Table Of ContentCardiac Glycosides 1785-1985
Boehringer Mannheim International Symposia
E. Erdmann, K. Greef, J. C. Skou ( eds.)
Cardiac Glycosides 1785-1985
Biochemistry - Pharmacology - Clinical Relevance
With Contributions by C. Achenbach, K. vanA ckern, T. Akera, M. F. Andersen,
K. Andersson, J. K. Aronson, P. Bach, H. Bardenheuer, I. Blömer, H. H. Bodemann,
D. Branco, E. Braunwald, D. Brent, L. Brown, D. L. Brutsaert, E. Bucha,
C. Bufalino, V. P. Butler, M. B. Cannell, M. C. Chan, D. Charlemagne, K. Chatterjee,
R. Dahlqvist, T. Daldrup, H. Daying, R. Dietz, W.D oelle, W. Doering, R. Doliwa,
W. Drohn, D. A. Eisner, E. Erdmann, 0 . Faergeman, M. Fagoo, H. Fasold, B. Ficht!,
K. Fischer, M. Fischer, J. L. Fleg, A. A. L. Fox, C. Freiin, L. Frey, L.,Fridrich, A. Gaßner,
M. H. Gault, R. A. Gillis, T. Godfraind, H. K. Gold, M. L. Gon~alves, B. Grabensee,
K. Greeff, W. Grille, G. Grupp, I. L. Grupp, N. Gustafson, E. Haber, T. Hair, S. Halbach,
0. Hansen, K.-0. Haustein, S. Herzig, T. Hickerson, P. M. Hooymans,
E. Hug, P. G. Hugenholtz, G. Hüller, I. Hutton, A. S. Jaffe, W. Jenkel, T. Jogestrand,
W. Johnsen, E. Johnson, T. Joreteg, P. H. Joubert, L. M. Jung, A. M. Katz, B. Kaufmann,
T. L. Kirley, K. Kjeldsen, W. Knippenberg, K. Kochsiek, K.-D. Kolenda, M. L. P. Koten,
M. Krekler, W. Kübler, R. Kuske, C. Lafleur, M. Lazdunski, W. J. Lederer, G. Lee,
S. W. Lee, L. G. Lelievre, J. Lindenbaum, J. J. H. ML. ohman, L. Longerich,
B. Lorenz, H. Lüllmann, D. Magometschnigg, C. Maier, J. M. Maixent, D. T.M ason,
W. Mäurer, E. Mayoux, W. Meister, F. WH. . M. Merkus, L. von Meyerinck, K. Mohr,
K. Moreth, C. Mouas, R. G. Murray, J. E. Muller, M. S. Nieminen, G. Oltmanns,
W. Osswald, H. J. Partanen, E. Passamani, T.J . Pellinen, E. Petzinger, M. Pichler,
F. Piscione, J. Plum, W. K. Poole, R. Preisler, M. Preteseille, J. A. Quest, D. S. Raabe,
D. S. Regal, C. Reithmann, D. Renner, K. R. H. Repke, T. Risler, R. E. Rude, U. Rüegg,
J. Sander, H. Schadewaldt, S. G. Schäfer, W. Schaumann, M.S cheininger, K. Schenk
Gustafsson, P.S chlieper, W.-D. Schlott, A. Schmoldt, G. Scholtysik, H. Scholz,
A. Schömig, W. Schoner, W. Schönfeld, G.S chönsteiner, H. Schühlen, K. P. Schüren,
A. Schwartz, H. Schweitzer, 0. M. Sejersted, P. W.S erruys, J. C. Skou, T. W. Smith,
G. Sommer, G. Steinbeck, B. Sterndorff, P. H. Stone, H. Strobach, B. Swynghedauw,
S. U. Sys, L. B. Tan, K. A. Taubert, H. Tawfik, K. Theisen, G. Tittel, Z. G.T uri,
A. C. Tweddel, M. Valdeolmillos, S. Vasdev, E.V igholt-Sv;rensen, P. Vigne, H. Waginger,
H. Wagner, E. T. Wallick, E. Weber, K. TW. eber, J. Wieland, T. Wenger, K. Werdan,
K. E. Wirth.
Springer-Verlag
Berlin Heidelberg GmbH
Prof. Dr. E. Erdmann Prof. Dr. K. Greeff Prof. Dr. J. C. Skou
Klinikum Großhadern Institut für Pharmakologie Biophysik Institut
der Universität München der Universität Düsseldorf Aarhus Universitet
Medizinische Klinik I Moorenstraße 5 U niversitetparken
Marchioninistraße 15 4000 Düsseldorf 8000 Aarhus/Denmark
8000 München 70 West Germany
West Germany
CIP-Kurztitelaufnahme der Deutschen Bibliothek
[Cardiac glycosides seventeen hundred and eighty-five to nineteen hundred and eighty-five]
Cardiac glycosides 1785 - 1985 : biochemistry -
pharmacology - clin. relevance / E. Erdmann .. .
