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Digitalis: New facts about an old drug∗
The A,merican Journal of Cardiology Volume
22
AUGUST
Number
1968
2
Symposium on Congestive Heart Failure-II Digitalis:
New Facts About
DEAN T. MASON, M.D., F.A.C.C. &EUGENE Bethesda,
an Old Drug*
BRAUNWALD, M.D., F.A.C.C.
Maryland
T
but present evidence suggests that this action may be mediated through the potentiation of exPresent knowlcitation-contraction coupling. edge of the mechanisms that underlie the normal process of this coupling in heart muscle indicates that, at the time of the spike of the action potential or depolarization of the cell membrane, calcium and sodium ions selectively enter the cell, and potassium ions leave it.le3 Associated with excitation and altered membrane permeability to calcium ions is an increased concentration of free calcium available to the contractile proteins actin and myosin. These are arranged in overlapping filaments within the sarcomeres, the basic functional units of the myofibrils. There is considerable debate whether this calcium in the cytoplasm adjacent to the myofilaments (myoplasmic calcium) represents the same calcium taken up during depolarization. It may instead be derived, in whole or in part, from calcium bound in the sarcoplasmic reticulum, the release of which is stimulated by the calcium influx.3-6 Nevertheless, it is postulated that when the myoplasmic concentration of calcium ions exceeds a critical level, in the presence of mitochondrial-produced adenosine
HE PRECISE mechanisms of action and proper clinical applications of the cardiac glycosides have been the subject of more intensive investigation than any other area in cardiovascular Although many aspects of these pharmacology. agents continue to excite controversy, advances in the past few years have provided a great body of useful information concerning their pharmacodynamia: effects. This review focuses attention on recent studies that have permitted a new understanding of the mechanisms of action of the digitalis glycosides. Their fundamental cellular actions are stressed, and their possible effects on the contractile machinery of cardiac muscle formulated; then these concepts are extended to the important alterations of circulatory function the glycosides produce. Finally, these observations are integrated to provide a unified concept of the actions of the glycosides and to suggest a more rational clinical use of these agents. CELLULAR MECHANISM OF INOTROPIC ACTION Opinion is not unanimous concerning the exact manner in which digitalis initiates its powerful inotropic action on the myocardium,
* From the Cardio.logy Branch, National Heart Institute, Bethesda, Md. Section of Cardiovascular Address for reprints : Dean T. Mason, M.D., School of Medicine, Davis, Calif. 151
Medicine,
University
of California
152
Mason
and Braunwald
triphosphate (ATP) and the enzyme rnyofibrillar ATPase, cardiac contraction occurs as the thin actin filaments slide toward the mid-point of the sarcomere, thereby leading to the developThe relaxament of force and shortening.‘f8 tion phase of the cycle is thought to occur as the myoplasmir calcium is reaccumulated by the sarcoplasmir reticulum and calcium ions are displaced outward across the cell membrane. g,10 Calcium and Digitalis Action: These observations, which assign a central role to calcium in the process of excitation-contraction coupling, have been postulated to apply to the mechanism Thus, of action of cardiac-stimulating drugs. it has been suggested that an augmentation in the myoplasmic concentration of calcium ions produced by rardiotonic agents may lead to a In this manner, more forceful contractiorL3 the providing of a greater quantity of calcium ions for the enhancement of the chemical process involved with the active state of myocardial contraction may represent the final common cellular pathway by which a variety of drugs produce their inotropic action. These agents, however, may differ in the way they supply calcium ions The digitalis to the contractile machinery. glycosides, for example, appear to be capable of both increasing the influx of calcium during depolarization11v12 and promoting the release of In recalcium from sarcoplasmic reticulum.13 gard to this latter action, it has recently been demonstrated that sodium ions are able to release bound calcium from sarcoplasmic reticulum.14 Although there is no evidence to indicate a primary role for the influx of sodium at the time of depolarization in the initiation of the normal contractile process in cardiac muscle, the proposed competition between sodium and calcium in sarcoplasmic reticulum may be significant in the inotropic effect of the glycosides. The latter have recently been shown to enhance intracellular sodium transport through stimulation of cell membrane ATPase.15-20 However, the relevance of an action of glycosides on intracellular sodium is not clear. Thus, it is acknowledged that injections of sodium directly into skeletal muscle fiber cells do not produce and a specific effect of visible contractions,“’ sodium on microsomal-bound calcium has not been shown in some preparations.22 Digitalis and the Transverse Tubular System: Recent findings concerning the ultrastructure and function of the cardiac cell have been helpful in providing additional insight into the possible mode of action of digitalis.23-25
It has been shown that the cell membrane enveloping the cardiac fiber makes deep invaginations into the cell to form the transverse tubular system, thereby providing ready access of digitalis to the important enzyme systems of the transverse tubular membranes in the vicinity of the contractile proteins even if the drug does not leave the interstitial compartment. This observation is consonant with the view held by some investigators that physiologic concentrations of glycosides do not enter the intracellular space and thus may not have a direct action on Indeed, it has been sugactin and myosin. gested that radioactive digoxin may be specifically localized within the transverse tubular system adjacent to the sarcoplasmic reticulum in close proximity to the myofibrils.26 However, some investigations favor a more random distribution of the glycoside in heart muscle.27 DIGITALS
AND
POTASSIUM
The findings of recent investigations are compatible with the possibility that the arrhythmic action of digitalis may be mediated by a mechanism separate from that underlying the inotropic action. Thus, it was shown in experimental animals that the toxic actions of the glycoside may be diminished by potassium in clinically meaningful concentrations, although the positive contractile effect remains unalThis simple experiment demonstrated tered.28 that digitalis toxicity may be suppressed by the action of potassium, which reduces the autotnaticity of idioventricular pacemakers, without antagonizing the beneficial actions of the drug. When these findings are translated into a clinical setting, it would appear that in a patient with congestive heart failure undergoing rapid diuresis the administration of potassium to protect against the development of extrasystoles does not counteract the inotropic properties of Moreover, since the production of digitalis. digitalis-induced extrasystoles is accompanied by the loss of intracellular potassium, a basis is established for the administration of potassium to oppose the arrhythmias brought on by the glycoside. Digitalis-Induced Arrhythmias: The cellular mechanism by which the glycoside produces arrhythmias has not been fully elucidated. During repolarization of the cardiac cell, sodium is removed from it, and potassium returned to it by a membrane pump system. This system is also active throughout the period of diastole and maintains the characteristic THE AMERICAN
JOURNAL
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I Xgitalis c.oncentrations of the cations on either side of the cell membrane.2 Large concentrations of digitalis inhibit the pump ATPase activity in cellular membrane fractions prepared from a \:ariety of tissues.*8.2g~30 It is of interest that the inhibitory effects of digitalis on membrane ATPase are antagonized by excess potassium.‘s Inhibition of the pump mechanism results in the delayed return to the cell of potassium that effluxed after depolarization as well as continued loss of potassium from the cell during the remainder of the cardiac cycle. As a consequence of the actions of the glycosides, intracellular potassrum declines but intracellular sodium rises. Thus, it is suggested that some of the toxic properties of the glycoside are associated with intracellular potassium loss, and the inotropic actions with an augmentation of myoplasmic calcium concentration. These observations are contrary to the traditional belief that potassium loss from the cell is causally related to the cardiotonic action of the drug.31 On the other hand, the postulation that the fundamental cell.ular effects of the digitalis glycosides are the result of certain shifts of calcium, sodium and potassium is by no means settled. It is important to emphasize that the digitalisinduced toxicity referred to in this schema incorporates those arrhythmias resulting from an augmentation of pacemaker or spontaneous activity and a rise in diastolic resting potential within the cell. These disorders of increased automaticity include the atrial, nodal and ventricular extrasystoles and tachycardias which are often suppressed clinically by the administration of potassium. Not explained by this concept, and thus operative through yei another mechanism, are the toxic effects of digitalis related to its other electrophysiologic properties, such as the depression of conduction velocity which underlies the development of atrioventricular block and is thought to be intensified by potassium.32 Digitalis and Potassium Toxicity: The administration of digitalis to patients is known to result in a small elevation of serum potassium, the major source of which appears to be the liver.3a In addition, the drug tends to inhibit the potassium uptake by skeletal muscle.34 These observations which underscore the fact that potassium toxicity is readily provoked in patients receiving glycosides must be considered when treating digitalis intoxication with potassium. At the same time, in conditions leading to VOLUME
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potassium loss from the body and thereby predisposing toward digitalis intoxication, the potassium loss is largely from the intracellular pool ; thus, the level of the serum potassium does not necessarily indicate increased susceptibility to digitalis intoxication. Relation Between Dose and hotropic Eject of Digitalis: Another important finding was disclosed during the study of the dissociation of the toxic from the inotropic effects of digitalis by the administration of potassium: the relation between the dose and the positive actions of digitalis on contractile force is essentially Iinear.2s This linear dose-inotropic effect was observed even when the glycoside was given in doses that produced arrhythmias that had to be suppressed by potassium. Thus, small and large doses of digitalis have similar qualitative effects. From these and other observations3* it is apparent that a patient need not receive a maximally tolerated dose of digitalis to achieve a beneficial effect. Even small amounts of the drug provide some therapeutic action, a point to be kept in mind if glycosides are used in a patient prone to digitalis intoxication or if the drug is employed prophylactically. ,METABOLIC EFFECTS AND MODIFICATION OF ACTIONS Since digitalis does not alter the amount of energy available for myocardial contraction, it has been traditionally believed that the drug somehow improves the contractility of the heart without augmenting myocardial oxygen consumption.35*36 This view implies that the drug ability to improve the possesses a unique efficiency of the heart by producing mechanical work without utilizing chemical energy. Since myocardial oxygen requirements are directly related to the tension developed by the myocardium, and therefore to the size of the heart and intraventricular pressure as well as to the velocity of contraction, the possibility was considered that digitalis might exert an over-all effect on myocardial oxygen consumption dependent on the hemodynamic setting in which it is administered. In the nonfailing heart of experimental animals the drug was demonstrated actually to augment the oxygen consumption of the heart and thus diminish cardiac Thus, in the absence of heart efFiciency.37 failure, digitalis markedly increases the velocity of myocardial shortening but minimally diHowever, in the minishes the size of the heart. enlarged and failing heart this direct effect on
