lACC Vol. ~ . No.2 389 August J98· ~ 389-97

BASIC CONCEPTS IN CARDIOLOGY

Arnold M. Katz, MD, FACC, Guest Editor

Inotropic Drugs and Their Mechanisms of Action

HASSO SCHOLZ, MD Hamburg, West Germany

This report describes various old and new positive ino­ The latter resemble theophylline and other methylxan­ tropic drugs with respect to their mechanisms of action. thines in that they appear to act mainly as phosphodi­ Drugs with established cardiotonic effects include car­ esterase inhibitors with a subsequent increase in cyclic diac glycosides, betaj-adrenergic agents, glucagon, his­ adenosine monophosphate (cAMP). The mechanism of tamine and the methylxanthines. New agents discussed the positive inotropic effect of alpha-adrenergic stimu­ art: prenalterol, betas- and alpha-adrenergic drugs, am­ lating agents (for example, phenylephrine) is unknown. rinone and sulmazole. Prenalterol is a betaj-adrenergic It is independent of the cAMP system and is not accom­ agent. Betaj-adrenerglc drugs, amrinone and sulmazole, panied by changes in frequency. combine a positive inotropic and a vasodilator effect.

Agents that increase the force of contraction of the heart (Fig. I) (7-11). Depolarization of the sarcolemma, that is, are referred to as positive inotropic or cardiotonic drugs. the Na + -dependent upstroke of the action potential , is the The increase in the force of myocardial contraction is ul­ initial event. The depolarization of the cell membrane allows 2 z timately due to an increase in intracellular free Ca + [Ca + li CaZ+ to move down its electrochemical gradient and enter to interact with the contractile proteins or to an increased the cell from the extracellular space during the plateau phase sensitivi ty of the myofilaments for Caz+ , or both. This re­ of the action potential (slow CaZ + inward current [Isil; Fig. port discusses how these variables might be affected by I , step I). The major part of the Caz+ entering the cell various inotropic drugs. Agents with established inotropic during the action potential serves to fill intracellular stores effect, such as cardiac glycosides, beta-adrenergic drugs, (presumably the subsarcolemmal cisternae of the sarco­ methylxanthines, glucagon and histamine, are described first. plasmic reticulum) and trigger the release of Ca? + from the The second part of the report is concerned with new car­ sarcoplasmic reticulum into the cytosol to react with the diotonic agents or those still under investigation. These in­ contractile proteins (Fig. I, step 2). The mean rest level of clude prenalterol, beta-adrenergic and alpha-adrenergicdrugs, [Ca2+]i is about 0.3 p.M; the activation of the contractile arnrinone and sulmazole. For a more comprehensive dis­ proteins requires an increase to above this value with half cussion of the topic and a more extensive bibliograph y, the maximal and maximal responses occurring at about 2 p.M reader is referred to several recent reviews (1-6). and 10 p.M, respectively (12) . Relaxation occurs on low­ ering the [Ca2 +]j to below the rest level. This results from Mechanisms Activating Contraction and the uptake of Caz+ by the longitudinal part of the sarco­ Relaxation of Cardiac Muscle plasmic reticulum (Fig. I, step 3). Finally, there is an ex­ trusion of Caz+ to the extracellular space to avoid a Ca! " All cardiotonic drugs interact with one or more of the overload. This transport of Caz+ out of the cell is achieved steps involved in contraction and relaxation of the heart mainly through a CaZ +INa+ exchange system (Fig. 1, step

From the Abteilung Allgemeine Pharmakologie , Universitiits-Kran­ kenhaus Eppendorf , Universitiit Hamburg , Hamburg, West Germany . Manuscript received February I, 1984; revised manuscript received March This article is part ofa continuing series ofinformal teach­ 5, 1984, accepted March 16, 1984. ing reviews devoted to subjects in basic cardiology that are Address for reprints: Hasso Scholz. MD , Abteilung Allgemeine Pharmako.ogie, Universitats-Krankenhaus Eppendorf, Martinistrasse 52, of particular interest because of their high potential for n-zooo Hamburg 20, West Germany . clinical application.

