Potassium Channel Blockade as an Antiarrhythmic Principle

Cardiovascular Drug Reviews

Vol. 1 1 , No. 3, pp. 37&384 0 1993 Neva Press, Branford, Connecticut

Potassium Channel Blockade as an Antiarrhythmic Principle Elin Mortensen, Tao Yang,and Helge Refsum Department of Medical Physiology, Institute of Medical Biology, University of Tromsl, Trams@, Norway

Key Words: Potassium channel blocker-Heart-Class III antiarrhythmic action.

Class 111 antiarrhythmic drugs exert their antiarrhythmic effectiveness by blocking potassium currents. This selectively slows repolarization and correspondingly increases refractoriness (i.e., class 111 antiarrhythmic action). In comparison to other classes of antianhythmic drugs, class ILI drugs may have the following advantages: First, potassium channel blockers lengthen cardiac refractoriness without altering cardiac excitability and conductivity, an effect that is beneficial in treating reentrant arrhythmias. Second, the absence of negative inotropic or the presence of a moderate positive inotropic effect of class 1LI drugs may be unique, this property being of greal importance in the case of heart failure. Third, an increase in spontaneous cycle length of sinus pacemaker cells due to lengthening of repolarization produces a negative chronotropic effect that may help in slowing tachyarrhythmias. These advantages may make potassium channel blockers a very useful alternative in the treatment of patients with cardiac arrhythmias.

CARDIAC POTASSIUM CHANNELS AND THEIR PHYSIOLOGICAL ROLE Our understanding of the diversity of cardiac K+ channel currents has increased dramatically over the last few years with the advent of the patch voltage clamp technique applied to isolated cardiomyocyte preparations. These K currents have particularly important roles in maintaining the normal electrical activity in cardiac cells. The K + currents control the membrane resting potential and action potential duration in different cardiac cell types under physiological and pathophysiological conditions. Up to now, at least eight functionally different types of K + currents have been identified in the heart. These K t currents have been named (a) the inward rectifier K + current (IK1), (b) the transient outward K + current (Ito),(c) the delayed rectifier K ' current (IK), (d) the high conductance plateau K + current (IKp),(e) the intracellular Ca2+-activated K' current +

Address correspondence and reprint requests to Dr. E. Mortensen at Department of Medical Physiology, Institute of Medical Biology, University of Tromse, N-9037 Tromsb, Norway.

370

371 (IKCa), (f) the intracellular Na+-activated K + current (Zma), (g) the acetylcholineand (h) the adenosine triphosphateactivated inward rectifying K + current (IKAch), sensitive K + current (IKAw).Among these currents, the currents ordered from (a) to (d) are primarily activated in a voltage-dependent manner, whereas those from (e) to (h) are primarily activated by some chemical modulators. Although all functions of the above-mentioned K+ currents in the cardiac electrical activity have not yet been completely clarified, some of them appear to be obvious in the heart. According to currently available knowledge (2,19,52,61), major properties of the K + currents associated with the cardiac membrane potential are summarized in Table 1. The physiological roles of IK1may include (i) maintenance of the membrane resting potential near the K + equilibrium potential in atrial, atrial-ventricular nodal, HisPurkinje, and ventricular cells (29), (ii) contribution to the outward current for the final phase of repolarization (particularly in the later part of phase 3 during the action potenTABLE 1. Classification of cardiac K + currents and their related properties ~~~

~

Channel type Voltage activated Inward rectifier K + current (IK 1)

Transient outward K ' current

Conductance (PSI 5-30

20

(I,) Delayed rectifier K' current

5-60

(Id a. Slow component (IKs) b. Rapid component (Irn) High conductance K + current

Activation mechanism

Function

Blockers

Activated by hyper., inactivated by depol.

Re and later

TEA, Cs+, 4-AP

Activated by depol. ( - 65 to -40 mV)

Phase 1 of AP

4-AP. TEA

Activated by depol. (above -40 mV)

Early phase 3 of AP

Sot., Ami., Qui.

I? 5-60

E-403 1, Sot., Dof. Phase 2 of AP?

?

Activated by [ca" li

Phase 2 of AP

TEA

Activated by "a'], Activated by ACh and adenosine

opposes depol.