the velocity of contractiorl to iwrease ~nyocardial oxygen consumption is masked and overridden by the marked fall in ventricular end-diastolic volume and systolic wall tension, and the result is an over-all decline of lnyocardial oxygen utilization and an increase in efflciency.3x From these observations, it is correct to consider that the beneficial actions of digitalis in the treatment of angina pectoris result from the improvement of impaired performance of the heart by reduction of the size of the heart and ventricular wall tension. In a patient without some degree of impairment of cardiac contractility, the glycoside may actually intensify angina1 symptoms, since the inotropic action in the nonfailing heart is produced at the cost of a disproportionately large increment of energy utilization. Thus, digitalis directly enhances the force of contraction accompanied by an increase in myocardial oxygen requirements, and in this respect acts like other positive inotropic agents. In agreement with these observations is the recent demonstration that acetylstrophanthidin augments myocardial oxygen consumption in papillary muscles from normal hearts of experimental animals.38 Digitalis and Cardiac Norepinephrint-: Digitalis evokes its powerful inotropic effect on the myocardium by a direct action, as outlined in the preceding section. The contention that it stimulates the heart by the release of cardiac norepinephrine3g has not been substantiated by recent investigations. Thus, digitalis exhibits its full inotropic properties in the absence of cardiac norepinephrine, and this action is additive to those of the catecholamines and to drugs that act through the release of endogenous Further, the complete stimunorepinephrine.40 lating effect of digitalis may be anticipated in the presence of beta adrenergic receptor blockade and in the presence af antiadrenergic drugs other than reserpine. In spite of the finding that reserpine interferes somewhat with the inotropic properties of digitalis, it does so apart from its norepinephrine-depleting actions4” Although the cardiac contractile actions of digitalis are not altered by changes in cardiac electronorepinephrine the concentration, physiologic properties of the drug are influenced by the catecholamine content. Thus, norepinephrine depletion or beta adrenergic receptor blockade reduces the incidence of digitalisinduced ventricular arrhythmias.41*42 In addition, a large part of the ability of digitalis to lengthen the functional refractory period of the
EKG
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Figure 1. Simultaneous Idcordings of left ventricular (LV) pressure and of teft ventkdar rate of change (dpldt) during controlperiod (top) and after ouabain administration (bottom). The presystolic augmentation of ventricular pressure, a, is barely perceptible before ouabain, but becomes clearly evident in the tracings recorded 35 minutes after the administration of the drug. (Reproduced by permission from MASON, D. T. and BRAUNWALD, E. J. C&n. I7west., 42: 1105, 1963.)47
atrioventricular node is dependent on sympathetic and parasympathetic innervation.43 The level of thyroid hormone may also modify the actions of the glycoside.44 In hyperthyroidism the cardiotonic and atrioventricular nodeblocking actions of any given dose of digitalis may be diminished, whereas patients with myxedema derive an enhanced inotropic effect and are particularly susceptive to digitalis intoxication with relatively small doses of the drug.45 ACTIONS
ON THE
NONFAILING
HEART
Although it has been appreciated for some time that digitalis stimulates the force of contraction of the failing heart, there has been considerable debate concerning its effects on the contractile state of the normal heart. Until quite recently the glycosides were thought to depress the function of the nonfailing heart, since their administration resulted in lowering of the cardiac output. The demonstration that the THE AMERICANJOURNALOF
CARDIOLOCY
I>igitalis
155
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Figure 2. EJects of ouobain on the force-velocity rrlationshifi of the left ventricle in a patient who had undergone surgical correction of mitral stenosis. A, representative curves relating left ventricular dimensions, determined at 1 per 30 second intervals, to time of individual cardiac cycles before and after the drug. The top of the cycle refers to ventricular end-diastolic length and the bottom to end-systolic length. The horizontal broken line represents the isolength (1~1) line at which bath instantaneous velocity of shortening and intraventricular pressure were determined. The diagonal broken lines are tangents to the length curves and represent the velocity of shortening. The steeper tangent after ouabain signifies an increase of veloci ty. The temporally related ventricular pressure is shown in millimeters of mercury, and the calculated velocity in length per second. Below are shown the corresponding values for cardiac index (C.I.), stroke volume index (S.I.), left ventricular ejection time (E.T.) and the mean systolic ejection rate (MSER). B, the force (pressure)-velocity relation before and after ouabain. Each point represents analysis of a single cardiac cycle. Ouabain raised the velocity considerably and the pressure minimally. (Reproduced by permission from SONNENBLICK, E. H. et al. Circulation, 34: 532, 1366.)‘s
measurement of the cardiac output response alone does not necessarily equate with the inotropic state of the myocardium has led to the reassessment of this problem in relation to the actions of the glycosides on the nonfailing heart. In studies of the effects of acute digitalization at the time of surgical correction in patients .with uncomplicated congenital cardiac defects, it was shown that the glycosides are capable of increasing the contractile force of the nonfailing human heart.46 These observations have recently been extended to nonfailing hearts of intact unanesthetized patients. Thus, both in patients with heart disease but without heart failure and in normal subjects, digitalis increases the rate of rise of intraventricular pressure, and presumably tension, during contraction, thus indicating that the drug augments the contractility of the nonfailing myocardium (Fig. 1).47 There is also indirect evidence that the force of atria1 contraction is stimulated as well (Fig. 1).47 These VOLUME
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AUGUST
1968
findings are further substantiated in these patients by the demonstration that digitalis augments the velocity of ventricular shortening during systolic emptying at a constant ventricular size and tension (Fig. 2).48 From these observations, it is apparent that the glycosides exert the same fundamental inotropic action on both normal and failing hearts; therefore the notion that the drug has a harmful effect on the nonfailing heart can no longer be maintained. Further support to the view that digitalis may produce a favorable effect on the nonfailing heart is the finding that it lowers the oxygen debt after exercise in patients with cardiomegaly but without heart failure.49 Thus, the performance of the circulatory system may be improved by digitalis in some patients with a limited cardiac reserve but without cardiac decompensation. In addition, the glycosides appear to have the capacity to support the response of the heart to the long-standing augmentation of ventricular afterload or the resistance to
ventricular ejection. In experimental animals, the drug reduced total mortality and the degree of ventricular hypertrophy resulting froul chronic constriction of the descending aorta.j” The prophylactic value of digitalization in sustaining cardiac performance during cxperimentally produced chronic increase in ventrirular preload is currently under im-estigation. ACTIONS ON
ARTERIOLES
AKD \7er~s
Normal Subjects: The finding that the digitalisinduced stimulation of the force of contraction of the normal heart is not translated into an increase in cardiac output suggests possible extracardiac effects of the drug. Early observations that digitalis constricts isolated arterial and venous segments and produces arteriolar and venous constriction in the dogi’--j3 have been extended to man. Patients 011 cardiopulmonary bypass at a constant perfusion rate were found to increase their systemic vascular resistance in response to acetylstrophanthidin.4” This action has been clarified more recently by the finding that commonly used doses of ouabain result in constriction of both the arteriolar and venous beds of the forearm, and elevate the total peripheral vascular resistance in intact normal subjects (Fig. 3).“”
Since these peripheral vascular actions of digitalis in normal subjects are not diminished b) the prior administration of antiadrenergic drugs, the vasoconstriction is mediated by a direcr stimulating action of the glycoside.“4 Patients with Heart Failurr: In contrast to normal subjects, in patients with heart failure the digitalis glycosides lower the elevated total peripheral vascular resistance and forearm arteriolar resistance and venous tone toward normal (Fig. 4).54 It is now well documented that the activity of the sympathetic nervous system increases in congestive heart failure to support the circulation in the face of diminished myocardial contractility and cardiac output.55r5” The explanation for the opposite over-all effects of digitalis in patients with heart failure and normal subjects appears to be that the marked inotropic action and elevation of cardiac output
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Figure 3. Serial determinations of brachial arterial e ssure (BA), forearm blood flow, forearm vascular resistance, venous tone, cardiac output, and systemic vascular resistance before and after ouabain in a normal subject. (Reproduced by permission from Masori, D. T. and BRAUNWALD, E. J. Clin. Invest., 43: S32. 1964.)&a
OUTPUT
TIME
(L
IN
IminI
MINUTES
Figure 4. S&al measurements before and after ouab& in a patient with congestive heart failure. (Reproduced by permission from MASON, D. T. and BRAUNWALD, E. J. Cfin. Imest., 43 : 532, 1964.)&t I HE
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Digitalis produced by the drug indirectly allows a withdrawal of some of this adrenergically mediated vasoconstriction. This vasodilation is not a direct effect of digitalis; rather, it occurs in spite of the direct vasoconstrictor action of the drug and overrides this latter effect. In this regard, it is interesting to postulate that if adrenergic blockade could be safely produced in patients with heart failure, the administration of digitalis should result in unopposed vasoconstriction. UNIITIED CONCEPT OF HEM~DYNAMIC ACTIONS Having considered the central and peripheral vascular actions of digitalis it is now possible to synthesize the over-all effects of the drug on the circulation. In the hearts of normal subjects and patients with heart disease without failure, the drug directly increases the force of contraction, but an increase in cardiac output may not be observed. The arteriolar constriction produced by the drug augments the resistance to ventricular ejection. Some investigators have suggested that the drug-induced systemic venoconstriction i;s accompanied by a rise in the hepatic venous wledge pressure and a widening of the gradient between the portal venous and the inferior vena caval pressuress7 Thus, the increase in ventricular afterload, in the presence of an inconstant or weak effect on ventricular preload, may mask the effect of the drug in increasing myocardial contractility, thus leading to no change or a fall in cardiac output. In addition, it is now acknowledged that there is at least a minor component of vagal innervation of the ventricles58:, stimulation of this system by the parasympathomimetic actions of digitalis may produce a negative inotropic effect, which also tends to offset the more powerful direct action of the glycoside. positive inotropic Finally, in attempting to explain the absence of an increase in cardiac output in response to digitalis in the normal heart, it is pertinent to recall that the cardiac output is determined and maintained at an appropriate level by the interaction of a number of cardiac and extracardiac factors. Thus, although digitalis directly enhances cardiac contraction, this action may be offset to an extent by withdrawal of sympathetic stimulation of myocardial contend to tractility, as reflex mechanisms modulate the effects of the drug in order to maintain cardiac output at a constant level. In this regard, the failure of the glycoside to VOLUME