(eds.). With contributions by C. Achenbach .. .
(Boehringer Mannheim international symposia)
ISBN 978-3-662-11294-6 ISBN 978-3-662-11292-2 (eBook)
DOI 10.1007/978-3-662-11292-2
NE: Erdmann, Erland [Hrsg.]; Achenbach, Christopher
[Mitverf.]
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting,
reproduction by photocopying machine or similar means, and storage in data banks.
Copyright © 1986 by Springer-Verlag Berlin Heidelberg
Originally published by Dr. Dietrich Steinkopff Verlag, GmbH & Co. KG, Darmstadt in 1986
Softcover reprint of the hardcover I st edition 1986
Medical Editorial: Juliane K. Weller - Copy Editing: Cynthia Feast - Production: Hcinz J. Schäfer
The use of registered namcs, trademarks, etc. in this publication does not imply, evcn in thc absence of
a specific statement, that such names are excmpt from thc relevant protcctive laws and regulations and
therefore free for general usc.
Preface
The bicentenary of William Withering's now famous medical report entitled "An Account
of the Foxglove and Some of its Medical Uses" has given us the occasion to analyze the state
of the art. Cardiac glycosides in 1985 are considered tobe the basis for medical treatment of
myocardial failure, together with diuretics and vasodilators in the more severe cases.
Nevertheless, the controversy as to their exact place in the treatment of heart failure with
sinus rhythm has never ceased. Although cardiac glycosides are of unquestionable value in
tachycardia caused by atrial fibrillation or atrial flutter, the chronic use of these drugs in
sinus rhythm is not generally accepted. The development of tolerance has been reported. It
is of interest that Withering hirnself wrote: "- let it (foxglove) be continued until it either
acts on the kidneys, the stomach, the pulse, or the bowels; Iet it be stopped upon the first
appearance of any of these effects, and I will maintain that the patient will not suffer from its
exhibition, nor the practitioner be disappointed in any reasonable expectation."
In West Germany alone, more than three million patients (about 5% of the total
population) are constantly taking cardiac glycosides. These drugs are the most prescribed
medicaments in many countries. Thus, we considered it worthwhile and necessary to review
in a critical way today's knowledge about the foxglove; to report new findings and to
evaluate old Statements.
Cardiac glycosides are used as tools in biochemistry and as model substances in
pharmacokinetics. We know that they bind specifically and reversibly to the (Na+ + K+)
ATPase, the enzyme that actively transports Na+ and K+ through the cell membraneofall
mammalian cells. Therefore, biochemists, physiologists and pharmacologists as weil as
clinicians have always been interested in the actions of cardiac glycosides at the molecular
Ievel. Their work has added greatly to the understanding of glycoside effects and side effects
in our patients and recently has resulted in producing specific antibodies to cardiac
glycosides (Fab-fragments). These antibodies have a higher affinity for these drugs than the
myocardial receptor enzyme itself, the (Na+ + K+)-ATPase. Thus, the treatment of severe
glycoside intoxication with these antibodies has now become possible.