TEA, 4-AP, TTX

Slows sinus rhythm

Atropine

Activated by decreased tATPli

Protects against ischemic changes

Glibenclamide

14

(IKP) Agonist activated Ca'+-activated K+ current

20-30

UKCA

Na+-activated K + current

220

(jKNa)

ACh-activated K + current

20-50

(kACh)

ATP-sensitive K+ current (*IcATP)

repol.

20-200

RP, resting potential; AP, action potential; hyper., hyperpolarization; depol., depolarization; repol., repolarization; TEA, tetraethylammonium; 4-AP, 4-aminopyridine; Sot., sotalol; Ami., amiodarone; Qui., quinidine; Dof., dofetilide; TTX, tetrodotoxin.

Cardiovascular Drug Reviews, Vol. 11. No. 3 , 1993

3 72

tial), (iii) the importance of letting small currents control the pacemaker rate because of the absence of I,, in sinus pacemaker cells, and (iv) a relationship to the rising phase of the cardiac action potential. Simulated computations have shown that inhibition of the inward rectifier K C current can lead to membrane depolarization and lengthening of the action potential duration (36). Ito is a K + current that turns on rapidly after depolarization and then inactivates. It consists of two types, i.e., one is activated by intracellular Ca2+ whereas another one is voltage activated and modulated by neurotransmitters. The two types of It, may play a major role in modifying the early cardiac repolarization, i.e., phase 1 of the cardiac action potential. This current is more prominent in the ventricular epicardium than in the endocardium, and thus I,, is believed to be responsible for a pronounced spike and dome morphology of the action potential in the epicardial cells (3). I, is also a well-studied K + current that conducts through voltage-gated channels with slow activation kinetics. The current is slowly activated during the action potential plateau and is mainly responsible for initiating and sustaining repolarization in multiple cardiac cell types (36). Following repolarization, IK is slowly deactivated. The decay of the current contributes partially to diastolically automatic depolarization (phase 4) in sinus pacemaker cells. More recently, I , is divided into a large and slowly activating component (I,,) and a small and rapidly activating component (I,) (63). I,, is the dominant component and often referred to as I,. I , is pharmacologically interesting since it can be modulated markedly by certain catecholamines or antiarrhythmic drugs. For instance, both norepinephrine and isoproterenol induce shortening of the action potential duration mainly through enhancement of the I,, component in guinea pig ventricular cells (30, 37,64). I, is potently blocked by some methane sulfonamide class 111 antiarrhythmic agents (sotalol, dofetilide, and E-4031) (20,21,63), whereas the quaternary class I11 agent clofilium appears to block both components (5). I,, is a recently described K + current during the whole action potential duration, and this current has high conductance during the plateau (88). In addition to the four primarily voltage-dependent K currents described above, I&.+& and I,,, are two broadly studied members of the remaining four primarily agonistactivated K + currents. Generally speaking, IKAch is a K + current whose channel is opened by the muscarinic (M2) receptor via guanosine triphosphate (GTP) regulatory protein signal transduction (62,63). It shuts down during depolarization, but it contributes to outward current both at the resting potential and during the action potential. It is particularly important in sinus, atrioventricular nodal, and atrial cells. IKATp is a K f current that carries through a metabolically regulated channel, called the ATP-sensitive K + channel (49,50). Under physiological conditions, this type of K + channel is inhibited by a normal content of intracellular ATP (3-4 mM), and may not play a role in cardiac electrical activity. Under pathophysiological conditions (e.g., myocardial hypoxia, ischemia, or applications of some metabolic inhibitors), the ATP-sensitive K channel is activated mainly as a result of a fall in the intracellular ATP level and thus carries a prominent outward K + current. The conductance of this current is large enough to accelerate cardiac repolarization dramatically and shorten the action potential. Experimentally, such an effect of ImTPon cardiac electrical activity has been demonstrated to be associated with the genesis of cardiac arrhythmias during myocardial ischemia. I, and I,, are K + currents that carry through a channel activated by a high level of +

+

Cardiovascular Drug Reviews, Val. 11, No. 3, 1993

373 intracellular Na+ or Ca2', respectively. Their physiological role is not yet clear. There is information suggesting a possible role of ZKNa in digitalis intoxication.