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augment cardiac output is similar to the effect of paired electrical stimulation on the normal heart and circulation.5s These observations are also consistent with the existence of an absolute ceiling of myocardial contractility and the fact that the normal heart operates close to this top level of performance.+jO In patients with cardiac decompensation, digitalis directly improves the contractile state of the heart apparently to the same degree as Because this cardiotonic in normal hearts.60 effect is not accompanied by compensatory readjustments that tend to reduce cardiac output, the powerful direct inotropic action of the drug results in a large augmentation of the lowered cardiac output and improvement of the other hemodynamic features characteristic of the state In contrast to normal subof heart failure. jects, in patients with heart failure there is indirect over-all arteriolar and venodilation that is derived from the large rise of cardiac output, leading to the reflex release of elevated sympathetic tone in the peripheral vascular beds. In this manner, arterial blood pressure and cardiac output are maintained with less of an augmentation of arteriolar resistance and venous tone. the digitalis-induced reduction of Further, peripheral vascular resistance in itself allows for some improvement in cardiac output. The observed vasodilation occurs in spite of the direct vascular constrictor action of digitalis and would be even greater if the latter effect were Of interest is that if cardiac failure is absent. only mild, the direct stimulating effect and the indirect relaxing action of the drug on the blood vessels may be equally balanced, and thus no alteration of vascular tone is observed. The relaxing effects of the glycosides on the veins in heart failure provide a basis for the clinical observation that the rapid administration of digitalis to these patients produces a fall in the systemic venous pressure before the onset of diuresis and decline of the elevated blood volume. Further, Bradley61s62 has shown that digitalis results in a decline of the splanchnic blood volume in patients with heart failure, presumably due to its ability to eliminate wideBy this acspread systemic venoconstriction. tion there is displacement of blood from the splanchnic vascular bed to the systemic venous system. Thus, despite over-all systemic venodilation and reduced central venous pressure after digitalis, venous return is actually increased as a result, in part, of this shift of blood in the venous reservoirs to the systemic bed. In ad-
158 dition, allows from a ducing
Mason
and Braunwald
the glycoside-induced inotropic effect a more forceful ventricular contraction relatively lower filling pressure, thus promarked enchancement of cardiac output. CURRENT CLINICAL APPLICATIONS
A thorough understanding of the pharmacodynamics of the digitalis glycosides is central to The the sound use of these drugs in patients. principal direct action of digitalis of clinical importance is its ability to stimulate the contractile state of the heart. Thus, the primary indication for its use continues to be the presence of heart failure secondary to absolute or relative myocardial dysfunction, regardless of the setting As might in which the decompensation occurs. be expected, digitalis is of most benefit when heart failure is the result of chronic muscle malfunction or of systolic and diastolic overThe glycosides are of loading of the ventricles. little value in conditions in which heart failure is due to pure extramyocardial causes which limit the filling of the ventricle, such as constrictive pericarditis or mitral stenosis with normal sinus rhythm. 63 The inotropic action of digitalis may actually be harmful in one condition, idiopathic hypertrophic subaortic stenosis, in which not only the force of contraction of the left ventricular body is augmented, but also that of the obstructing myocardium in the outflow tract within the left ventricle, thus leading to a further mechanical burden to systolic emptying.64 There is increasing agreement that digitalis may be beneficial during special situations of stress in certain patients with heart disease Thus, prophylactic without heart failure. digitalization may protect the myocardium in such patients who experience the depressing effects of anesthesia and operation, serious illness such as pneumonia, or hypervolemia during Of potential clinical importance pregnancy. is the possibility that digitalis may diminish the degree of ventricular hypertrophy in patients with hypertension and obstruction to left ventricular outflow even in the absence of heart failure. Since a state of heart failure often exists in acute myocardial infarction without pulmonary edema, digitalis is now often used before the more obvious signs of decompensation and in the presence of cardiogenic shock. Of related importance is that the digitalis glycosides have been helpful in enhancing survival in hypovolemic shock in experimental animals.65 The other major therapeutic action of digitalis results from its effect on the electrophysiologic
properties of the heart, and it is therefore useful in the treatment of certain disorders of cardiac rhythm. Thus, even in the absence of heart failure, the glycosides increase the refractory period of the atrioventricular node, thereby reducing the ventricular rate and increasing the cardiac output in patients with atria1 fibrillation. In addition, they are helpful in suppressing all types of supraventricular tachycardias, apparently by a parasympathomimetic action. SUMMARY Present evidence suggests that the fundamental hemodynamic property of the digitalis glycosides to improve the contractile state of the myocardium rests upon the cellular action of the drugs to potentiate excitation-contraction coupling. This effect appears to be mediated by glycoside-induced enhancement of the concentration of calcium ions in the endoplasm surrounding the myofibrils at the time of cardiac contraction. It is likely that the arrhythmiaprovoking properties of digitalis are related to the loss of intracellular potassium and the inhibition by the drug of the membrane pump ATPase system required for maintaining inThe postracellular potassium concentrations. tulation that the inotropic and certain toxic actions of digitalis are mediated by different mechanisms is helpful clinically since the two properties of the glycoside can be dissociated by the administration of potassium. The over-all metabolic and hemodynamic effects of the glycosides are closely dependent on the state of the circulation at the time the agent is employed. Thus, the drugs have the direct property of increasing the oxygen utilization of the myocardium while producing their inotropic effect, manifested by a rise in the velocity of contraction, and in this respect they possess no unique ability to improve the efficiency of the heart. However, this action to increase myocardial oxygen requirements is masked and offset in the presence of heart failure, since the reduction of myocardial systolic wall tension by the drug diminishes the oxygen demand of the heart more than the direct inotropic effect tends to augment it. Similarly, the alterations of cardiocirculatory dynamics produced by the drug are related to the hemodynamic condition of the patient. Thus, in the absence of heart failure, the inotropic effect is not translated into an increase in cardiac output. In contrast, in patients with congestive heart failure, the improveTHE
AMERICAN
JOURNAL
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CARDIOLOGY
Digitalis ment of the contractile state of the failing myocardium by the glycoside elevates the cardiac output to a marked degree, allowing a diminution of the ele\rated adrenergically-induced arteriolar resistance and venous tone and a shift of venous blood out of the portal into the systemic venous compartment. Thus, digitalis possesses both direct and indirect cardiac and extracardiac actions, and the over-all alterations of circulatory dynamics depend on the hemodynamic status of the patient. REFERENCES 1. WINEGRAD, S. and SHANES, A, M. Calcium flux and contractility in guinea pig atria. J. Gen. Physiol., 45: 3X1, 1962. 2. SINGER, D. H., LAZZARA, R. and HOFFMAN, B. F. Transmembrane potentials of cardiac cells and their ionic basis. In: The Myocardial Cell. Structure, Function, and Modification by Cardiac Drugs, p. 73. Edited by BRILLER, S. and CONN, H., JR. Philadelphia, 1966. University of Pennsylvania Press. 3. NAYLER, W. G. Calcium exchange in cardiac muscle: A basic mechanism of drug action. Am. Heart J., :‘3: 379, 1967. 4. WINEGRAD, S. The possible role of calcium in excitation-contraction coupling of heart muscle, Circulation, 24: 523, 1961. 5. NIEDERGERKE,R. Movements of Ca in beating ventricles of the frog. J. Physiol., 167: 551, 1963. 6. SANDOW, A. Excitation-contraction coupling in skeletal muscle. Pharmwol. Rev., 17: 265, 1965. 7. DAVIES, R. E. .4 molecular theory of muscle contraction: Calcium-dependent contractions with hydrogen bond formation plus ATP-dependent extensions of part of the myosin-actin crossbridges. N&tire, London, 199: 1068, 1963. 8. DAVIES, R. E. The role of ATP in contraction. In Ref. 2, p. 157. 9. WEBER, A., HER.Z, R. and REISS, I. On the mechanisms of the relaxing effect of fragmented sarcoplastic reticulum. J. Gen. Physiot., 46: 679, 1963. 10. WEBER, A. The role of Ca in the regulation of muscle activity. In Ref. 2, p. 131. Il. LULLMANN, N. and HOLLARD, W. Influence of ouabain on an exchangeable calcium fraction, contractile force, and resting tension of guinea pig atria. J. Pharmacol. &? Exfer. Therap., 137: 186, 1962. 12. GROSSMAN, A. and FURCHGOTT,R. F. The effects of external calcium concentration on the distribution and exchange of calcium in resting and beating guinea-pig auricles. J. Pharmacol. & E.x@r. Therap., 143: 107, 1964. 13. LEE, K. S., Yu, D. H. and STRUTHERS, J. J. A study of the effect of cardiac glycosides on the syneresis of myofibrils in the presence of relaxing factor. J. Pharmacol. &? Exper. Thzraj., 148: 227, 1965. 14. PALMER, R. F. and POSEY, V. A. Ion effects on calcium accumulation by cardiac sarcoplasmic reticulum. J. Gen. Physiol., 50: 2085, 1967. VOLUME 22, AUGUST 1968
15. BONTING, S. L. and CARAVAGGIO,L. L. Studies on sodium-potassium-activated adenosine triphosv. Correlation of enzyme activity phatase. with cation flux in six tissues. Arch. Biochem., 101, 37, 1963. 16. LEE, K. S. and Yu, D. H. A study of the sodiumand potassium-activated adenosinetriphosphatase activity of heart microsdmal fraction. Biothem. Pharmacol., 12, 1253, 1963. Metabolism of cardiac glycosides. In : 17. REPKE, K. First International Pharmacological Meeting, Vol. 3, p. 47. Edited by WILBRANDT, W. and LINDGREN, P. Oxford, England, 1961. Pergamon Press. 18. PALMER, R. F. and NECHAY, B. R. Biphasic renal Correlation effects of ouabain in the chicken: with a microsomal Na+-K+ stimulated ATP-ase. J. Pharmacol. tY Exper. Therap., 146: 92, 1964. 19. PALMER,R. F., LASSETER,K. C. and MELVIN, S. L. Stimulation of Na+andK+dependent adenosine triphosphatase by ouabain. Arch. Biochem., 113: 629,1966. 20. WILBRANDT, W. The mechanism of action of cardiac glycosides. In Ref. 2, p. 297. 21. CALDUTELL,P. C. and WALSTER, G. Studies on the micro-injection of various substances into crab muscle fibers. J. Physiol., 169: 353, 1963. 22. KATZ, A. M. and REPKE, D. I. Sodium and potassium sensitivity of calcium uptake and calcium binding by dog cardiac microsomes. Circulation Res., 21: 767, 1967. 23. SPIRO, D. The fine structure and contractile mechanism of heart muscle. In Ref. 2, p. 13. 24. SONNENBLICK, E. H. The mechanics of myocardial contraction. In Ref. 2, p. 173. 25. BRAUNWALD, E., Ross, J., JR. and SONNENBLICK, E. H. Mechanisms of contraction of the normal and failing heart. New England J. Med., 277: 794,1967. 26. SONNENBLICK, E. H., SPOTNITZ, H. M. and SPIRO, D. Role of the sarcomere in ventricular function and the mechanism of heart failure. Circulation Res., 15 (Suppl. 2): 70, 1964. 27. LUCHI, R. J. Some biochemical reactions influenced by the digitalis glycosides. In Ref. 2, p. 309. 28. WILLIAMS, J. F., JR., KLOCKE, F. J. ~~~BRAUNWALD, E. Studies on digitalis. XIII. Comparison of the effects of potassium on the inotropic and arrhythmia-producing actions of ouabain. J. Clin. Invest., 45: 346, 1966. 29. GLYNN, I. M. The action of cardiac glycosides on sodium and potassium movement in human red cells. J. Physiol., 136: 148, 1957. 30. BONTING,S. L., CARAVAGGIO, L. L. and HAWKINS, N. M. Studies on sodium-potassium-activated adenosine triphosphatase. IV. Correlation with cation transport sensitive to cardiac glycosides. Arch. Biochem., 98: 413, 1962. 31. HAJDU, S. and LEONARD, E. The cellular basis of cardiac glycoside action. Pharmacoi. Rev., 11: 173,1959. 32. FISCH, C., GREENSPAN, K., KNOEBEL, S. B. and FEIGENBAUM,H. Effect of digitalis on conduction of the heart. Prop. Cardiovas. Dis., 6: 343, 1964.