©t984 by .he American College of Cardiology 0735-1097/84/$3 .00 390 SCHOLZ JACC Vol. 4, No.2 MECHANISMS OF ACTION OF INOTROPIC DRUGS August 1984:389-97

Ca++ elimination Figure 1. Schematic summaryof the mech­ from cytosol Na+ n anisms leading to contraction and relaxation Ca++ release in the mammalian heart. I = calciuminflow I into cytosol into the cell during the action potential;2 = releaseof calciumfrom subsarcolemmal cis­ ternaeof the sarcoplasmic reticulum (storage site) and diffusion throughthe cytosol to the contractile proteins; 3 = uptake of calcium into the longitudinal part of the sarcoplasmic reticulum (relaxation site); 4 = calcium transport outof the cellthrough theCa2 +INa+ exchange system; 5 = release of calcium fromand uptakeof calciuminto sarcolemmal stores; and 6 = the sodium pump (Na" + K+)-ATPase.

4) that, under equilibrium conditions, follows the equation: is the most important event. The inhibition of Na + transport out of the cell results in an increase in the intracellular Na+ [Ca2 +]. = [Ca2+] [Na+]f exp (n - 2) FV concentration which, by way of an effect on the transsar­ I 0 [Na+]~ RT' colemmal Caz+INa+ exchange described earlier, leads to where n is the number of Na + that exchanges for one Caz+ an increase in [Ca2+L. In other words, the accumulation of ion, V is the membrane potential and F, Rand T are the Na + at the inside of the sarcolemma competitively inhibits Faraday constant, the universal gas constant and the absolute the efflux of Ca!" by way of the Ca2+INa + exchange system temperature, respectively (13). Its driving force is the con­ that normally carries Caz+ out of the cell. The result of the centration gradient for Na + across the sarcolemma which, decrease in Ca?+ efflux is an increase in [Caz+Ji. This view in tum, is accomplished largely by the sarcolemmal sodium has recently gained considerable support by Lee and Da­ pump, (Na " + K+)-ATPase (Fig. 1, step 6). The exact gostino (18) and Wasserstrom et al, (19), who showed through stoichiometry of the Caz+INa + exchange system has not the use of Na +-sensitive intracellular microelectrodes that yet been resolved, but it is important to note in the present changes in intracellular Na + activity and in twitch tension context (especially with respect to the cardiac glycosides) produced by therapeutic concentrations of cardiac glyco­ that only a very small increase in [Na +]i is required to sides were closely correlated. Quantitatively, a 1 mM in­ achieve a relatively large increase in [Ca2+]i and, hence, crease in intracellular sodium activity (which is barely de­ in the force of contraction. tectable with chemical methods) was accompanied by about A smaller amount of Caz+ efflux may also be mediated a 100% increase in force of contraction. by a sarcolemmal Caz+ pump that uses adenosine triphos­ Other investigators (15) assume that such an inhibition phate in a fashion analogous to the sodium pump. of (Na " + K+)-ATPase activity is only important during toxic actions of these agents. The interaction of therapeutic concentrations with the (Na" + K+)-ATPase would not Established Cardiotonic Drugs necessarily inhibit the enzyme, but instead could lead to a less stable Caz+ binding within the sarcolemma and, hence, Cardiac Glycosides to an increased Caz+ release from sarcolemmal Ca2+ stores The cardiac glycosides remain the most commonly used during excitation (Fig, 1, step 5). This view, however, is agents for the long-term management of congestive heart still highly controversial. failure. It is generally accepted that these drugs ultimately Increase in (lsi)' Another still unresolved question is the lead to an increase in the amount of intracellular Ca' + avail­ effect ofcardiac glycosides on the slow Caz+ inward current able to react with the contractile proteins, but the exact (Is;)' Some authors found that cardiac glycosides increase mechanisms through which this can be achieved are still a Is;, but this was not in accord with reports from others matter of considerable debate (14-17). There is no doubt (20,21), However, the reported increase in lsiapparently did that the cardiac glycosides interact with the (Na + + K +)­ not result from a direct interaction between drugs and slow ATPase and that this enzyme represents the "cardiac gly­ channels, but instead was indirect and resulted from an coside receptor," but the subsequent steps are unsettled. increase in [Ca2+L achieved by other mechanisms, More­ Inhibition of (Na+ + K +)·ATPase activity. Many au­ over, the changes in Caz+ influx by way of lsidid not appear thors argue that inhibition of (Na + + K +)-ATPase activity to be absolutely required for positive inotropy. Thus, I be- JACC Vo . 4. No.2 SCHOLZ 391 August 1~M:389-97 MECHANISMS OF ACTION OF INOTROPIC DRUGS