Cardiac glycoside research is a good example of the value of mutual interaction and the
interrelation of basic and clinical sciences. Problems of treating heart failure with glycosides
can often be traced to changes in the quantity or affinity of cardiac glycoside receptors in the
myocardial cell membrane. Therefore, Kurt Greeff, Jens C. Skou and I decided to assemble
biochemists, physiologists, pharmacologists and clinicians for discussion and evaluation of
the present knowledge 200 years after Withering, and to encourage theoreticians and
clinicians to speak if not the same, at least a similar language. There are perhaps no other
drugs about which we know so much - however, when going into detail, it seems to be the
same as always in science - we know astonishingly little about the cardiac glycosides.
Therefore, this symposiumwas planned to demonstrate what we do know and what is still
obscure about the most ingested drugs in medicine. Hopefully, the next anniversary
symposium will succeed in clarifying these problems.
Last but not least, I should like to express my thanks to all who participated in this
symposium. Especially, I thank all authors for submitting their manuscripts on time,
although they are constantly pressed by important work.
The Steinkopff Verlag has made it possible for this book to appear so quickly by rapid,
efficient, and expert work.
Most of all, I should like to express my sincere gratitude to Dr. Wenzel, Dr. Bergmeyer
and Mr. Rühl from Boehringer Mannheim. They have generously supported this symposium
and this book but moreover, they have themselves carried most of the heavy burden of
organisational work. Without their skills, we would not have succeeded.
Even if William Withering may not have noticed that cardiac glycosides act by slowing the
ventricular rate and by increasing the force and the speed of myocardial contraction, hislast
sentence of the "inferences" is certainly still valid: "That it (foxglove) has apower over the
motion of the heart, to a degree yet unobserved in any other medicine, and that this power
may be converted to salutary ends."
Munich 1986 Erland Erdmann
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V
1. Historial aspects
William Withering - The man and bis work
Skou, J. C. ................ .
Fruitful routes and blind alleys taken by digitalis therapy since its introduction by
Withering
Schadewaldt, H.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II
Therapeutic use of digitalis until the time of William Withering
Jung, L. M ............................ . 17
2. Cardiac glycosides, (Na+ + K+)-ATPase and cation transport
The function of Na+, K+-ATPase and its importance for drug action
Akera, T ................................ . 19
Structural studies on the cardiac glycoside receptor
Wallick, E. T., T. L. Kirley, A. Schwartz ..... . 27
Isoenzymes of Na/K-ATPase identitied by pyrithiamin
Hansen, 0 ....................... . 35
Interaction of cardiac glycosides with Na/K-ATPase in intact myocardium
Herzig, S., H. Lüllmann, K. Mohr .................... . 41
The human red blood cell: A model for ouabain receptor regulation in the heart?
Brown, L., K. Werdan, E. Erdmann . . . . . . . . . . . . . . . . . . . . . . . . . 49
Binding and release of ouabain at low Mg2+ in reconstituted human red blood cell
ghosts
Bodemann, H. H.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
The ouabain receptor in the myocardium and conduction system of the sheep heart
Hug, E., L. Brown, E. Erdmann . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Electrophysiological effects of cardiac glycosides
Eisner, D. A., M. Valdeolmillos, W. J. Lederer, M. B. Cannell 69
Electrophysiological assay of glycoside-induced sodium pump inhibition in isolated
sheep heart Purkinje fibres at the onset of toxicity
Achenbach, C., H. Daying, R. Preisler . . . . . . . . . . . . . . . . . . . . . . . . . 79
Rat cardiac hypertrophy: Contribution of heteregeneous digitalis receptor forms
Lelievre, L. G., J. M. Maixent, D. Charlemagne, B. Swynghedauw. . . . . . . . . '!<,7
Digitalis receptors in normal and hypertrophied rat hearts. Differential effects of a
Ca2+ free perfusion
Charlemagne, D., E. Mayoux, M. Preteseille, J. M. Maixent, Ch. Mouas, B. Swynghe-
dauw, L. G. Lelievre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1)3
Biphasic contractile response to ouabain: Species specific? Calcium dependent?