160
Mason
and Braunwald
33.
LOWN, B., BLACK, H. and MOORE, F. D. Digitalis, Am. J. electrolytes and the surgical patient. CardioE., 6: 309, 1960.
34.
WEISSLER, A. M., GAMEL, W. G., GOODE, H. E., COHEN, S. and SCHOENFELD, C. D. The effects of digitalis on ventricular ejection in normal human subjects. Circulation, 29 : 721,1964.
35. SARNOFF, S. J., GILMORE, J. P., WALLACE, A. G., SKINNER, N. S., JR., MITCHELL, J. H. and DAGGETT, W. M. Effect of acetyl strophanthidin therapy on cardiac dynamics, oxygen consumption and efficiency in the isolated heart with and without hypoxia. Am. J. Med., 37: 3, 1964. 36.
Mechanism of digitalis action KOCH-WESER, J. New England J. Med., 277: 417, on the heart. 1967.
37.
COVELL, J. W., BRAUNWALD,E., Ross, J., JR. and SONNENBLICK,E. H. Studies on digitalis. XVI. Effects on myocardial oxygen consumption. J. Clin. Invest., 45: 1535, 1966.
38.
39.
COLEMAN, H. N., III. Role of acetylstrophanthidin in augmenting myocardial oxygen consumption: Relation of increased 02 consumption to changes Circulation Res., 21: in velocity of contraction. 487, 1967. TANZ, R. D. The action of ouabain on cardiac muscle treated with reserpine and dichloroisoproterenol. J. Pharmacol. G3 Exper. The@., 144: 205,1964.
40.
SPANN, J. F., JR., SONNENBLICK,E. H., COOPER, T., CHIDSEY, C. A., WILLMAN, V. L. and BRAUNWALD, E. Studies on digitalis. XIV. Influence of cardiac norepinephrine stores on the response Circulation of isolated heart muscle to digitalis. Res., 19: 326, 1966.
41.
ROBERTS, J., ITO, R., REILLY, J. and CAIROLI, V. J. Influence of reserpine and BTM 10 on digiCirculation talis-induced ventricular arrhythmia. Res., 13: 149, 1963.
42.
WILLIAMS, E. M. and SEKIYA, A. Prevention of arrhythmias due to cardiac glycosides by block of sympathetic beta receptors. Lancet, 1: 420,1963.
43.
MORROW, D. H., GAFFNEY, T. E. ~~~BRAUNWALD, E. Studies on digitalis. VIII. Effects of autonomic innervation and of myocardial catecholamine stores upon the cardiac action of ouabain. J. Pharmacol. & Exper. Therap., 140: 236, 1963.
44.
MORROW, D. H., GAPFNEY, T. E. and BRAUNWALD,
E. Studies on digitalis. VII. Influence of hyper- and hypothyroidism on the myocardial response to ouabain. J. Pharmacol. H Exper. Therap., 140: 324, 1963. 45.
FRYE, R. L. and BRAUNWALD, E. Studies on digitalis. 111. The influence of triiodothyroidine Circulation, 23: 376, on digitalis requirements. 1961.
BRAUNWAW, E., BLOODWELL, R. D., GOLDBERG, L. I. and MORROW, A. G. Studies on digitalis. IV. Observations in man on the effects of digitalis preparations on the contractility of the nonfailing heart and on total vascular resistance. J. Clin. Invest., 40: 52, 1961. 47. MASON, D. T. and BRAUNWALD, E. Studies on
digitalis. IX. Effects failing human heart. 1963.
of ouabain on the nonJ. Clin. Znuest., 42: 1105,
48.
SONNENBLICK,E. H., WILLIAMS, J. F., JR., GLICK, G., MASON, D. T. and BRAUNWALD, E. Studies on digitalis. xv. Effects of cardiac glycosides on myocardial force-velocity relations in the nonfailing human heart. Circulation, 34: 532, 1966.
49.
KAHLER, R. L., THOMPSON,R. H., BUSKIRK, E. R., FRYE, R. L. and BRAUNWALD, E. Studies on digitalis. VI. Reduction of the post-exercise oxygen debt with digoxin in patients with cardiac disease without heart failure. Circulation, 27: 397, 1962.
50.
WILLIAMS, J. F., JR. and BRAUNWALD, E. on digitalis. XI. Effects of digitoxin on velopment of cardiac hypertrophy in subjected to aortic constriction. Am. J. 16: 534, 1965.
51.
FRANKLIN, K. J. lated vein ring. 26: 215, 1925.
52.
LEONARD, E. Alteration of contractile response of artery strips by a potassium-free solution, cardiac glycosides, and changes in stimulation frequency. Am. J. Physiol., 189: 18.5, 1957.
53.
Extrakardiale LENDLE, L. and MERCKER, H. digitalis-wirkungen. Ergebn. Physiol., 51: 199, 1961.
54.
MASON, D. T. and BRAUNWALD, E. Studies on digitalis. x. Effects of ouabain on forearm vascular resistance and venous tone in normal subjects and in patients in heart failure. J. Clin. Invest., 43: 532, 1964.
55.
BRAUNWALD, E., CHIDSEY, C. A., POOL, P. E., SONNENBLICK,E. H., Ross, J., JR., MASON, D. T., SPANN, J. F., JR. and COVELL, J. W. Congestive heart failure. Biochemical and physiological considerations. Combined Clinical Staff Conference at the National Institutes of Health. Ann. Znt. Med., 64: 904, 1966.
56.
CHIDSEY, C. A. and BRAUNWALD, E. Sympathetic activity and neurotransmitter depletion in conPharmacol. Rev., 18: 685, gestive heart failure. 1966.
57.
BASCHIERI, L., RICCI, P. D., MAZZIJOLI, G. F. and VASSALLE, M. Studi su la portata epatica nell’ Modificazioni de1 flusso epatico da uomo: digitale. &ore e circoiaz., 41 : 103, 1957.
58.
DEGEEST,H., LEVY, M. N., ZIESKE, H. and LIPMAN, R. I. Repression of ventricular contractility by stimulation of the vagus nerves. Circulation Res., 17: 222, 1965.
59.
FROMMER,P. L., ROBINSON,B. F. AND BRAUNWALD, E. Paired electrical stimulation. A comparison of the effects on performance of the failing and nonfailing heart. Am. J. Cardiol., 18: 738, 1966.
60.
SPANN, J. F.,
46.
Studies the dethe rat Cardiol.,
The pharmacology of the isoJ. Pharmacol. G3 Exper. Therap.,
JR., BUCCINO, R. A., SONNENBLICK, E. H. and BRAUNWALD,E. Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circulation Res., 21: 341, 1967. THE AMERICAN JOURNAL OF CARDIOLOGY
Digitalis 61. BRADLEY, S. E. Discussion 62. 63.
of GREEN, H. D. Physiology of peripheral circulation in shock. Fed. Pm., 20: 61,1961. BRADLEY, S. E. The circulation and the liver. Gastroenterology.,44: 403, 1963. BEISER, G. D., EPSTEIN, S. E., STAMPFER, M., ROBINSON, B. and BRAUNWALD, E. Effects of oubain on reqlonse to exercise in mitral stenosis. New England J. Med., 278: 131, 1968.
DRUGS 280 VMOdihtO~ CoronuY
161 BRAUNWALD,E., BROCKENBROUGH, E. D. and FRYE, R. L. Studies on digitalis. V. Comoarison of the effects of ouabain on left ventricular dynamics in valvular aortic stenosis and hypertrophic subaortic stenosis. Circulation, 26: 166, 1962. CROWELL, J. W. and SMITH, E. E. Oxygen deficit and irreversible hemorrhagic shock. Am. J. Physiot., 206 : 313, 1964.
