Calcium Entry Blockers in Cardiovascular and Cerebral Dysfunctions

312 Pages·1984·6.708 MB·English

by  A. G. Herman (auth.), Théophile Godfraind M.D., Arnold G. Herman M.D., Donald Wellens Dr. Sc. (eds.)

CALCIUM ENTRY BLOCKERS IN CARDIOVASCULAR AND CEREBRAL
DYSFUNCTIONS
DEVELOPMENTS IN
CARDIOVASCULAR MEDICINE
Lancee CT, ed: Echocardiology, 1979. ISBN 90-247-2209-8.
Baan J, Arntzenius AC, Yellin EL, eds: Cardiac dynamics. 1980. ISBN 90-247-2212-8.
Thalen HJT, Meere CC, eds: Fundamentals of cardiac pacing. 1970. ISBN 90-247-2245-4.
Kulbertus HE, Wellens H11, eds: Sudden death: 1980. ISBN 9O-247-2290-X.
Dreifus LS, Brest AN, eds: Clinical applications of cardiovascular drugs. 1980. ISBN 90-247-2295-0.
Spencer MP, Reid JM, eds: Cerebrovascular evaluation with Doppler ultrasound. 1981. ISBN 90-247-2348-1.
Zipes DP, Bailey JC, Elharrar V, eds: The slo-w inward current and cardiac arrhythmias. 1980. ISBN 90~247-2380-9.
Kesteloot H, Joossens JV, eds: Epidemiology of arterial blood pressure. 1980. ISBN 90-247-2386-8.
Wackers FJT, ed: Thallium-20l and technetium-99m-pyrophosphate myocardial imaging in the coronary care unit.
1980. ISBN 90-247-2396-5.
Maseri A, Marchesi C, Chierchia S, Trivella MG, eds: Coronary care units. 1981. ISBN 90-247-2456-2.
Morganroth J, Moore EN, Dreifus LS, Michelson EL, eds: The evaluation of new antiarrhythmic drugs. 1981.
ISBN 90-247-2474-0.
Alboni P: Intraventricular co.nduction disturbances. 1981. ISBN 90-247-2484-X.
Rijsterborgh H, ed: Echocardiology. 1981. ISBN 90-247-2491-0.
Wagner GS, ed: Myocardial infarction: Measurement and intervention. 1982. ISBN 90-247-2513-5.
Meltzer RS, Roelandt J, eds: Contrast echocardiography. 1982. ISBN 90-247-2531-3.
Amery A, Fagard R, Lijnen R, Staessen J, eds: Hypertensive cardiovascular disease; pathophysiology and treatment.
1982. ISBN 90-247-2534-8.
Bouman LN, Jongsma HJ, eds: Cardiac rate and rhythm. 1982. ISBN 90-247-2626-3.
Morganroth J, Moore EN, eds: The evaluation of beta blocker and calcium antagonist drugs. 1982.
ISBN 90-247-2642-5.
Rosenbaum MB, ed: Frontiers of cardiac electrophysiology. 1982. ISBN 90-247-2663-8.
Roelandt J, Hugenholtz PG, eds: Long-term ambulatory electrocardiography. 1982. ISBN 90-247-2664-8.
Adgey AAJ, ed: Acute phase of ischemic heart disease and myocardial infarction. 1982. ISBN 90-247-2675-1.
Hanrath P, Bleifeld W, Souquet, J. eds: Cardiovascular diagnosis by ultrasound. Transesophageal, computerized,
contrast, Doppler echocardiography. 1982. ISBN 90-247-2692-1.
Roelandt J, ed: The practice of M-mode and two-dimensional echocardiography. 1983. ISBN 90-247-2745-6.
Meyer J, Schweizer P, Erbel R, eds: Advances in noninvasive cardiology. 1983. ISBN 0-89838-576-8.
Morganroth J, Moore EN, eds: Sudden cardiac death and congestive heart failure: Diagnosis and treatment. 1983.
ISBN 0-89838-580-6.
Perry HM, ed: Lifelong management of hypertension. 1983. ISBN 0-89838-582-2.
Jaffe EA, ed: Biology of endothelial cells. 1984. ISBN 0-89838-587-3.