ANTIARRHYTHMIC MECHANISMS OF POTASSIUM CHANNEL BLOCKERS The concept that slowing cardiac repolarization would become an important antiarrhythmic principle has been known and appreciated for many years (68,69,79). To date, the experimental and clinical observations have well demonstrated that slowing cardiac repolarization per se is associated with a corresponding increase in the voltagedependently effective refractory period and may constitute a discrete antiarrhythmic mechanism, the so-called class ILI antiarrhythmic action. Electrophysiologicallyand pharmacologically, drugs that selectively lengthen the cardiac action potential duration are categorized as class 111 antiarrhythmic drugs in the Vaughan Williams classification scheme (Table 2) (78,79). Much attention is currently being paid to inhibition of the K C channel currents known to contribute to cardiac repolarization. In this aspect, the delayed rectifier Kt current (IK)appears to be most attractive for certain reasons. First, the contribution of this K ' current to repolarization should be greater at shorter cycle lengths because the slow deactivation of the current during diastole will result in a progressive accumulation of open channels from one action potential to the next. Second, the effect produced by inhibition of ZK should be potentiated in depolarized tissue because the inwardly rectifying properties of this channel will accentuate the action of the drug at less negative potentials (about between - 60 and -40 mV), at which the fully activated current-voltage relationship provides a maximum outward current. These considerations might provide the theoretical basis for the development of selective I , blockers as a first choice in the design of new class ILI antiarrhythmic drugs. This class of drugs exerts the effects on the repolarization course by blocking cardiac,Z channels. This action reduces the amount of outward current flowing during the plateau phase of the cardiac action potential and delays the onset of repolarization (24), TABLE 2. Classification of antiarrhythmic drugs Classes

I. Na+ channel blockers

Drugs

la. Quinidine and related drugs (major effects: depress phase 0, slow conduction, and lengthen repolarization) Ib. Lidocaine and related drugs (major effects: less effect on phase 0 in normal tissue, depress phase 0 in ischemic tissue, and shorten the action potential duration) Ic. Encainide, flecainide, and related drugs (major effects: markedly depress phase 0, slow conduction, and slightly lengthen repolarization)

U. P-Adrenoceptor blockers In. K + channel blockers

Propranolol and related drugs

IV. Ca"

Verapamil, diltiazem, and others

channel blockers

Sotalol, amiodarone, and others (major effects: lengthen the action potential duration and refractoriness)

Cardiovascular Drug Reviews, Vol. 11, No. 3, 1993

3 74 thereby prolonging the action potential duration. Sotalol and amiodarone are two widely studied and recognized class III antiarrhythmic drugs. In addition, other class I11 antiarrhythmic drugs, such as clofilium, bretylium, and N-acetylprocainamide, are also currently available for clinical application. Meanwhile, this class of compounds is rapidly growing. Included among these drugs are a number of newly developed compounds (e.g., dofetilide, UK-66,914, E-403 1, acecainide, sematilide, almokalant, and RP-58866), which are at various stages of preclinical and clinical investigation. Sotalol was initially developed as a noncardioselective P-adrenoceptor blocker. Its unique class III electrophysiological properties were not recognized until sotalol was found to lengthen the cardiac action potential duration and effective refractory period without affecting the maximal rising rate of phase 0 (18,69,72). The effects of three structural forms of sotalol (dextrorotary, levorotary, and racemic isomers) on cardiac electrophysiological characteristics are quite similar and independent of P-blocking activity (38). Despite the fact that d-sotalol also possesses some P-adrenoceptor blocking action (58), it does not produce a depressant effect on cardiac contractility. In fact, it causes a positive inotropic action in some in vitro myocardial preparations (75). In addition, in vivo studies showed that intravenously administered sotalol had no significant depressant effects on hemodynamics in patients with cardiac failure (14), in contrast to the well-known cardiac depressant actions of conventional P-receptor blockers. The above-mentioned actions of sotalol are attributed to its effects on cellular membrane K + currents. Voltage clamp studies (77) have demonstrated that at concentrations equal to or less than M ,sotalol-induced lengthening of the action potential duration may be associated with a substantial inhibition of the delayed rectifier K + current (I,) and a small reduction in the inward rectifier K + current (I,,). Furthermore, sotalol may primarily block the small and rapidly activating (I,) component of I, (63). At higher concentrations, sotalol induces action potential shortening because of inhibition of an inward sodium “window” current sensitive to the Na+ channel blocker tetrodotoxin (ITX) during repolarization. The second drug in the class III category is amiodarone. Initially this drug was clinically used as a coronary vasodilator. Amiodarone possesses two principal cardiac electrophysiological effects (4,343 1,83), i.e., lengthening of the action potential duration and inhibition of the maximal rising rate of depolarization. Amiodarone also produced a slight positive inotropic effect in isolated myocardium (76). Amiodarone-induced lengthening of the action potential duration is also due to suppression of I, (7,8). The theoretical basis for the so-called class III antiarrhythmic action may be as follows: Slowing cardiac repolarization with a corresponding lengthening of the effective refractory period is clearly likely to form an antifibrillatory mechanism. In this case, the tachycardia cycle length will be prolonged, and some arrhythmias will be prevented from deteriorating into fibrillation; an increase in the refractory period will retard the onset of the next action potential, and therefore the tachycardias will be slowed. A great deal of experimental and clinical evidence indicates that class LII drugs exert their antiarrhythmic effects mainly via slowing of repolarization. Under certain circumstances (e.g., bradycardia, hypokalemia, and hypomagnesemia), however, excessive lengthening of cardiac repolarization will probably also become arrhythmogenic in terms of development of the clinical entity of polymorphic ventricular arrhythrmas, torsades de pointes (59). The