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22
AUGUST
Number
1968
2
Symposium on Congestive Heart Failure-II Digitalis:
New Facts About
DEAN T. MASON, M.D., F.A.C.C. &EUGENE Bethesda,
an Old Drug*
BRAUNWALD, M.D., F.A.C.C.
Maryland
T
but present evidence suggests that this action may be mediated through the potentiation of exPresent knowlcitation-contraction coupling. edge of the mechanisms that underlie the normal process of this coupling in heart muscle indicates that, at the time of the spike of the action potential or depolarization of the cell membrane, calcium and sodium ions selectively enter the cell, and potassium ions leave it.le3 Associated with excitation and altered membrane permeability to calcium ions is an increased concentration of free calcium available to the contractile proteins actin and myosin. These are arranged in overlapping filaments within the sarcomeres, the basic functional units of the myofibrils. There is considerable debate whether this calcium in the cytoplasm adjacent to the myofilaments (myoplasmic calcium) represents the same calcium taken up during depolarization. It may instead be derived, in whole or in part, from calcium bound in the sarcoplasmic reticulum, the release of which is stimulated by the calcium influx.3-6 Nevertheless, it is postulated that when the myoplasmic concentration of calcium ions exceeds a critical level, in the presence of mitochondrial-produced adenosine
HE PRECISE mechanisms of action and proper clinical applications of the cardiac glycosides have been the subject of more intensive investigation than any other area in cardiovascular Although many aspects of these pharmacology. agents continue to excite controversy, advances in the past few years have provided a great body of useful information concerning their pharmacodynamia: effects. This review focuses attention on recent studies that have permitted a new understanding of the mechanisms of action of the digitalis glycosides. Their fundamental cellular actions are stressed, and their possible effects on the contractile machinery of cardiac muscle formulated; then these concepts are extended to the important alterations of circulatory function the glycosides produce. Finally, these observations are integrated to provide a unified concept of the actions of the glycosides and to suggest a more rational clinical use of these agents. CELLULAR MECHANISM OF INOTROPIC ACTION Opinion is not unanimous concerning the exact manner in which digitalis initiates its powerful inotropic action on the myocardium,
* From the Cardio.logy Branch, National Heart Institute, Bethesda, Md. Section of Cardiovascular Address for reprints : Dean T. Mason, M.D., School of Medicine, Davis, Calif. 151
Medicine,
University
of California
152
Mason
and Braunwald
triphosphate (ATP) and the enzyme rnyofibrillar ATPase, cardiac contraction occurs as the thin actin filaments slide toward the mid-point of the sarcomere, thereby leading to the developThe relaxament of force and shortening.‘f8 tion phase of the cycle is thought to occur as the myoplasmir calcium is reaccumulated by the sarcoplasmir reticulum and calcium ions are displaced outward across the cell membrane. g,10 Calcium and Digitalis Action: These observations, which assign a central role to calcium in the process of excitation-contraction coupling, have been postulated to apply to the mechanism Thus, of action of cardiac-stimulating drugs. it has been suggested that an augmentation in the myoplasmic concentration of calcium ions produced by rardiotonic agents may lead to a In this manner, more forceful contractiorL3 the providing of a greater quantity of calcium ions for the enhancement of the chemical process involved with the active state of myocardial contraction may represent the final common cellular pathway by which a variety of drugs produce their inotropic action. These agents, however, may differ in the way they supply calcium ions The digitalis to the contractile machinery. glycosides, for example, appear to be capable of both increasing the influx of calcium during depolarization11v12 and promoting the release of In recalcium from sarcoplasmic reticulum.13 gard to this latter action, it has recently been demonstrated that sodium ions are able to release bound calcium from sarcoplasmic reticulum.14 Although there is no evidence to indicate a primary role for the influx of sodium at the time of depolarization in the initiation of the normal contractile process in cardiac muscle, the proposed competition between sodium and calcium in sarcoplasmic reticulum may be significant in the inotropic effect of the glycosides. The latter have recently been shown to enhance intracellular sodium transport through stimulation of cell membrane ATPase.15-20 However, the relevance of an action of glycosides on intracellular sodium is not clear. Thus, it is acknowledged that injections of sodium directly into skeletal muscle fiber cells do not produce and a specific effect of visible contractions,“’ sodium on microsomal-bound calcium has not been shown in some preparations.22 Digitalis and the Transverse Tubular System: Recent findings concerning the ultrastructure and function of the cardiac cell have been helpful in providing additional insight into the possible mode of action of digitalis.23-25
It has been shown that the cell membrane enveloping the cardiac fiber makes deep invaginations into the cell to form the transverse tubular system, thereby providing ready access of digitalis to the important enzyme systems of the transverse tubular membranes in the vicinity of the contractile proteins even if the drug does not leave the interstitial compartment. This observation is consonant with the view held by some investigators that physiologic concentrations of glycosides do not enter the intracellular space and thus may not have a direct action on Indeed, it has been sugactin and myosin. gested that radioactive digoxin may be specifically localized within the transverse tubular system adjacent to the sarcoplasmic reticulum in close proximity to the myofibrils.26 However, some investigations favor a more random distribution of the glycoside in heart muscle.27 DIGITALS
AND
POTASSIUM
The findings of recent investigations are compatible with the possibility that the arrhythmic action of digitalis may be mediated by a mechanism separate from that underlying the inotropic action. Thus, it was shown in experimental animals that the toxic actions of the glycoside may be diminished by potassium in clinically meaningful concentrations, although the positive contractile effect remains unalThis simple experiment demonstrated tered.28 that digitalis toxicity may be suppressed by the action of potassium, which reduces the autotnaticity of idioventricular pacemakers, without antagonizing the beneficial actions of the drug. When these findings are translated into a clinical setting, it would appear that in a patient with congestive heart failure undergoing rapid diuresis the administration of potassium to protect against the development of extrasystoles does not counteract the inotropic properties of Moreover, since the production of digitalis. digitalis-induced extrasystoles is accompanied by the loss of intracellular potassium, a basis is established for the administration of potassium to oppose the arrhythmias brought on by the glycoside. Digitalis-Induced Arrhythmias: The cellular mechanism by which the glycoside produces arrhythmias has not been fully elucidated. During repolarization of the cardiac cell, sodium is removed from it, and potassium returned to it by a membrane pump system. This system is also active throughout the period of diastole and maintains the characteristic THE AMERICAN
JOURNAL
OF
CARDIOLOGY
I Xgitalis c.oncentrations of the cations on either side of the cell membrane.2 Large concentrations of digitalis inhibit the pump ATPase activity in cellular membrane fractions prepared from a \:ariety of tissues.*8.2g~30 It is of interest that the inhibitory effects of digitalis on membrane ATPase are antagonized by excess potassium.‘s Inhibition of the pump mechanism results in the delayed return to the cell of potassium that effluxed after depolarization as well as continued loss of potassium from the cell during the remainder of the cardiac cycle. As a consequence of the actions of the glycosides, intracellular potassrum declines but intracellular sodium rises. Thus, it is suggested that some of the toxic properties of the glycoside are associated with intracellular potassium loss, and the inotropic actions with an augmentation of myoplasmic calcium concentration. These observations are contrary to the traditional belief that potassium loss from the cell is causally related to the cardiotonic action of the drug.31 On the other hand, the postulation that the fundamental cell.ular effects of the digitalis glycosides are the result of certain shifts of calcium, sodium and potassium is by no means settled. It is important to emphasize that the digitalisinduced toxicity referred to in this schema incorporates those arrhythmias resulting from an augmentation of pacemaker or spontaneous activity and a rise in diastolic resting potential within the cell. These disorders of increased automaticity include the atrial, nodal and ventricular extrasystoles and tachycardias which are often suppressed clinically by the administration of potassium. Not explained by this concept, and thus operative through yei another mechanism, are the toxic effects of digitalis related to its other electrophysiologic properties, such as the depression of conduction velocity which underlies the development of atrioventricular block and is thought to be intensified by potassium.32 Digitalis and Potassium Toxicity: The administration of digitalis to patients is known to result in a small elevation of serum potassium, the major source of which appears to be the liver.3a In addition, the drug tends to inhibit the potassium uptake by skeletal muscle.34 These observations which underscore the fact that potassium toxicity is readily provoked in patients receiving glycosides must be considered when treating digitalis intoxication with potassium. At the same time, in conditions leading to VOLUME
22,
AUGUST
1968
153
potassium loss from the body and thereby predisposing toward digitalis intoxication, the potassium loss is largely from the intracellular pool ; thus, the level of the serum potassium does not necessarily indicate increased susceptibility to digitalis intoxication. Relation Between Dose and hotropic Eject of Digitalis: Another important finding was disclosed during the study of the dissociation of the toxic from the inotropic effects of digitalis by the administration of potassium: the relation between the dose and the positive actions of digitalis on contractile force is essentially Iinear.2s This linear dose-inotropic effect was observed even when the glycoside was given in doses that produced arrhythmias that had to be suppressed by potassium. Thus, small and large doses of digitalis have similar qualitative effects. From these and other observations3* it is apparent that a patient need not receive a maximally tolerated dose of digitalis to achieve a beneficial effect. Even small amounts of the drug provide some therapeutic action, a point to be kept in mind if glycosides are used in a patient prone to digitalis intoxication or if the drug is employed prophylactically. ,METABOLIC EFFECTS AND MODIFICATION OF ACTIONS Since digitalis does not alter the amount of energy available for myocardial contraction, it has been traditionally believed that the drug somehow improves the contractility of the heart without augmenting myocardial oxygen consumption.35*36 This view implies that the drug ability to improve the possesses a unique efficiency of the heart by producing mechanical work without utilizing chemical energy. Since myocardial oxygen requirements are directly related to the tension developed by the myocardium, and therefore to the size of the heart and intraventricular pressure as well as to the velocity of contraction, the possibility was considered that digitalis might exert an over-all effect on myocardial oxygen consumption dependent on the hemodynamic setting in which it is administered. In the nonfailing heart of experimental animals the drug was demonstrated actually to augment the oxygen consumption of the heart and thus diminish cardiac Thus, in the absence of heart efFiciency.37 failure, digitalis markedly increases the velocity of myocardial shortening but minimally diHowever, in the minishes the size of the heart. enlarged and failing heart this direct effect on