Surawicz B, Reddy CP, Prystowsky EN, eds: Tachycardias. ISBN 0-89838-588-1.
Spencer MP, ed: Cardiac Doppler diagnosis. 1983. ISBN 0-89838-591-1.
Villarreal H, Sambhi MP, eds: Topics in pathophysiology of hypertension. 1984. ISBN 0-89838-595-4.
Messerli FH, ed: Cardiovascular disease in the elderly. 1984. ISBN 0-89838-596-2.
Simoons ML, Reiber JHC, eds: Nuclear imaging in clinical cardiology. 1984. ISBN 0-89838-599-7.
Ter Keurs HEDJ, Schipperheyn 11, eds: Cardiac left ventricular hypertrophy. 1983. ISBN 0-89838-612-8.
Sperelakis N, ed: Physiology and pathophysiology of the heart. ISBN 0-89838-612-2.
Messerli FH, ed: Kidney in essential hypertension. ISBN 0-89838-616-0.
Sambhi MP, ed: Fundamental fault in hypertension. ISBN 0-89838-638-1.
Marchesi C, ed: Ambulatory monitoring: Cardiovascular system and allied applications. ISBN 0-89838-642-X.
Kupper W, MacAlpin RN, Bleifeld W, eds: Coronary tone in ischemic heart disease. ISBN 0-89838-646-2.
Sperelakis N, Caulfield JB, eds: Calcium antagonists: Mechanisms of action on cardiac muscle and vascular smooth
muscle. ISBN 0-89838-655-1.
Godfraind T, Herman AG Wellens D, eds: Calcium entry blockers in cardiovascular and cerebral dysfunctions.
ISBN 0-89838-658-1.
Morganroth J, Moore EN, eds: Interventions in the acute phase of myocardial infarction. ISBN 0-89838-659-4.
CALCIUM ENTRY BLOCKERS
IN CARDIOVASCULAR AND
CEREBRAL DYSFUNCTIONS
edited by
THEOPHILE GODFRAIND, M.D.
Laboratoire de Pharmacodynamie Generale et de Pharmacologie
Universite Catholique de Louvain,
Brussels, Belgium
ARNOLD G. HERMAN, M.D.
Department oj Medicine, University oj Antwerp, Wilrijk, Belgium
DONALD WELLENS, Dr. Sc.
Janssen Pharmaceutica, Beerse, Belgium
1984 MARTINUS NIJHOFF PUBLISHERS
a member of the KLUWER ACADEMIC PUBLISHERS GROUP
BOSTON / THE HAGUE / DORDRECHT / LANCASTER
Distributors
for the United States and Canada: Kluwer Boston, Inc., 190 Old Derby Street,
Hingham, MA 02043, USA
for all other countries: Kluwer Academic Publishers Group, Distribution Center,
P .O.Box 322, 3300 AH Dordrecht, The Netherlands
Library of Congress Cataloging in Publication Data
Main entry under title:
Calcium entry blockers in cardiovascular and cerebral
dysfunction.
(Developments in cardiovascular medicine)
Text in Engl., with resumes in French, German, and
Spanish.
Includes bibliographical references.
1. Calcium--Antagonists--Therapeutic use. 2. Cardio
vascular system--Diseases--Chemotherapy. 3. Cerebrovascu
lar disease--Chemotherapy. I. Godfraind, T. (Th~ophile)
II. Herman, A. G. III. Wellens, Donald. IV. Series.
[DNLM: 1. Calcium Channel Blockers--pharmacodynamics.
2. Calcium Channel Blockers--therapeutic use. 3. Cardio
vascular Diseases--drug therapy. 4. Cerebrovascular
Disorders--drug therapy. Wl DE997VME / QV 276 c1429l
Rc684.C34c36 1984 616.1'061 84-7968
ISBN 0-89838-658-6
ISBN-13: 978-94-009-6035-0 e-ISBN-13: 978-94-009-6033-6
001: 10.1007/978-94-009-6033-6
Copyright
© 1984 by Martinus Nijhoff Publishers, The Hague.