CardiovascularDrug Reviews, Vol. 11, No. 3 , 1993

375 torsades de pointes may be associated with the occurrence of early afterdepolarizations (EADs) of membrane potentials during cardiac repolarization (59). This, perhaps, is a major clinical problem of some class III antiarrhythmic drugs. Besides the class 111antiarrhythmic drugs described above, much attention has recently been paid to the antiarrhythmic effect probably produced via blockade of adenosine triphosphate-sensitive K (KATp)channels in the heart. These channels are activated by a reduction of the intracellular ATP content to a critical level during hypoxia or ischemia. A large conductance of outward current caused by activation of Imp channels has been demonstrated to be responsible for the electrophysiological abnormalities (e.g ., membrane depolarization and action potential shortening) occurring in the acute phase of myocardial hypoxia or ischemia (27,35,49). Inhibition of activation of the KAp channels (e.g., by the antidiabetic drugs glibenclamide and tolbutamide) would be expected to attenuate the action potential shortening in hypoxic or ischemic myocardium and decrease the disparity of refractoriness between normal and abnormal zones, thereby producing the antiarrhyhmic effects. In fact, many recent studies (10,15,35,82) have demonstrated glibenclamide to be effective against arrhythmias associated with the setting of myocardial ischemia. These studies suggest that inhibition of activation of KATp channels in hypoxic or ischemic myocardium might become a new approach to control cardiac arrhythmias. Thus, such an effect would also be considered a class I11 antiarrhythmic action during myocardial ischemia. +

POTASSIUM CHANNEL BLOCKADE DURING MYOCARDIAL ISCHEMIA Myocardial ischemia resulting from coronary artery occlusion causes changes in cardiac automaticity, conductivity, and refractoriness, all of which are responsible for the Occurrence of ventricular dysrhythmias (8 I). During myocardial ischemia, the resting potential of ventricular muscle depolarizes from normal levels of about -80 mV to between - 65 and - 60 mV within 10 min after the occurrence of ischemia (42). This reduction of the resting potential has to a large extent been attributed to abnormal distribution of K+ between the intra- and extracellular space, i.e., accumulation of extracellular K + due to a net loss of intracellular K+ . There are also multiple metabolic changes in ischemic regions. Not only is the extracellular K + elevated, but there are also hypoxia, acidosis, shortage of substrates, increases in vasoactive substances (e.g., catecholamines), and accumulation of metabolic products (e.g., lysophosphoglycerides).Each of these factors may affect the membrane electrical activity, but those that mainly have been correlated to the cardiac electrical activity during ischemia are hypoxia, high extracellular K + concentration, cellular acidosis, and depletion of substrates for metabolism (8 1). Although class I11 antiarrhythmic drugs are thought to be valuable for the management of cardiac arrhythmias, several in vitro studies have suggested that the ability of the two recognized class 111 agents, sotalol and amiodarone, to lengthen the action potential duration is significantly attenuated, even lost, in hypoxic or ischemic myocardium (23,25). Similar changes have also been confirmed in other studies (9,84), in which some newly developed class I11 drugs, including dofetilide, were examined in the case of hypoxia or application of the ATP-sensitive K channel opener nicorandil . The action of hypoxia or nicorandil to induce a large conductance of the outward K+ current carried via activated ATP-sensitive K+ channels most likely overwhelms the effect of class I11 +