lieve that the most plausible mechanism of the cardiotonic evidence that the latter might, in part, also be due to a effect (If the cardiac glycosides at present is an increase in decrease in the Ca2 + sensitivity of the contractile proteins [Ca2+] due to (Na" + K+)-ATPase inhibition and sub­ (27). sequent alteration of Ca2 +INa + exchange. It is widely accepted that the effects of beta-adrenergic agonists on myocardial Ca2 + movements are not direct in nature, but instead are the result of a stimulation of the Beta-Adrenergic Drugs adenylate cyclase with a subsequent increase in cAMP lev­ The positive inotropic effect of the catecholamines nor­ els. cAMP leads to an activation of protein kinases and, as epinephrine, epinephrine, isoproterenol, dopamine and do­ a result, to phosphorylation of several proteins. This changes butamine is due mainly to stimulation of myocardial beta,­ the functional properties of the proteins, for example, their adrenoceptors (22-29). The increase in force of contraction ability to bind Ca2+ ions, and may thus explain the beta­ brought about by these agents characteristically develops adrenergic effects on the calcium movements in the sar­ very rapidly. Moreover, it is accompanied by an increase coplasmic reticulum and possibly also in the sarcolemma. in the rate of force development (positive clinotropic effect) In summary, the positive inotropic effect of beta-adre­ that is typical of almost all positive inotropic interventions nergic drugs is mainly the result of an increase in slow Ca2+ (with the exception of hypothermia, for example) and is, inward current and in Ca2 + uptake into the sarcoplasmic therefore, not very distinctive. More important is a decrease reticulum. This, in tum, is presumably due to a cAMP­ in the duration of the contraction. The latter action is mainly dependent phosphorylation of a variety of functional pro­ due to a more rapid relaxation of the contraction and is, teins. Hence, the beta-adrenergic effects on myocardial Ca2+ therefore, referred to as the "relaxant effect" of beta­ movements on the one hand and on the cAMP system on adrenoceptor stimulation. It is noteworthy that the ability the other are probably causally related in a common pathway of the beta-adrenergic drugs to shorten the contraction are where the beta-adrenergic drug represents the first messen­ shared only by agents known to increase myocardial cyclic ger and cAMP and Ca2+ represent the second and third AMP ( AMP) content. From a functional point of view, the messengers, respectively. relaxant effect of beta-adrenergic stimulation is important in permitting adequate ventricular filling in the face of in­ Glucagon and Histamine creased heart rates. Glucagon (32) and histamine (33) also have a well Effects on Ca2+ and cyclic AMP. The mechanism of established positive inotropic effect in the heart. This ef­ the positive inotropic action of beta-adrenergic catechol­ fect is qualitatively similar to that produced by the beta,­ amines has not been elucidated in detail. However, it is adrenergic catecholamines and is also related to an in­ generally accepted that these agents also produce an increase 2 creased cAMP level due to stimulation of the adenylate in Ca -t concentration in the vicinity of the contractile pro­ cyclase. However, the effects of glucagon or histamine are teins, that they lead to an increase in myocardial cAMP not mediated by beta-adrenoceptors and are not impaired levels, and that the effects on both the Ca2+ and the cAMP by beta-adrenoceptor blocking agents, so that these drugs systems are likely to be causally related to each other. can be administered, at least theoretically, after pretreatment The main effect of the beta-adrenergic agonists on myo­ with beta-adrenoceptor blocking drugs. However, the clin­ cardial Ca2 + movements is to increase the slow Ca2 + inward ical effectiveness of glucagon is not very pronounced and current during the action potential (Fig. I, step I). This the therapeutic usefulness of histamine is limited by serious effect which has been attributed to an increase in the number side-effects. of functional Ca2+ channels (30), and more recently, using the patch clamp method to record current flow through single channels, to an increase in the probability of Ca2 + channels Methylxanthines to open during depolarization (31). The increase in lsi leads The methylxanthines (especially theophylline) produce to an increased Ca2 + release from the sarcoplasmic retic­ not only positive inotropic, but also vasodilator effects ulum (Fig. 1, step 2), either because it serves as a greater (6,22,26,34). The former effect of theophylline is similar trigger for Ca2+- dependent Ca2 + release or because it in­ to that of the beta-adrenergic agents. It develops very rap­ creases the filling of these stores with Ca2 + that can be re­ idly (within a few seconds), is independent of the extra­ leased during subsequent beats. In addition, beta-adrenergic cellular Na + and K + concentration, is impaired by calcium agonists lead to an increase in Ca2+ uptake into the sar­ channel blocking agents such as verapamil and is also closely coplasmic reticulum (Fig. 1, step 3), which also increases related to an increase in Ca2+ influx from the extracellular the amount of releasable Ca2 + within and an increased Ca2 + space (Fig. 1, step 1). release -'rom these stores. This increase in Ca2+ uptake by Inhibition of Ca 2+ uptake. The positive inotropic ef­ the sarcoplasmic reticulum not only contributes to the pos­ fect of the methylxanthines has been attributed to: 1) a direct itive inotropic properties, but also explains the relaxant ef­ interaction with intracellular Ca2 + stores (inhibition of Ca2 + fects of the beta-adrenergic agonists. However, there is some uptake by the sarcoplasmic reticulum), 2) an increase in 392 SCHOLZ JACC Vol 4, No.2 MECHANISMS OF ACTION OF INOTROPIC DRUGS August 1984:389-97