Altered sensitivity?
Grupp, G., I. L. Grupp, T. Hickerson, S. W. Lee, A. Schwartz. . . . . . . . . . 1)9
The influence of a-tocopherol-nicotinate (Renascin®) on cardiac glycoside effects
Tawfik, H., P. Schlieper. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
On the connection between cardiac glycosides and calcium action
Waginger, H., D. S. Regal .................... . 119
Biochemical basis for the targeted s.ynthesis of cardiac glycosides with selective action
Schönfeld, W., J. Weiland, K. R. H. Repke ....................... 127
3. Digitalis-like substances
The "endogenous cardiac glycoside"
Schoner, W., K. Moreth, R. Kuske, D. Renner. ..... 135
Endogenous digitalis, cardiodigin and other regulators of the sodium pump
Godfraind,T., M. Fagoo ................................ 143
Digitalis-like factors in plasma of healthy human adults
Vasdev, S., L. Longerich, E. Johnson, D. Brent, M. H. Gault ............. 157
A Na+,K+-ATPase inhibitor isolated from pig kidney
Krekler, M., A. A. L. Fox, H. Strobach, K. Greeff ... . . . . . 165
Cardiac glycoside-Iike effects of a bufadienolide extracted from Kalanchoe
Daigremontiana
Scholtysik, G., H. Wagner, M. Fischer, U. Rüegg ................... 171
4. Mechanism of inotropic effects - cardiac glycosides and other positive
inotropic agents
Positive inotropic agents: Different mechanisms of action
Scholz, H .......................... . . . . . . . . 1' !<,1
Significance of calcium ions in the regulation of myocardial contractility
Katz, A. M. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Additive and non-additive positive inotropic effects in human and guinea-pig
myocardium
Brown, L., B. Lorenz, E. Erdmann ................. . 195
The cardiac Na+ /H+ exchange system. lts role in inotropy
Freiin, C., P. Vigne, M. Lazdunski ............ . 207
Evidence for pharmacodynamic differences between cardiac glycosides of different
polarities
Joubert, P. H. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
The positive inotropic action of mercury compounds on isolated heart muscle
Halbach, S., G. Schönsteiner . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Chronic pretreatment with amrinone or milrinone induces no tachyphylaxis in
mammalian cardiac muscle
Sys, S. U., D. L. Brutsaert ............................... 229
Left ventricular function after oral milrinone in patients with congestive heart failure.
A hemodynamic and angiographic study
Piscione, F., P. W. Serruys, P. G. Hugenholtz ..................... 237
5. Cardiac glycosides - metabolism, interactions and volume of distribution
The importance of skeletal musdes as a distribution volume for digitalis glycosides in
guinea-pigs and human subjects
Kjeldsen\K. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Relevant metabolism of cardiac glycosides
Wirth, K. E.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
The dihydrogenation of digoxin
Lindenbaum, J. ........ . 263
Renal excretion and plasma Ievels of dihydrodigitoxin in volunteers and renally healthy
and renally insufficient patients being treated with digitoxin
Strobach, H. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Enzymatic basis for digitoxin metabolism and possible drug interactions in man
Schmoldt, A., L. v. Meyerinck, W. Drohn, I. Blömer. . . . . . . . . . . . . . . 273
Effect of quinidine on the inotropic effect of digoxin in isolated cat or guinea-pig
papillary muscle
Taubert, K.A., C. Bufalino, T. Hair, C. Lafleur .................... 281
Quinidine decreases the intestinal secretion of digoxin and digitoxin in the guinea-pig
Schäfer, S. G., B. Ficht!, W. Doering .......................... 287
Quinidine-induced reduction of the biiiary excretion of digoxin in patients
Schenck-Gustafsson, K. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