Cardiovascukxr Drug Reviews, Vol. 11, No. 3, 195’3

376 drugs to inhibit the delayed rectifier outward K f current (Z,) contributing to repolarization. Consequently, this increased outward K current speeds repolarization and shortens the action potential duration. In the case of dofetilide, however, the magnitude of the hypoxia- or nicorandil-induced shortening of the action potential duration and the reduction in the contractile force were significantly attenuated, although the ability of dofetilide to lengthen the action potential duration was diminished during exposure to hypoxia or nicorandil (84). This influence of dofetilide was quite similar to that observed during application of an ATP-sensitive K + channel blocker, glibenclamide (Fig. 1). The results suggest that in addition to blocking I,, dofetilide, probably in a manner similar to that of glibenclamide, interferes with opening of ATP-sensitive K + channels induced by hypoxia or nicorandil. Further voltage clamp studies of the effects of dofetilide on ATP-sensitive K channels are necessary to clarify this potential mechanism of action of dofetilide and to better explain the effectiveness of some class Lu antiarrhythmic drugs in the setting of acute myocardial ischemia. In fact, several recent studies have demonstrated the antiarrhythmic efficacy of class ILL drugs, including dofetilide, in the ischemic heart (13,43,89). In an in vivo model of acute ischemic heart failure (45-49,the three class 111 antiarrhythmic drugs dofetilide, almokalant, and d-sotalol still increased the QT time and the effective refractory period in a dose-dependent manner. In addition, there was no depression of the left ventricular function after intravenous administration of the three drugs, this being reflected by the fact that the left ventricular dPldr,, during ischemia was not significantly changed after drug administration. Also, in the presence of either dofetilide or almokalant, a decreased left ventricular dP/drmi, (an index reflecting left ventricular relaxation) during ischemia was not affected. Alterations of this variable have been considered an early manifestation of cardiac impairment preceding ventricular systolic dysfunction (1 1). Furthermore, there were no significant effects on cardiac output or total peripheral vascular resistance. These results are in good agreement with other studies using class III antiarrhythmic drugs (45,71). These studies strongly support the concept that class 111 antiarrhythmic drugs acting by inhibiting K + channels do not produce negative inotropic effects in the setting of myocardial ischemia. +

+

A.

B.

C.

D o l t N i c , l mM

30 min

FIG. 1. Representative effects of nicorandil (Nic) alone (A) and after pretreatment with glibenclamide (Glib) (B) and dofetilide (Don (C) on guinea pig papillary muscle action potentials. Effects after 30 min of exposure to the drugs are shown. Note that dofetilide attenuates the shortening of the action potential duration caused by nicorandil. (From ref. 84.)

Cardiovascular Drug Reviews, Vol. 11, N o . 3, 1993

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POTASSIUM CHANNEL BLOCKADE AND HEART FAILURE Severe ventricular arrhythmias are frequently associated with congestive heart failure, and most patients with serious heart failure die suddenly most likely due to ventricular tachyarrhythmias (22). The prognosis in patients with heart failure secondary to left ventricular dysfunction is poor, with a mortality rate exceeding 50% within 5 years from diagnosis (12). Therefore, antiarrhythmic drugs would be expected to be most helpful in the treatment of cardiac arrhythmias with heart failure. Patients with congestive heart failure have many factors that may contribute to the high prevalence of ventricular arrhythmias. Table 3 lists some of the factors that may play a role in the pathogenesis of arrhythmias in heart failure. So far, however, no controlled clinical studies have been able to suggest any antiarrhythmic therapy that can prevent sudden cardiac death in this group of patients (22,80). These results may have been provoked by the fact that most antiarrhythmic drugs have a negative inotropic effect (65), as well as the fact that antiarrhythmic drugs also may provoke arrhythmias (33,70). This drawback may offset their antiarrhythmic benefit. Drugs with a class I11 antiarrhythmic mode of action, however, have been shown to exert a more favorable inotropic effect (54-56,71) (Fig. 2). It is, therefore, important to assess the possible depressant effects of new antiarrhythmic drugs on cardiac contractile function. Class I11 antiarrhythmic drugs have been proposed to be valuable in the treatment of arrhythmias in patients with or without cardiac dysfunction, because of the absence of a cardiac depressant effect or the presence of moderate positive inotropy (68). Accordingly, the development of new class III antiarrhythmic drugs could be expected to satisfy the need for antiarrhythmic drugs devoid of a cardiac depressant effect.