cellular cAMP content resulting from an inhibition of phos­ phodiesterase activity, 3) a blockade of receptors for en­ Db 01 Control dogenous adenosine (35), and 4) a sensitization of the con­ fL b) Isoproterenol 0.03 jJM tractile proteins to Ca2 +. The first possibility is probably significant only at high concentrations because the effect of the methylxanthines on the sarcoplasmic reticulum only oc­ curs at concentrations greater than I roM which are not reached during therapy as maximal therapeutic theophylline 0) Control plasma concentrations are 50 to 100 IJM (35). b) Theophylline 3 mM Increase in cellular cAMP. At therapeutic concentra­ JL tions, the second mechanism appears to be more likely. The similarity between the positive inotropic effects of the beta­ adrenergic catecholamines and theophylline suggests that an o ) Co n t ro l increase in myocardial cAMP levels might be involved not only in the former but also in the latter. In fact, theophylline b bl Isobutylmethylxonthine ~o 0.1 mM has been shown to produce a similarly pronounced enhance­ ment in cAMP content and in force of contraction, and the Figure 2. Effect of isoproterenol, theophylline and 3-isobutyl-l­ increase in cAMP in the presence of theophylline is closely methylxanthine at approximately equieffective concentrations on correlated to an inhibition in phosphodiesterase activity (34). the isometric contraction of the heart. The curves are redrawn It is, therefore, reasonable to conclude that the increase in from original traces obtained in electrically driven (frequency I cAMP in the case of the methylxanthines is due to an in­ Hz) papillary muscles from guinea pigs pretreated with reserpine. hibition of the degradation of cAMP, while the beta-adren­ ergic positive inotropic response is due to an increase in cAMP formation. In both cases, the increase in cAMP leads system, for example). In this context, the main argument to the increase in slow Ca2 + inward current which, in tum, is that the inotropic effects of theophylline and adenosine finally produces the cardiotonic effect. are opposite only in atria. While the cardiotonic effect of This explanation is not necessarily contradicted by the theophylline is similar in atrial and ventricular preparations, fact that the classic methylxanthines, caffeine and theophyl­ adenosine is negatively inotropic in the atrium, but not in line, especially at high concentrations, have some effects ventricular cardiac muscle. In the latter, adenosine does not that are opposite to those of the beta-adrenergic agonists change contractile force at concentrations up to 10 IJM, and (36-38). Most importantly, millimolar concentrations usu­ higher concentrations of adenosine even produce a slightly ally prolong rather than reduce the duration of the contrac­ positive inotropic effect (34). tion. However, as mentioned, at concentrations of I roM Sensitization of the contractile apparatus to Cal ". This and more, theophylline and other methylxanthines directly may also contribute to the cardiotonic effect of the meth­ inhibit the uptake of Ca2 + by the sarcoplasmic reticulum ylxanthines. Fabiato (39) reported that the Ca2 + sensitivity (Fig. I, step 3). This effect, which is independent of the of skinned single cardiac cells was increased by caffeine cAMP system, counteracts the cAMP-dependent increase (20 roM) and theophylline (10 roM). The potential impor­ in Ca2 + uptake and leads to a deceleration of relaxation tance of this effect has also been considered by Morgan and and, hence, to a prolongation of contraction. Blinks (40), who observed that millimolar concentrations Thus, the prolongation of contraction in the presence of of theophylline produced large inotropic effects without con­ theophylline does not exclude the possibility that cAMP sistently increasing the amplitude of the signal of the Ca2 + ­ serves as a mediator of the positive inotropic effect of the sensitive bioluminescent protein aequorin. However, apart methylxanthines. Instead, it suggests that the classic meth­ from the fact that these effects were again observed only at ylxanthines have cAMP-independent "side effects." In ac­ relatively high drug concentrations, they have not been ob­ cord with this explanation, the more potent phosphodies­ tained by others. Herzig et al. (41), for instance, reported terase inhibitor, l-methyl-3-isobutylxanthine, which has no that theophylline or caffeine in concentrations up to 10 roM direct action on the sarcoplasmic reticulum, increases the had no effect on the Ca2 + sensitivity of the contractile pro­ force of contraction and decreases the duration of contrac­ teins. This matter therefore remains controversial. tion in exactly the same way as beta-adrenergic agents (iso­ In summary, I believe that the cardiotonic action of theo­ proterenol, for example) (Fig. 2). phylline and other methylxanthines, at least at therapeutic Adenosine-antagonistic action. It appears unlikely that concentrations, is due primarily to their effect to inhibit the third mechanism mentioned, an adenosine-antagonistic phosphodiesterase, and, therefore, to increase cAMP levels. action, plays a major role in the effect of theophylline on These effects, together with those of the beta.vadrenergic myocardial force of contraction, although this is probably catecholamines, glucagon and histamine, are schematically of great importance in other systems (in the central nervous summarized in Figure 3. It should be noted that the increase JACC VoL 4, NO.2 SCHOLZ 393 August 1981389-97 MECHANISMS OF ACTION OF INOTROPIC DRUGS

