth Muscle Tone
G. Edwards and A.H. Weston 85
10. The Importance of Potassium for Vascular Protection in a Hypertensive Setting
L. Tobian 95
vi CONTENTS
III. CALCIUM ANTAGONISTS IN CARDIOVASCULAR THERAPY AND
ORGAN PROTECTION
11. The Antiatherosclerotic Effect of Calcium Antagonists
M.R. Soma, F. Bemini, A. Corsini, R. Fumagalli, and R. Paoletti 103
12. Clinical Pharmacology of Calcium Antagonists as Antihypertensives
P.A. van Zwieten III
13. Cardioprotection by Calcium Antagonists: Myocardial Ischemia and Secondary
Prevention
J. Fischer Hansen and L. Tingsted Andersen 119
IV. CALCIUM AND POTASSIUM MANIPULATION IN THE PREVENTION
AND REVERSAL OF STRUCTURAL CHANGES IN HYPERTENSION
14. Actions of Insulin and IGF-I on Vascular Smooth Muscle Cation and Glucose
Metabolism
J.R. Sowers 129
15. The Prevention of Vascular Injury in a Genetic Model of Hypertension
M. Volpe, M. Romano, R. Russo, B. Gigante, A.F. Mele, and S. Rubattu 139
16. Calcium Antagonists and Renal Protection: Current Status and Future Perspectives
M. Epstein 147
17. The Reversal of Hypertension-Induced Cardiac Damage by Antihypertensive Therapy
with Calcium Antagonists
B. Trimarco, L. Argenziano, G.L. Iovino, D. Sarno, and C. Morisco 159
V. BEYOND BLOOD PRESSURE REDUCTION: TISSUE PROTECTION BY
CALCIUM ANTAGONISM CAN BE ENHANCED BY ACE INIDBITORS
18. Rationale for Combined Therapy with Calcium Antagonists and ACE Inhibitors
R. Paoletti 167
19. Does the Combination of an ACE Inhibitor and a Calcium Antagonist Enhance
Cardioprotection?
M. Kirchengast, S. HergenrOder, and K. Munter 173
20. Hypertension in Diabetic Patients: How to Preserve Renal Function
L.M. Ruilope and R. Garcia-Robles 181
VI. MULTICENTER ISRADIPINE DIURETIC ATHEROSCLEROSIS STUDY
(MIDAS): RESULTS AND LESSONS LEARNED
21. Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): Rationale, Design,
and Description of Trial Patients
N.O. Borhani 189
CONTENTS vii
22. Metabolic Changes Associated with Isradipine and Hydrochlorothiazide in MIDAS:
Effects on Serum Cations and Uric Acid
J.R. Sowers 195
VII. CALCIUM AND POTASSIUM HOMEOSTASIS IN CEREBRAL ISCHEMIA
AND NEURODEGENERATIVE DISORDERS
23. Ionic Metabolism in Cerebral Ischemia
T. Kristim, K.-I. Katsura, and B.K. Siesjo 199
24. New Directions in Cerebral Ischemia: Sodium and Calcium Channel Modulators
M. Spedding, A. Lombet, C. Jean-Jean, P. Morain, and J. Lepagnol 209
25. Acute Ischemic Stroke Therapy
C. Fieschi, C. Cavalletti, D. Toni, G. Sette, M. Fiorelli, M.L. Sacchetti, E. Montinaro,
and C. Argentino 219
26. Potassium Channels and Internal Calcium Release: Relevance for Memory Storage
and Alzheimer's Disease
R. Etcheberrigaray and D.L. Alkon 227
VIII. MOLECULAR AND CLINICAL ASPECTS OF CURRENT AND NOVEL
USES OF POTASSIUM CHANNEL OPENERS
27. Molecular Physiology of a Novel cGMP-Gated Potassium Channel
G.V. Desir 237
28. ATP-Dependent K+ Channels in Vascular Smooth Muscle
V.A.W. Kreye, I. Anghelescu, S. Kajioka, C. Karle, and D. Pfriinder 247
29. Potassium Channel Openers in Therapy: Current Use and Perspective in Hypertension
G. Leonetti 255
30. Potassium Channel Openers in Therapy, Current Uses, and Perspectives: Cardiac
Ischemia and Angina
M. Marzilli and G. Sambuceti 263
Index 271
PREFACE
As the number of drugs acting on calcium and potassium channels grows, there is a need for
a continuous reappraisal of the cellular machinery controlling them. The present volume
provides an update on the basic knowledge, the molecular targets of the two channels, and
the importance the drugs that bind them have as pharmacological tools and therapeutic
agents. This work was presented at the 6th International Symposium on
PHARMACOLOGICAL CONTROL OF CALCIUM AND POTASSIUM HOMEOSTASIS:
BIOLOGICAL, THERAPEUTICAL, AND CLINICAL ASPECTS, in Florence (Italy) on October
4-6, 1994. Because of the recent advances in the field, discussions on potassium channels
were included for the first time.
At least six classes of voltage-dependent calcium channels have been defined based
on their physiological and pharmacological properties. Among them, L-type channels,
mediating long lasting currents, are better characterized. Calcium homeostasis within the cell
is not only regulated by calcium channels; intracellular calcium stores, in particular a pool
contained in the lumen of specialized areas of the endoplasmic reticulum, are rapidly
exchanged with the cytoplasm and playa key role in the control of calcium homeostasis.