the velocity of contractiorl to iwrease ~nyocardial oxygen consumption is masked and overridden by the marked fall in ventricular end-diastolic volume and systolic wall tension, and the result is an over-all decline of lnyocardial oxygen utilization and an increase in efflciency.3x From these observations, it is correct to consider that the beneficial actions of digitalis in the treatment of angina pectoris result from the improvement of impaired performance of the heart by reduction of the size of the heart and ventricular wall tension. In a patient without some degree of impairment of cardiac contractility, the glycoside may actually intensify angina1 symptoms, since the inotropic action in the nonfailing heart is produced at the cost of a disproportionately large increment of energy utilization. Thus, digitalis directly enhances the force of contraction accompanied by an increase in myocardial oxygen requirements, and in this respect acts like other positive inotropic agents. In agreement with these observations is the recent demonstration that acetylstrophanthidin augments myocardial oxygen consumption in papillary muscles from normal hearts of experimental animals.38 Digitalis and Cardiac Norepinephrint-: Digitalis evokes its powerful inotropic effect on the myocardium by a direct action, as outlined in the preceding section. The contention that it stimulates the heart by the release of cardiac norepinephrine3g has not been substantiated by recent investigations. Thus, digitalis exhibits its full inotropic properties in the absence of cardiac norepinephrine, and this action is additive to those of the catecholamines and to drugs that act through the release of endogenous Further, the complete stimunorepinephrine.40 lating effect of digitalis may be anticipated in the presence of beta adrenergic receptor blockade and in the presence af antiadrenergic drugs other than reserpine. In spite of the finding that reserpine interferes somewhat with the inotropic properties of digitalis, it does so apart from its norepinephrine-depleting actions4” Although the cardiac contractile actions of digitalis are not altered by changes in cardiac electronorepinephrine the concentration, physiologic properties of the drug are influenced by the catecholamine content. Thus, norepinephrine depletion or beta adrenergic receptor blockade reduces the incidence of digitalisinduced ventricular arrhythmias.41*42 In addition, a large part of the ability of digitalis to lengthen the functional refractory period of the
EKG
--L..$_-~
c
&__
Figure 1. Simultaneous Idcordings of left ventricular (LV) pressure and of teft ventkdar rate of change (dpldt) during controlperiod (top) and after ouabain administration (bottom). The presystolic augmentation of ventricular pressure, a, is barely perceptible before ouabain, but becomes clearly evident in the tracings recorded 35 minutes after the administration of the drug. (Reproduced by permission from MASON, D. T. and BRAUNWALD, E. J. C&n. I7west., 42: 1105, 1963.)47
atrioventricular node is dependent on sympathetic and parasympathetic innervation.43 The level of thyroid hormone may also modify the actions of the glycoside.44 In hyperthyroidism the cardiotonic and atrioventricular nodeblocking actions of any given dose of digitalis may be diminished, whereas patients with myxedema derive an enhanced inotropic effect and are particularly susceptive to digitalis intoxication with relatively small doses of the drug.45 ACTIONS
ON THE
NONFAILING
HEART
Although it has been appreciated for some time that digitalis stimulates the force of contraction of the failing heart, there has been considerable debate concerning its effects on the contractile state of the normal heart. Until quite recently the glycosides were thought to depress the function of the nonfailing heart, since their administration resulted in lowering of the cardiac output. The demonstration that the THE AMERICANJOURNALOF
CARDIOLOCY
I>igitalis
155
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Figure 2. EJects of ouobain on the force-velocity rrlationshifi of the left ventricle in a patient who had undergone surgical correction of mitral stenosis. A, representative curves relating left ventricular dimensions, determined at 1 per 30 second intervals, to time of individual cardiac cycles before and after the drug. The top of the cycle refers to ventricular end-diastolic length and the bottom to end-systolic length. The horizontal broken line represents the isolength (1~1) line at which bath instantaneous velocity of shortening and intraventricular pressure were determined. The diagonal broken lines are tangents to the length curves and represent the velocity of shortening. The steeper tangent after ouabain signifies an increase of veloci ty. The temporally related ventricular pressure is shown in millimeters of mercury, and the calculated velocity in length per second. Below are shown the corresponding values for cardiac index (C.I.), stroke volume index (S.I.), left ventricular ejection time (E.T.) and the mean systolic ejection rate (MSER). B, the force (pressure)-velocity relation before and after ouabain. Each point represents analysis of a single cardiac cycle. Ouabain raised the velocity considerably and the pressure minimally. (Reproduced by permission from SONNENBLICK, E. H. et al. Circulation, 34: 532, 1366.)‘s
measurement of the cardiac output response alone does not necessarily equate with the inotropic state of the myocardium has led to the reassessment of this problem in relation to the actions of the glycosides on the nonfailing heart. In studies of the effects of acute digitalization at the time of surgical correction in patients .with uncomplicated congenital cardiac defects, it was shown that the glycosides are capable of increasing the contractile force of the nonfailing human heart.46 These observations have recently been extended to nonfailing hearts of intact unanesthetized patients. Thus, both in patients with heart disease but without heart failure and in normal subjects, digitalis increases the rate of rise of intraventricular pressure, and presumably tension, during contraction, thus indicating that the drug augments the contractility of the nonfailing myocardium (Fig. 1).47 There is also indirect evidence that the force of atria1 contraction is stimulated as well (Fig. 1).47 These VOLUME
22,
AUGUST
1968
findings are further substantiated in these patients by the demonstration that digitalis augments the velocity of ventricular shortening during systolic emptying at a constant ventricular size and tension (Fig. 2).48 From these observations, it is apparent that the glycosides exert the same fundamental inotropic action on both normal and failing hearts; therefore the notion that the drug has a harmful effect on the nonfailing heart can no longer be maintained. Further support to the view that digitalis may produce a favorable effect on the nonfailing heart is the finding that it lowers the oxygen debt after exercise in patients with cardiomegaly but without heart failure.49 Thus, the performance of the circulatory system may be improved by digitalis in some patients with a limited cardiac reserve but without cardiac decompensation. In addition, the glycosides appear to have the capacity to support the response of the heart to the long-standing augmentation of ventricular afterload or the resistance to
ventricular ejection. In experimental animals, the drug reduced total mortality and the degree of ventricular hypertrophy resulting froul chronic constriction of the descending aorta.j” The prophylactic value of digitalization in sustaining cardiac performance during cxperimentally produced chronic increase in ventrirular preload is currently under im-estigation. ACTIONS ON
ARTERIOLES
AKD \7er~s
Normal Subjects: The finding that the digitalisinduced stimulation of the force of contraction of the normal heart is not translated into an increase in cardiac output suggests possible extracardiac effects of the drug. Early observations that digitalis constricts isolated arterial and venous segments and produces arteriolar and venous constriction in the dogi’--j3 have been extended to man. Patients 011 cardiopulmonary bypass at a constant perfusion rate were found to increase their systemic vascular resistance in response to acetylstrophanthidin.4” This action has been clarified more recently by the finding that commonly used doses of ouabain result in constriction of both the arteriolar and venous beds of the forearm, and elevate the total peripheral vascular resistance in intact normal subjects (Fig. 3).“”
Since these peripheral vascular actions of digitalis in normal subjects are not diminished b) the prior administration of antiadrenergic drugs, the vasoconstriction is mediated by a direcr stimulating action of the glycoside.“4 Patients with Heart Failurr: In contrast to normal subjects, in patients with heart failure the digitalis glycosides lower the elevated total peripheral vascular resistance and forearm arteriolar resistance and venous tone toward normal (Fig. 4).54 It is now well documented that the activity of the sympathetic nervous system increases in congestive heart failure to support the circulation in the face of diminished myocardial contractility and cardiac output.55r5” The explanation for the opposite over-all effects of digitalis in patients with heart failure and normal subjects appears to be that the marked inotropic action and elevation of cardiac output
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Figure 3. Serial determinations of brachial arterial e ssure (BA), forearm blood flow, forearm vascular resistance, venous tone, cardiac output, and systemic vascular resistance before and after ouabain in a normal subject. (Reproduced by permission from Masori, D. T. and BRAUNWALD, E. J. Clin. Invest., 43: S32. 1964.)&a
OUTPUT
TIME
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Figure 4. S&al measurements before and after ouab& in a patient with congestive heart failure. (Reproduced by permission from MASON, D. T. and BRAUNWALD, E. J. Cfin. Imest., 43 : 532, 1964.)&t I HE
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Digitalis produced by the drug indirectly allows a withdrawal of some of this adrenergically mediated vasoconstriction. This vasodilation is not a direct effect of digitalis; rather, it occurs in spite of the direct vasoconstrictor action of the drug and overrides this latter effect. In this regard, it is interesting to postulate that if adrenergic blockade could be safely produced in patients with heart failure, the administration of digitalis should result in unopposed vasoconstriction. UNIITIED CONCEPT OF HEM~DYNAMIC ACTIONS Having considered the central and peripheral vascular actions of digitalis it is now possible to synthesize the over-all effects of the drug on the circulation. In the hearts of normal subjects and patients with heart disease without failure, the drug directly increases the force of contraction, but an increase in cardiac output may not be observed. The arteriolar constriction produced by the drug augments the resistance to ventricular ejection. Some investigators have suggested that the drug-induced systemic venoconstriction i;s accompanied by a rise in the hepatic venous wledge pressure and a widening of the gradient between the portal venous and the inferior vena caval pressuress7 Thus, the increase in ventricular afterload, in the presence of an inconstant or weak effect on ventricular preload, may mask the effect of the drug in increasing myocardial contractility, thus leading to no change or a fall in cardiac output. In addition, it is now acknowledged that there is at least a minor component of vagal innervation of the ventricles58:, stimulation of this system by the parasympathomimetic actions of digitalis may produce a negative inotropic effect, which also tends to offset the more powerful direct action of the glycoside. positive inotropic Finally, in attempting to explain the absence of an increase in cardiac output in response to digitalis in the normal heart, it is pertinent to recall that the cardiac output is determined and maintained at an appropriate level by the interaction of a number of cardiac and extracardiac factors. Thus, although digitalis directly enhances cardiac contraction, this action may be offset to an extent by withdrawal of sympathetic stimulation of myocardial contend to tractility, as reflex mechanisms modulate the effects of the drug in order to maintain cardiac output at a constant level. In this regard, the failure of the glycoside to VOLUME
22,
AUGUST
1968
157