ECS Beta - adrenergic agonist Glucagon Ca" Histamine ! ~ Membrane ] Beta .Atenocepto~ Adenyl,cyclase (" Receptor

CS 1 "",, SR ATP

Theophylline-i ~POE

S'-AMP Ca++

in cAMP and the subsequent increase in slow Ca 2 + inward Figure3. Schematic summary of the mechanisms of the positive current and in Ca2 + uptake into the sarcoplasmic reticulum inotropic effects of beta-adrenergic agents, glucagon, histamine are the most important common events in all cases, The and theophylline (Theo). All drugs increase the cyclic adenosine monophosphate (cAMP)level, either throughstimulation of aden­ agents differ only in the way through which this increase ylate cyclase (increase in cAMP formation) or through inhibition in myocardial cAMP content is achieved, of phosphodiesterase (PDE; impairment of cAMP degradation). The increase in cAMP leads to an increase in slow Ca2 + inward current and to an increased filling of the sarcoplasmic reticulum (SR) with releasable Ca2 + and, hence, to an increase in Ca2+ concentration at the contractile proteins (CP). The direct cAMP­ New Positive Inotropic Drugs independent inhibitory action of theophylline on Ca2 + uptakeinto the sarcoplasmic reticulum is probably responsible for the the­ The Ideal positive inotropic drug should, according to ophylline-produced increase in the duration of the contraction. Opie (21, cause neither tachycardia nor arrhythmias and ATP = adenosine triphosphate; ECS = extracellular space; ICS should not lead to a greatly increased oxygen demand, An = intracellularspace. additional vasodilation would be of advantage, Chronic use requires sufficiently high oral bioavailability and long du­ ration of action, No pronounced tolerance should develop demonstrated whether prenalterol is still effective after chronic after prolonged treatment. The following new cardiotonic application (tolerance?) and whether and to what extent the agents are discussed and evaluated in the light of these drug may produce tachyarrhythmias. criteria, Betas-Adrenergic Drugs Prenalterol Salbutamol (44), terbutaline (45), fenoterol (46) and pir­ Prenalterol (42) is a beta-adrenergic partial agonist with buterol (47) interact mainly with betaj-adrenoceptors and relatively selective effects on beta.cadrenoceptors. In con­ are preferentially used in patients with bronchial asthma. trast to norepinephrine, epinephrine, isoproterenol, dopa­ They produce positive inotropic effects (possibly due to mine and dobutamine, the drug can be administered orally residual beta-adrenoceptor stimulation) and vasodilation. (bioavailability about 45%) and the duration of action is 4 It is not clear which of these actions predominates in patients to 6 hours. The positive inotropic effect of prenalterol has with myocardial insufficiency. In any case, the vasodilator been reported to be more pronounced than its positive chron­ effect of these drugs contributes to the increase in cardiac otropic action. That the ratio of inotropic to chronotropic index and is probably of greater clinical importance than effect may be greater for prenalterol than for other beta­ the direct cardiostimulatory action. The positive chrono­ adrenergic agents has been attributed to the observation that tropic effect of these agents is claimed to be relatively small. the relative amount of beta-adrenoceptors is greater in the These drugs may be given orally (bioavailability 40 to 85%) left ventricle than in the right atrium, at least in guinea pigs and their duration of action is 4 to 8 hours. As in the case and cats (43). This argument, however, should apply to all of prenalterol, the questions of potential tachyarrhythmias beta,-adrenergic drugs and is, therefore, only partially con­ caused by cardiostimulation and of persistence of the ther­ clusive. With respect to therapeutic use, it remains to be apeutic effect are not yet resolved. 394 SCHOLZ JACe Vol. 4. No.2 MECHANISMS OF ACTION OF INOTROPIC DRUGS August 1984:389-97