This area, however, has not yet been exploited from a therapeutic point of view.
Potassium channels are present in virtually every cell type, excitable and
nonexcitable, and are distinguished by structural, biophysical, and pharmacological criteria.
Different classes including voltage-gated, ligand-gated, AP-sensitive, and G-protein coupled
among others, have been defined by their primary regulatory and gating mechanisms.
The family of voltage-gated potassium channels. including delayed rectifiers (IK)'
inward rectifiers (I~, and A channels (lJ, is important to cell excitability and gating
depends on transmembrane potential changes. The molecular basis for inward rectification
in K+ channels has been clarified by the development of chimeras and by using point
mutations in the genes encoding two new potassium channels. Also evidence for a novel
cyclic nucleotide regulated potassium channel was presented at this meeting.
By blocking L-type calcium channels, calcium antagonists act as selective inhibitors
of calcium influx in depolarized smooth muscle. This property is the cornerstone of
therapeutic effectiveness in treating cardiovascular disease. A combination therapy of ACE
inhibitors and calcium antagonists may become more important in the treatment of
hypertensive patients. It has also been stressed that few compounds possess additional,
potentially useful properties, such as antiatherogenic activity, at least in animal and cellular
models.
In contrast, in hypertension, K+ channel openers (KCOs) present some
disadvantages; they are potent vasodilators and therefore effective compounds in lowering
blood pressure. However, they have side effects such as headache, compensatory
ix
x PREFACE
tachycardia, and salt and water retention due to excessive vasodilation. Moreover, it was
reported that they can increase plasma renin activity by direct action on juxtaglomerular
cells.
As far as cardiac ischemia is concerned, in experimental settings calcium antagonists
preserve energy phosphates and the contractile function of heart muscle cells reducing
infarct size. On the other hand, as discussed in Florence, the clinical studies on the use of
calcium antagonists for secondary prevention after acute myocardial infarction, have shown
that only verapamil and diltiazem have a negative chronotropic effect. Nifedipine may induce
hypotension, reduction of myocardium perfusion pressure, and reflex tachycardia due to its
pronounced vasodilator effect. Phenylalkylamines and benzothiazepines act through a
combination of effects, including reduction of afterload, heart rate, and contractility.
In the case of K+ channels, the observations reported at the meeting suggest that
activation of ATP-sensitive potassium channels (KATP)' could improve myocardial response
to ischemia by simultaneously increasing blood flow and decreasing myocardial metabolic
demand. However, KCOs of different chemical structure are profibrillatory and
proarrhythmic. Development of new antiarrhythmic drugs with greater cardiac selectivity
is needed to counterbalance the risk of arrhythmia as we improve perfusion.
In cerebral ischemia, breakdown of ion homeostasis follows brain energy failure
leading to cellular release ofK+ and uptake ofNa+, n, and Ca2+ ions. Clinically, the relevant
question is how long can brain tissue resist hypoperfusion. The therapeutic window in man
is thought to be very similar to that of primates, around 6-8 hours; therefore, restoring flow
as soon as possible, to protect neurons from irreversible damage is the most important goal.
In terms of the development of new anti-ischemic agents, it has been proposed during the
meeting, that substances presenting a less specific action than the known channel blockers
and more allosteric interaction with other channels may be potentially useful in stroke. Also,
the development of new drugs that preferentially interact with the ischemic areas of the brain
without changing unaffected neurons are needed.
This monograph also includes new areas in which calcium antagonists show
beneficial effects, such as improving renal blood flow and graft rejection.
The organizers gratefully acknowledge the advice and the aid provided by the staff
of the Fondazione Giovanni Lorenzini, which allowed the smooth functioning of the
meeting. We are also grateful for the financial support by the sponsors making the
conference possible.
The Editors
List of Contributors
Daniel L. Alkon F. Bernini
Laboratory ofA daptive Systems Institute of Pharmacology and
NINDS -Building 36, Room B-205 Pharmacognosy
National Institutes of Health University of Parma
Bethesda, Maryland 20892 Via delle Scienze
USA 43100 Parma
ITALY
Ion Angbelescu
2. Physiologisches Institut Antonella Boraso
Ruprechts-Karls-Un iversitiit Fondazione Clinica del Lavoro
1m Neuenheimer Feld 326 Centro di Fisiopatologia
69120 Heidelberg Cardiovascolare "S. Maugeri" , Gussago
GERMANY Brescia
ITALY
Corrado Argentino
Department of Neurosciences, I Chair of Nemat O. Borbani
Neurology Internal Medicine, Department of
University La Sapienza Community Health,
Viale dell Universitii 30 School of Medicine
00185 Rome University ofCalijornia, Davis
ITALY Davis, California
and
Luigi Argenziano School of Medicine
1a Clinica Medica University of Nevada
"FEDERICO II" University Reno, Nevada
80131 Naples USA
ITALY
William A. Catterall
Luiz Belardinelli Department of Pharmacology, SJ-30
Departments of Medicine and University of Washington
Pharmacology Seattle, Washington 98195
P.O. Box 100277 USA
University of Florida
Gainesville, Florida 32610-0277 Cristina Cavalletti
USA Department of Neurosciences, I Chair of
Neurology
Massimo Benigno University La Sapienza
Fondazione Clinica del Lavoro Viale dell Universitii 30
Centro di Fisiopatologia 00185 Rome
Cardiovascolare "S. Maugeri" , Gussago ITALY
Brescia
ITALY
xi