augment cardiac output is similar to the effect of paired electrical stimulation on the normal heart and circulation.5s These observations are also consistent with the existence of an absolute ceiling of myocardial contractility and the fact that the normal heart operates close to this top level of performance.+jO In patients with cardiac decompensation, digitalis directly improves the contractile state of the heart apparently to the same degree as Because this cardiotonic in normal hearts.60 effect is not accompanied by compensatory readjustments that tend to reduce cardiac output, the powerful direct inotropic action of the drug results in a large augmentation of the lowered cardiac output and improvement of the other hemodynamic features characteristic of the state In contrast to normal subof heart failure. jects, in patients with heart failure there is indirect over-all arteriolar and venodilation that is derived from the large rise of cardiac output, leading to the reflex release of elevated sympathetic tone in the peripheral vascular beds. In this manner, arterial blood pressure and cardiac output are maintained with less of an augmentation of arteriolar resistance and venous tone. the digitalis-induced reduction of Further, peripheral vascular resistance in itself allows for some improvement in cardiac output. The observed vasodilation occurs in spite of the direct vascular constrictor action of digitalis and would be even greater if the latter effect were Of interest is that if cardiac failure is absent. only mild, the direct stimulating effect and the indirect relaxing action of the drug on the blood vessels may be equally balanced, and thus no alteration of vascular tone is observed. The relaxing effects of the glycosides on the veins in heart failure provide a basis for the clinical observation that the rapid administration of digitalis to these patients produces a fall in the systemic venous pressure before the onset of diuresis and decline of the elevated blood volume. Further, Bradley61s62 has shown that digitalis results in a decline of the splanchnic blood volume in patients with heart failure, presumably due to its ability to eliminate wideBy this acspread systemic venoconstriction. tion there is displacement of blood from the splanchnic vascular bed to the systemic venous system. Thus, despite over-all systemic venodilation and reduced central venous pressure after digitalis, venous return is actually increased as a result, in part, of this shift of blood in the venous reservoirs to the systemic bed. In ad-
158 dition, allows from a ducing
Mason
and Braunwald
the glycoside-induced inotropic effect a more forceful ventricular contraction relatively lower filling pressure, thus promarked enchancement of cardiac output. CURRENT CLINICAL APPLICATIONS
A thorough understanding of the pharmacodynamics of the digitalis glycosides is central to The the sound use of these drugs in patients. principal direct action of digitalis of clinical importance is its ability to stimulate the contractile state of the heart. Thus, the primary indication for its use continues to be the presence of heart failure secondary to absolute or relative myocardial dysfunction, regardless of the setting As might in which the decompensation occurs. be expected, digitalis is of most benefit when heart failure is the result of chronic muscle malfunction or of systolic and diastolic overThe glycosides are of loading of the ventricles. little value in conditions in which heart failure is due to pure extramyocardial causes which limit the filling of the ventricle, such as constrictive pericarditis or mitral stenosis with normal sinus rhythm. 63 The inotropic action of digitalis may actually be harmful in one condition, idiopathic hypertrophic subaortic stenosis, in which not only the force of contraction of the left ventricular body is augmented, but also that of the obstructing myocardium in the outflow tract within the left ventricle, thus leading to a further mechanical burden to systolic emptying.64 There is increasing agreement that digitalis may be beneficial during special situations of stress in certain patients with heart disease Thus, prophylactic without heart failure. digitalization may protect the myocardium in such patients who experience the depressing effects of anesthesia and operation, serious illness such as pneumonia, or hypervolemia during Of potential clinical importance pregnancy. is the possibility that digitalis may diminish the degree of ventricular hypertrophy in patients with hypertension and obstruction to left ventricular outflow even in the absence of heart failure. Since a state of heart failure often exists in acute myocardial infarction without pulmonary edema, digitalis is now often used before the more obvious signs of decompensation and in the presence of cardiogenic shock. Of related importance is that the digitalis glycosides have been helpful in enhancing survival in hypovolemic shock in experimental animals.65 The other major therapeutic action of digitalis results from its effect on the electrophysiologic
properties of the heart, and it is therefore useful in the treatment of certain disorders of cardiac rhythm. Thus, even in the absence of heart failure, the glycosides increase the refractory period of the atrioventricular node, thereby reducing the ventricular rate and increasing the cardiac output in patients with atria1 fibrillation. In addition, they are helpful in suppressing all types of supraventricular tachycardias, apparently by a parasympathomimetic action. SUMMARY Present evidence suggests that the fundamental hemodynamic property of the digitalis glycosides to improve the contractile state of the myocardium rests upon the cellular action of the drugs to potentiate excitation-contraction coupling. This effect appears to be mediated by glycoside-induced enhancement of the concentration of calcium ions in the endoplasm surrounding the myofibrils at the time of cardiac contraction. It is likely that the arrhythmiaprovoking properties of digitalis are related to the loss of intracellular potassium and the inhibition by the drug of the membrane pump ATPase system required for maintaining inThe postracellular potassium concentrations. tulation that the inotropic and certain toxic actions of digitalis are mediated by different mechanisms is helpful clinically since the two properties of the glycoside can be dissociated by the administration of potassium. The over-all metabolic and hemodynamic effects of the glycosides are closely dependent on the state of the circulation at the time the agent is employed. Thus, the drugs have the direct property of increasing the oxygen utilization of the myocardium while producing their inotropic effect, manifested by a rise in the velocity of contraction, and in this respect they possess no unique ability to improve the efficiency of the heart. However, this action to increase myocardial oxygen requirements is masked and offset in the presence of heart failure, since the reduction of myocardial systolic wall tension by the drug diminishes the oxygen demand of the heart more than the direct inotropic effect tends to augment it. Similarly, the alterations of cardiocirculatory dynamics produced by the drug are related to the hemodynamic condition of the patient. Thus, in the absence of heart failure, the inotropic effect is not translated into an increase in cardiac output. In contrast, in patients with congestive heart failure, the improveTHE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Digitalis ment of the contractile state of the failing myocardium by the glycoside elevates the cardiac output to a marked degree, allowing a diminution of the ele\rated adrenergically-induced arteriolar resistance and venous tone and a shift of venous blood out of the portal into the systemic venous compartment. Thus, digitalis possesses both direct and indirect cardiac and extracardiac actions, and the over-all alterations of circulatory dynamics depend on the hemodynamic status of the patient. REFERENCES 1. WINEGRAD, S. and SHANES, A, M. Calcium flux and contractility in guinea pig atria. J. Gen. Physiol., 45: 3X1, 1962. 2. SINGER, D. H., LAZZARA, R. and HOFFMAN, B. F. Transmembrane potentials of cardiac cells and their ionic basis. In: The Myocardial Cell. Structure, Function, and Modification by Cardiac Drugs, p. 73. Edited by BRILLER, S. and CONN, H., JR. Philadelphia, 1966. University of Pennsylvania Press. 3. NAYLER, W. G. Calcium exchange in cardiac muscle: A basic mechanism of drug action. Am. Heart J., :‘3: 379, 1967. 4. WINEGRAD, S. The possible role of calcium in excitation-contraction coupling of heart muscle, Circulation, 24: 523, 1961. 5. NIEDERGERKE,R. Movements of Ca in beating ventricles of the frog. J. Physiol., 167: 551, 1963. 6. SANDOW, A. Excitation-contraction coupling in skeletal muscle. Pharmwol. Rev., 17: 265, 1965. 7. DAVIES, R. E. .4 molecular theory of muscle contraction: Calcium-dependent contractions with hydrogen bond formation plus ATP-dependent extensions of part of the myosin-actin crossbridges. N&tire, London, 199: 1068, 1963. 8. DAVIES, R. E. The role of ATP in contraction. In Ref. 2, p. 157. 9. WEBER, A., HER.Z, R. and REISS, I. On the mechanisms of the relaxing effect of fragmented sarcoplastic reticulum. J. Gen. Physiot., 46: 679, 1963. 10. WEBER, A. The role of Ca in the regulation of muscle activity. In Ref. 2, p. 131. Il. LULLMANN, N. and HOLLARD, W. Influence of ouabain on an exchangeable calcium fraction, contractile force, and resting tension of guinea pig atria. J. Pharmacol. &? Exfer. Therap., 137: 186, 1962. 12. GROSSMAN, A. and FURCHGOTT,R. F. The effects of external calcium concentration on the distribution and exchange of calcium in resting and beating guinea-pig auricles. J. Pharmacol. & E.x@r. Therap., 143: 107, 1964. 13. LEE, K. S., Yu, D. H. and STRUTHERS, J. J. A study of the effect of cardiac glycosides on the syneresis of myofibrils in the presence of relaxing factor. J. Pharmacol. &? Exper. Thzraj., 148: 227, 1965. 14. PALMER, R. F. and POSEY, V. A. Ion effects on calcium accumulation by cardiac sarcoplasmic reticulum. J. Gen. Physiol., 50: 2085, 1967. VOLUME 22, AUGUST 1968
15. BONTING, S. L. and CARAVAGGIO,L. L. Studies on sodium-potassium-activated adenosine triphosv. Correlation of enzyme activity phatase. with cation flux in six tissues. Arch. Biochem., 101, 37, 1963. 16. LEE, K. S. and Yu, D. H. A study of the sodiumand potassium-activated adenosinetriphosphatase activity of heart microsdmal fraction. Biothem. Pharmacol., 12, 1253, 1963. Metabolism of cardiac glycosides. In : 17. REPKE, K. First International Pharmacological Meeting, Vol. 3, p. 47. Edited by WILBRANDT, W. and LINDGREN, P. Oxford, England, 1961. Pergamon Press. 18. PALMER, R. F. and NECHAY, B. R. Biphasic renal Correlation effects of ouabain in the chicken: with a microsomal Na+-K+ stimulated ATP-ase. J. Pharmacol. tY Exper. Therap., 146: 92, 1964. 19. PALMER,R. F., LASSETER,K. C. and MELVIN, S. L. Stimulation of Na+andK+dependent adenosine triphosphatase by ouabain. Arch. Biochem., 113: 629,1966. 20. WILBRANDT, W. The mechanism of action of cardiac glycosides. In Ref. 2, p. 297. 21. CALDUTELL,P. C. and WALSTER, G. Studies on the micro-injection of various substances into crab muscle fibers. J. Physiol., 169: 353, 1963. 22. KATZ, A. M. and REPKE, D. I. Sodium and potassium sensitivity of calcium uptake and calcium binding by dog cardiac microsomes. Circulation Res., 21: 767, 1967. 23. SPIRO, D. The fine structure and contractile mechanism of heart muscle. In Ref. 2, p. 13. 24. SONNENBLICK, E. H. The mechanics of myocardial contraction. In Ref. 2, p. 173. 25. BRAUNWALD, E., Ross, J., JR. and SONNENBLICK, E. H. Mechanisms of contraction of the normal and failing heart. New England J. Med., 277: 794,1967. 26. SONNENBLICK, E. H., SPOTNITZ, H. M. and SPIRO, D. Role of the sarcomere in ventricular function and the mechanism of heart failure. Circulation Res., 15 (Suppl. 2): 70, 1964. 27. LUCHI, R. J. Some biochemical reactions influenced by the digitalis glycosides. In Ref. 2, p. 309. 28. WILLIAMS, J. F., JR., KLOCKE, F. J. ~~~BRAUNWALD, E. Studies on digitalis. XIII. Comparison of the effects of potassium on the inotropic and arrhythmia-producing actions of ouabain. J. Clin. Invest., 45: 346, 1966. 29. GLYNN, I. M. The action of cardiac glycosides on sodium and potassium movement in human red cells. J. Physiol., 136: 148, 1957. 30. BONTING,S. L., CARAVAGGIO, L. L. and HAWKINS, N. M. Studies on sodium-potassium-activated adenosine triphosphatase. IV. Correlation with cation transport sensitive to cardiac glycosides. Arch. Biochem., 98: 413, 1962. 31. HAJDU, S. and LEONARD, E. The cellular basis of cardiac glycoside action. Pharmacoi. Rev., 11: 173,1959. 32. FISCH, C., GREENSPAN, K., KNOEBEL, S. B. and FEIGENBAUM,H. Effect of digitalis on conduction of the heart. Prop. Cardiovas. Dis., 6: 343, 1964.