Alpha-Adrenergic Drugs guanosine monophosphate (cGMP) levels and (Na" + K 'f-)_ ATPase activity also remain unchanged. Some investigators There is no doubt that the positive inotropic response to (51) have observed a small increase in slow Ca2 + inward adrenergic agents in the heart is mediated predominantly by current which, however , has not been observed in all species beta-adrenoceptors. However, there is increasing evidence and which is less pronounced than that produced by beta­ that alpha-adrenoceptors also exist in the myocardium and that an increase in force of contraction may be produced by adrenoceptor stimulating agents . stimulation of these sites (26,48-50). These are alphal­ The biologic significance of alpha-adrenergic stimulation adrenoceptors, and the most important drugs of this group in cardiac muscle remains to be established. There is evi­ used experimentally are phenylephrine and methoxamine . dence that the alpha-adrenoceptors of the heart differ from The principle of an alpha-adrenoceptor-mediated cardi­ those of other tissues. Thus , it appears conceivable that otonic action appears promising, but it should be stressed drugs that are positively inotropic through stimulation of that the agents hitherto available have as yet not been used myocardial alpha-adrenoceptors without vasoconstrictor ef­ clinically for this purpose, largely because of their predom­ fects will become available for clinical use. From the phys­ iologic point of view, the alpha-adrenergic positive inotropic inant vasoconstrictor action. The positive inotropic effect of alpha-adrenergic agents effects of catecholamines may be important under conditions is qualitatively different from that of beta-adrenergic drugs. where the stimulation of beta-adrenoceptors is relatively The alpha-adrenergic response develops relatively slowly small (in hypothyroidism, hypothermia and at low heart and is accompanied by a prolongation, rather than a short­ rates). ening, of the contraction. Thus, alpha-adrenergic agents do not produce relaxant effects . Moreover, the alpha-adren­ ergic positive inotropic effect is not accompanied by distinct Amrinone chronotropic effects, and is particularly pronounced at low Arnrinone is a bipyridine derivative with positive ino­ stimulation frequencies, in hypothermia and in hypo­ tropic, positive chronotropic and vasodilator effects (52). thyroidism. The positive inotropic effect develops rapidly within several The mechanism of the alpha-adrenergic positive inotropic minutes and the duration of action is 60 to 90 minutes. It response is unknown. It is generally accepted , however, is not impaired by beta- and alpha-adrenoceptor blocking that there is no increase in cAMP levels, quite in accord agents, or reserpine pretreatment and histamine (HI and H2)­ with the observation that there is no relaxant effect. Cyclic receptor blocking drugs. Farah (53) Alousi (54) and their

Table 1. Drugs With Positive Inotropic Effects and Their Main Mechanisms of Action Drug Mechanism