Softcover reprint of the hardcover 1s t edition 1984
All rights reserved. No part of this publication may be reproduced, stored in a
retrieval system, or transmitted in any form or by any means, mechanical, photoco
pying, recording, or otherwise, without the prior written permission of the
publishers,
Martinus Nijhoff Publishers, P.O. Box 566,2501 CN The Hague,
The Netherlands.
Contents
Chapter I: Introductory considerations
The major steps in the discovery of calcium entry blockers.
A G. Herman. 3
Basic mechanisms and classification of calcium entry blockers.
T. Godfraind. 9
Calcium entry blockers: perspectives.
A Schwartz. 19
Twenty-seven calcium entry blockers in development:
a new chapter in pharmacology.
D. Wellens. 25
Chapter": Calcium entry blockers and
peripheral circulatory function. 43
Calcium-ions and excitation contrac~on coupling in
vascular smooth muscle cells.
R. Casteels. 45
Laser microprobe mass analysis (LAMMA) as a technique to
quantitate Ca2 + ions.
S. De Nollin, W. Jacob and R. Hertsens. 53
Vascular pharmacology of calcium entry blockers.
J. M. Van Nueten. 59
Calcium homeostasis in human red blood cells.
H. J. Schatzmann. 73
Impact of Ca2 + entry blockers on Ca2 + dependent mechanisms in red
blood cells, platelets and endothelial cells.
F. De Clerck and J. Hladovec. 81
Red blood cell microrheology and calcium antagonists.
J.F. Stoltz. 91
Calcium entry blockers in the treatment of
peripheral obliterative arterial disease.
T. Di Perri, F. Laghi Pasini, M. Guerrini. 103
Chapter"': Calcium entry blockers and myocardial function. 111
Pharmacology of calcium entry blockers in animal and human coronary
arteries.
T. Godfraind and R.C. Miller. 113
Calcium paradox and calcium entry blockers.
T.J.C. Ruigrok, AM. Slade, w.G. Nayler and F.L. Meijler. 125
Myocardial oxygen deprivation and calcium deprivation: ultrastructural
characteristics and clinical significance.
G.R. Bullock and D.J. Hearse. 135
Basic and clinical aspects of myocardial protection by calcium entry blockers.
M. Borgers and W. Flameng. 145
Effect of calcium entry blockers on impaired left ventricular wall motion.
P.F. Cohn. 155
The influence of Ca2+ entry blockers on hemodynamics and coronary blood
flow, and its importance for the treatment of angina pectoris.
P.R. Lichtlen, W. Rafflenbeul, I. Amende, R. Simon and G. Reil. 161
The use of selective calcium antagonism in variant (vasospastic) and classical
(effort) angina pectoris.
PH Kidner. 181
Calcium entry blockers in cardiovascular therapy. Influence of diltiazem
on hemodynamics and coronary blood flow.
M.G. Bourassa. 193
Chapter IV: Calcium entry blockers and cerebral function. 205
Calcium entry blockers and cerebral function: an introduction.
B.S. Meldrum. 207
Calcium entry blockers and cerebral resuscitation.
B.C. White, C.D. Winegar, P.J. Hoehner, D.S. Gadzinski,
T. Hoehner and J. Trombley Jr. 221
Effect of calcium entry blockers in models of brain hypoxia.
A. Wauquier. 241
Calcium entry blockers in the therapy of vertebrobasilar insufficiency.
B. Hofferberth. 255
Calcium entry blockers and pharmacological aspects of migraine.
R. Towart. 263
Clinical evaluation of calcium entry blockers in migraine.
E.L.H. Spierings. 271
Chapter V: Calcium entry blockers in hypertension treatment. 283
Double-blind comparison of the antihypertensive effects of verapamil
and nifedipine.
K. Midtb¢, O. Hals, J. van der Meer, L. Storstein and K.-D. Ramsch. 285
Treatment of hypertension emergencies and chronic arterial hypertension with
calcium entry blockers.
W. Klein. 295
The effect of nifedipine on arterial pressure and reflex cardiac control.
WA Littler. 299
Concluding remarks 305
Why are Ca2+ entry blockers effective in the treatment of hypertension
and tissue hypoxia?
P.M. Vanhoutte. 307
List of authors and co-authors 313
Chapter I:
Introductory considerations
The major steps in the discovery
of calcium entry blockers
A. G. Herman
Summary
The discovery of calcium entry blockers stresses the importance of the ubiquitous calcium gradient in all
living cells.