160
Mason
and Braunwald
33.
LOWN, B., BLACK, H. and MOORE, F. D. Digitalis, Am. J. electrolytes and the surgical patient. CardioE., 6: 309, 1960.
34.
WEISSLER, A. M., GAMEL, W. G., GOODE, H. E., COHEN, S. and SCHOENFELD, C. D. The effects of digitalis on ventricular ejection in normal human subjects. Circulation, 29 : 721,1964.
35. SARNOFF, S. J., GILMORE, J. P., WALLACE, A. G., SKINNER, N. S., JR., MITCHELL, J. H. and DAGGETT, W. M. Effect of acetyl strophanthidin therapy on cardiac dynamics, oxygen consumption and efficiency in the isolated heart with and without hypoxia. Am. J. Med., 37: 3, 1964. 36.
Mechanism of digitalis action KOCH-WESER, J. New England J. Med., 277: 417, on the heart. 1967.
37.
COVELL, J. W., BRAUNWALD,E., Ross, J., JR. and SONNENBLICK,E. H. Studies on digitalis. XVI. Effects on myocardial oxygen consumption. J. Clin. Invest., 45: 1535, 1966.
38.
39.
COLEMAN, H. N., III. Role of acetylstrophanthidin in augmenting myocardial oxygen consumption: Relation of increased 02 consumption to changes Circulation Res., 21: in velocity of contraction. 487, 1967. TANZ, R. D. The action of ouabain on cardiac muscle treated with reserpine and dichloroisoproterenol. J. Pharmacol. G3 Exper. The@., 144: 205,1964.
40.
SPANN, J. F., JR., SONNENBLICK,E. H., COOPER, T., CHIDSEY, C. A., WILLMAN, V. L. and BRAUNWALD, E. Studies on digitalis. XIV. Influence of cardiac norepinephrine stores on the response Circulation of isolated heart muscle to digitalis. Res., 19: 326, 1966.
41.
ROBERTS, J., ITO, R., REILLY, J. and CAIROLI, V. J. Influence of reserpine and BTM 10 on digiCirculation talis-induced ventricular arrhythmia. Res., 13: 149, 1963.
42.
WILLIAMS, E. M. and SEKIYA, A. Prevention of arrhythmias due to cardiac glycosides by block of sympathetic beta receptors. Lancet, 1: 420,1963.
43.
MORROW, D. H., GAFFNEY, T. E. ~~~BRAUNWALD, E. Studies on digitalis. VIII. Effects of autonomic innervation and of myocardial catecholamine stores upon the cardiac action of ouabain. J. Pharmacol. & Exper. Therap., 140: 236, 1963.
44.
MORROW, D. H., GAPFNEY, T. E. and BRAUNWALD,
E. Studies on digitalis. VII. Influence of hyper- and hypothyroidism on the myocardial response to ouabain. J. Pharmacol. H Exper. Therap., 140: 324, 1963. 45.
FRYE, R. L. and BRAUNWALD, E. Studies on digitalis. 111. The influence of triiodothyroidine Circulation, 23: 376, on digitalis requirements. 1961.
BRAUNWAW, E., BLOODWELL, R. D., GOLDBERG, L. I. and MORROW, A. G. Studies on digitalis. IV. Observations in man on the effects of digitalis preparations on the contractility of the nonfailing heart and on total vascular resistance. J. Clin. Invest., 40: 52, 1961. 47. MASON, D. T. and BRAUNWALD, E. Studies on
digitalis. IX. Effects failing human heart. 1963.
of ouabain on the nonJ. Clin. Znuest., 42: 1105,
48.
SONNENBLICK,E. H., WILLIAMS, J. F., JR., GLICK, G., MASON, D. T. and BRAUNWALD, E. Studies on digitalis. xv. Effects of cardiac glycosides on myocardial force-velocity relations in the nonfailing human heart. Circulation, 34: 532, 1966.
49.
KAHLER, R. L., THOMPSON,R. H., BUSKIRK, E. R., FRYE, R. L. and BRAUNWALD, E. Studies on digitalis. VI. Reduction of the post-exercise oxygen debt with digoxin in patients with cardiac disease without heart failure. Circulation, 27: 397, 1962.
50.
WILLIAMS, J. F., JR. and BRAUNWALD, E. on digitalis. XI. Effects of digitoxin on velopment of cardiac hypertrophy in subjected to aortic constriction. Am. J. 16: 534, 1965.
51.
FRANKLIN, K. J. lated vein ring. 26: 215, 1925.
52.
LEONARD, E. Alteration of contractile response of artery strips by a potassium-free solution, cardiac glycosides, and changes in stimulation frequency. Am. J. Physiol., 189: 18.5, 1957.
53.
Extrakardiale LENDLE, L. and MERCKER, H. digitalis-wirkungen. Ergebn. Physiol., 51: 199, 1961.
54.
MASON, D. T. and BRAUNWALD, E. Studies on digitalis. x. Effects of ouabain on forearm vascular resistance and venous tone in normal subjects and in patients in heart failure. J. Clin. Invest., 43: 532, 1964.
55.
BRAUNWALD, E., CHIDSEY, C. A., POOL, P. E., SONNENBLICK,E. H., Ross, J., JR., MASON, D. T., SPANN, J. F., JR. and COVELL, J. W. Congestive heart failure. Biochemical and physiological considerations. Combined Clinical Staff Conference at the National Institutes of Health. Ann. Znt. Med., 64: 904, 1966.
56.
CHIDSEY, C. A. and BRAUNWALD, E. Sympathetic activity and neurotransmitter depletion in conPharmacol. Rev., 18: 685, gestive heart failure. 1966.
57.
BASCHIERI, L., RICCI, P. D., MAZZIJOLI, G. F. and VASSALLE, M. Studi su la portata epatica nell’ Modificazioni de1 flusso epatico da uomo: digitale. &ore e circoiaz., 41 : 103, 1957.
58.
DEGEEST,H., LEVY, M. N., ZIESKE, H. and LIPMAN, R. I. Repression of ventricular contractility by stimulation of the vagus nerves. Circulation Res., 17: 222, 1965.
59.
FROMMER,P. L., ROBINSON,B. F. AND BRAUNWALD, E. Paired electrical stimulation. A comparison of the effects on performance of the failing and nonfailing heart. Am. J. Cardiol., 18: 738, 1966.
60.
SPANN, J. F.,
46.
Studies the dethe rat Cardiol.,
The pharmacology of the isoJ. Pharmacol. G3 Exper. Therap.,
JR., BUCCINO, R. A., SONNENBLICK, E. H. and BRAUNWALD,E. Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circulation Res., 21: 341, 1967. THE AMERICAN JOURNAL OF CARDIOLOGY
Digitalis 61. BRADLEY, S. E. Discussion 62. 63.
of GREEN, H. D. Physiology of peripheral circulation in shock. Fed. Pm., 20: 61,1961. BRADLEY, S. E. The circulation and the liver. Gastroenterology.,44: 403, 1963. BEISER, G. D., EPSTEIN, S. E., STAMPFER, M., ROBINSON, B. and BRAUNWALD, E. Effects of oubain on reqlonse to exercise in mitral stenosis. New England J. Med., 278: 131, 1968.
DRUGS 280 VMOdihtO~ CoronuY
161 BRAUNWALD,E., BROCKENBROUGH, E. D. and FRYE, R. L. Studies on digitalis. V. Comoarison of the effects of ouabain on left ventricular dynamics in valvular aortic stenosis and hypertrophic subaortic stenosis. Circulation, 26: 166, 1962. CROWELL, J. W. and SMITH, E. E. Oxygen deficit and irreversible hemorrhagic shock. Am. J. Physiot., 206 : 313, 1964.
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