Cardiac glycosides Reaction with (Na" + K+)-ATPase. subsequent steps unsettled BetaI-adrenergic drugs Increased cAMP level due to stimulation of adenylate cyclase, increase in lsi and Ca2 + uptake by Norepinephrine sarcoplasmic reticulum Epinephrine Isoproterenol Dopamine Dobutamine Glucagon and histamine Increased cAMP level due to stimulation of adenylate cyclase; effect similar to that of beta-adrenergic drugs but independent of beta-adrenoceptor Methylxanthines Increased cAMP level due to inhibition of phosphodiesterase; effect similar to that of betai-adrenergic Caffeine drugs (except lack of relaxant effect) but independent of beta-adrenoceptor: no evidence for adenosine Theophylline antagonism Prenalterol Beta-adrcnoceptor stimulation, chronotropic effect relatively small; bioavailability 45%, duration of action 4 to 6 hours Beta--adrenergic drugs Positive inotropic and vasodilatation, bioavailability 40 to 85%, duration of action 4 to 8 hours Salbutamol Terbutaline Fenoterol Pirbuterol (Pfizer) Alpha-adrenergic drugs Positive inotropic effect, no chronotropic effect; no relaxant effect; no effect on cAMP Phenylephrine Amrinone (Winthrop) Phosphodiesterase inhibitor; similar to theophylline; positive inotropic effect and vasodilation Sulmazole (AR-L lIS BS, Thomae) Phosphodiesterase inhibitor; similar to theophylline; possible effect on Ca2 + sensitivity of contractile proteins; positive inotropic effect and vasodilation JACC Vol. 4, No. 2 SCHOLZ 395 August 1184:389-97 MECHANISMS OF ACTION OF INOTROPIC DRUGS

coworkers initially reported that amrinone also does not concentration (350 J-lM) increases the Ca2 + sensitivity of change phosphodiesterase and (Na + + K +)-ATPase activ­ the contractile proteins (4 1), an effect that might contribute ities or cAMP levels . This led several investigators to con­ to the positive inotropic action of the drug. Herzig et al. clude that amrinone has an entirely new although as yet (4 1) emphasized that sulmazole would be the first example unknown mechanism of action. However , Honerjager (55) where a change in Ca2 + sensitivity of the myofilaments and Endoh (56) and their coworkers showed recently that contributes to the positive inotropic effect of a cardiostim­ the positive inotropic effect of amrinone is accompanied by ulatory agent. However, whether or not this effect is unique an inhibition of phosphodiesterase and an increase in cAMP . is still a matter of debate , as discussed earlier in the case Moreover, amrinone potentiated the effects of isoprenaline of the methylxanthines. But it should be noted that in the and histamine and increased the rate of increase of Ca2 + ­ study of Herzig et al. (4 1), theophylline or caffeine in con­ dependent slow action potentials. From these effects , it is centrat ions of up to 10 roM and amrinone in concentrations reasonable to assume that amrinone is not a novel drug, but of up to 350 pM failed to produce any effect on the Ca2 + is instead a phosphodiesterase inhibitor with an action sim­ sensitivity of the contractile proteins . ilar to that of theophylline. This does not exclude the pos­ Conclusions. This brief review has attempted to classify sibility that other effects could emerge (57), but the simi­ various old and new positive inotropic drugs according to larity between amrinone and theophylline is important because their mechanisms of action. The major effects involved are any theophylline-like drug must be regarded as a potential summarized in Table 1. The inotropic properties of many inducer of tachyarrhythmias. At high concentrations, am­ of the agents discussed are related to an increase in myo­ rinone produced a prolongation of the contraction . This cardial cAMP levels, although these are brought about by effect is also shared by theophylline, as noted earlier. different mechanisms. This is important as an increase in Milrinone is a recently developed derivative ofamrinone cAMP may potentially lead to tachyarrhythmias. Among which is 10 to 30 times more potent than the parent com­ the new inotropic agents , no drug appears to provide major pound . but otherwise appears to possess a similar phar­ advantages. The potential development of tolerance during rnacologic profile and a similar cAMP-increasing action chronic treatment and the occurrence and significance of (58-60). However, since in the study of Alousi et al. (58) possible side effects appear to be the most significant un­ the rnilrinone-induced increase in force of contraction de­ resolved questions. veloped faster than the increase in cAMP , mechanisms other than phosphodiesterase inhibition may also be involved in References the cardiotonic effect of this agent. I. Mason DT, Awan NA, Amsterdam E, et al. New therapeutic ap­ proaches to the failing heart: recent advances in vasodilators, cardi­ otonics, and mechanical circulatory assistance . Adv Heart Dis Sulmazole 1980;3:403-46. 2. Opie LH. Drugs and the heart. V. 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