The chemical structure as well as the functional selectivity of different calcium entry blockers may differ
markedly. Some are primarily active on the myocardium, others on erythrocytes or on mast cells.
The potent antivasoconstrictor effect of some diphenylmethylderivatives was ascribed to Ca2+ entry
blockade as early as 1968. The myocardial effects of verapamil and methoxyverapamil were also attribu
ted to calcium entry blockade. The various mechanisms by which drugs can interfere with Ca2+ fluxes
through the cell membrane are currently becoming more and more apparent.
There is no doubt that pharmacologists are getting a better insight into the basic mechanisms of cellular
calcium homeostasis and that clinicians are obtaining new valuable medicines.
3
Resume
La decouverte de substances qui inhibent f'entree intracellulaire des ions calciques confirme !'importan
ce du gradient calcique transmembranaire qui caracterise toute cellule vivante.
Ce groupe de substances est tres Mterogene aussi bien quant a leur structure chimique que quant a leur
action fonctionnelle selective. Certaines substances excellent par leur action sur Ie coeur, d'autres par
leur action au niveau des erythrocytes ou des mastocytes. L 'effet antivasoconstricteur tres puissant de
certains derives dipMnylmethyles a deja ete attribue a un antagonisme calcique en 1968. Bientot, les ef
fets cardiaques du verapamil et du methoxyverapamil furent aussi decrits comme etant Ie resultat d'un
antagonisme calcique. /I devient de plus en plus clair que les inhibiteurs calciques peuvent interferer de
a
plusieurs fayons avec les voies de passage de Ca2+ travers la membrane cellulaire. Indubitablement,
a
les pharmacologues arrivent mieux decrire les mecanismes fondamentaux de f'homeostasie calcique
cellulaire tout en offr ant de nouvelles tMrapeutiques cliniques valables.
Resumen
EI descubrimiento de inhibidores de la penetracion intracelular de iones calcicos acentua la importancia
del gradiente de calcio en toda celula viva.
Las estructuras qufmicas de las moleculas activas pueden ser muy diferentes y tambien sus efectos so
bre varias funciones celulares. Unos farmacos son muy efectivos en el miocardio, otros en eritrocitos 0
en mastocitos. La fuerte accion inhibidora de vasoespasmos causada por derivados de difenilmetil ya se
la atribuyo a un antagonismo de calcio en 1968. Los efectos miocardfacos de verapamil y metoxiverapa
mil tampoco tardaron en atribuirse a un antagonismo de calcio. Se va observando cada dfa mas que los
farmacos pueden influir de varias maneras sobre el transito de Ca2+ a traves de la membrana celular.
Esta claro que los farmacologos van haciendose una mejor idea de los mecanismos fundamentales de
la homeostasis intracelular de calcio y que los investigadores clfnicos van descubriendo mejores agentes
terapeuticos.
Zusammenfassung
Die Entdeckung von Kalzium-Antagonisten hat die grosse Bedeutung des Kalzium-Membrangradienten
in allen lebenden Zellen bestatigt.
Kalzium-Antagonisten k6nnen sowohl in der chemischen Struktur als auch in ihrer Interferenz mit
bestimmten zellularen Prozessen verschiedenartig sein. Einige wirken stark am Myokard, andere an den
Erythrozyten oder den Mastozyten. 1968 wurde zum ersten Male die kraftige antivasokonstriktorische
Wirkung von Diphenylmethyl-Derivaten einer kalziumantagonistischen Wirkung zugeschrieben. Ebenso
ist die Myokardbeeinflussung durch Verapamil und Methoxyverapamil auf eine kalziumantagonistische
Wirkung zuruckzufuhren. Gegenwartig wird zunehmend deutlich, dass die Arzneimittel an verschiede
nen Punkten des Kalziumtransportes angreifen k6nnen. Die Substanzen dienen den Pharmakologen
beim Verstandnis der grundlegenden Mechanismen der zellularen Kalzium-Hom60stase, wahrend sie fur
den Therapeuten zweifellos neue, wertvolle Medikamente liefem k6nnen.
4