POTASSIUM CHANNEL BLOCKADE AND POSITIVE INOTROPY The excitation-contraction coupling is a complex series of cellular events that starts with the action potential and ends with contraction of the myofilaments, followed by restoration of diastolic calcium levels. Changes in the duration of the action potential will affect the excitation-contraction coupling at different levels. The duration of the action potential seems to be governed by three separate mechanisms: (a) secondary inward TABLE 3. Pathogenesis of ventricular arrhythmias in heart failure Mechanical factors Ischemia Scarring Electrolyte depletion

K+ Mg2+ Arrhythmogenic drugs Antiarrhythmic drugs Diuretics Digitalis Phosphodiesterase inhibitors Antidepressantsheuleptics Humoral factors ' High renin High catecholamines

Cardiovascular Drug Reviews, Vol. 11, No. 3, 1993

3 78 3500

A

u

-s

embolizolion

7

1

0)

I

E E

3000 -

2500 -

v X

0

E

u

D

2000.

\

a U

1500.

3 1000

-

7

1

baseline

'

0

'

30

mdkg

90 min

60

2 mdkg

FIG. 2. Effect of d-sotalol (0-0) at 1 and 2 mgkg intravenously vs. control (0-0) on left ventricular dPldt,, after induction of acute ischemic heart failure (embolization) (n = 7, mean k SEM). Note that d-sotalol did not have a cardiodepressive effect in acute heart failure. (From ref. 45.)

current carried largely by calcium (but also sodium); (b) outward currents canied by potassium; and (c) inward calcium current transported by the Naf/Ca2+ exchange mechanism dependent on sodium loading during the first part of the action potential. A study by Kavaler (40) demonstrated increased tension development as a function of sustained depolarization in isolated cardiac muscle preparations. In this study, the long action potential duration caused the tension to remain at near peak levels, and relaxation occurred only when the preparations were repolarized. Subsequently, this finding was further confirmed by Morad and Trautwein (44).These observations appear to be well explained by the slow Ca2+ channel and the delineation of its kinetics in the heart. The slow Ca2 channel is responsible for excitatiorrcontraction coupling in the myocardium. This type of channel is inactivated in a voltage-dependent manner and has a long time constant of inactivation. Theoretically, as a result of lengthening of the repolarization time, the slow Ca2' channel activity will be delayed in being inactivated, thereby allowing continuous influx of Ca2+ into the cell for a longer time during a cardiac cycle. Thus, any interventions that interfere with the repolarization course and lengthen the action potential duration in the case of a normal extracellular Ca2' level are most likely to increase the net Ca2+ influx per excitation across the myocardial cell membrane and thereby enhance cardiac contractility. Another consequence of the prolongation of the action potential would be a longer time for release of activator calcium from the intracellular stores. Accordingly, it might be expected that drugs that significantly lengthen the action potential duration produce a positive inotropic action. In fact, studies have demonstrated these theoretical considerations to be tenable. Kaumann and Olson (39)initially found that at concentrations required to prolong the action potential duration in cat ventricular muscle, sotalol produced a corresponding increase in peak tension often accompanied by the appearance of aftercontractions, which could be correlated to lengthening of the action +

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379

potential duration. Subsequently, other drugs known to prolong the action potential duration (such as melperone, amiodarone, dofetilide, and almokalant) have also been shown to produce a moderate positive inotropic effect in vitro (17,56,74,76) (Fig. 3) and in vivo (71). Therefore, class I11 antiarrhythmic action may be linked with positive inotropy (54,5537). This property of class 111 drugs is of particular importance, since other classes of antiarrhyhmc drugs have to a varying extent cardiac depressive effects (53,65). It should be emphasized, however, that rarely does a pharmacological agent exhibit a “pure” effect in vitro and particularly in vivo, where the net effect often is a balance between direct cardiac and indirect extracardiac actions of a particular compound. Nevertheless, within these limitations, it appears that the concept of augmented myocardial contractility as a function of lengthened repolarization is valid and has clinical relevance in the case of certain antiarrhythmic compounds.

POTASSIUM CHANNEL BLOCKADE AND HEART RATE The ability of class I11 drugs to lengthen repolarization is always associated with a negative chronotropic effect in cardiac sinus node tissue (6,31,74,83). The mechanism by

Do1e tilide

I

0

1

100 ma

FIG. 3. Representative effects of dofetilide (10 nM) on the action potential (top) and developed force (bottom) of isolated guinea pig ventricular muscle. Tracing 1 represents the baselie and tracing 2 represents drug treatment. Note the action potential lengthening and increased contractile force after dofetilide. (From ref. 87.)

