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.