Cardiovascular Drug Reviews, Vol. 11, No. 3, 1993

380 which dofetilide and almokalant lengthen the action potential duration through delaying repolarization has been attributed to blockade of a small and rapidly activating component (I,) of the delayed rectifier K + current (IK), contributing to repolarization (17,20,21). It has been demonstrated that dofetilide decreases the spontaneous beating rate in guinea pig right atria with sinus node tissue in a concentration-dependent manner and that this negative chronotropic effect is not related to P-adrenoceptors, because dofetilide was devoid of P-receptor blocking action (86). As the delayed rectifier K + current also greatly contributes to repolarization in sinus node cells (48), many class I11 antiarrhythmic drugs that block this current induce an increase in the spontaneously beating cycle length through lengthening of the action potential duration without affecting the rate of diastolic depolarization in sinus node cells (6,16,83). For some class Ia and ILI antiarrhythmic drugs that block cardiac K + channels and lengthen repolarization, reverse use dependence has been proposed. That means that drug-induced lengthening of repolarization is more prominent at slow than at fast heart rates (32). This is in contrast to the use dependence of class I antiarrhythmic drugs in which Nat channel block is most pronounced at a fast heart rate. In theory, drugs exhibiting a reverse use dependence would both produce less antiarrhythmic effectiveness in the case of tachyarrhythmias and probably induce the development of bradycardiarelated arrhythmias such as torsades de pointes, a polymorphic ventricular arrhythmia associated with early afterdepolarizations caused by excessive lengthening of repolarization. In the presence of some factors (e.g., bradycardia, hypokalemia, and hypomagnesemia) in which the prolonged repolarization in itself exists, the reverse usedependent effect may facilitate repolarization-slowingdrugs to induce torsades de pointes. This is the case with patients receiving quinidine (class Ia) or sotalol (class 111), two drugs that prolong cardiac repolarization (60,67). In spite of these drawbacks, this reverse use dependence is not entirely applied to all drugs with class 111 action, and, in fact, these drugs are obviously effective against experimental and clinical tachyarrhythmias. Amiodarone, which possesses the same multiple blocking effects on N a+ , K + , and Ca2+ channels as quinidine, lacks reverse use dependence, and amiodarone lengthens the action potential duration at normal and fast heart rates to a similar extent (1). Torsades de pointes rarely occurs in patients receiving amiodarone (32). In addition, both amiodarone and also melperone, a neuroleptic drug that lengthens cardiac repolarization, were found to be equally effective in converting atrial fibrillation and flutter in dogs to sinus rhythm (5437). In vivo studies (46,47) have shown that at fast heart rates of 170-180 beatdmin, dofetilide and almokalant still significantly increased the QT time and effective refractory period in dogs with acute ischemic heart failure. Other studies have also demonstrated that dofetilide and other class I11 drugs protect against atrial and ventricular tachyarrhythmias, such as tachycardia and fibrillation in the dog (13,31), rat (43), and human (26,66,73) heart with or without ischemia. In an in vitro study (85), at five pacing cycle lengths ranging from 300 to 5,000 ms, dofetilide lengthened the myocardial action potential duration to a similar degree. A recent clinical study has also shown that dofetilide significantly increases the effective refractory period in the different areas of the human heart at three driving cycle lengths of 400, 500, and 600 ms (28). Thus, the action of dofetilide to slow cardiac repolarization is probably not reverse use dependent, or shows less reverse use dependence, compared to some other drugs that lengthen the action potential duration,

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since the effectiveness of the drug exhibiting reverse use dependence would be minimized or lost during tachyarrhythmias.

SUMMARY Class 111 antiarrhythmic drugs exert their antiarrhythmic effectiveness by blocking potassium currents. Potassium channel blockers lengthen cardiac refractoriness without altering cardiac excitability and conductivity, an effect being beneficial in treating reentrant arrhythmias. The absence of a negative inotropic or a presence of a moderate positive inotropic effect of class III drugs may be a unique property of great importance in the case of heart failure. An increased spontaneous cycle length of sinus pacemaker cells due to lengthening of repolarization produces a negative chronotropic effect that may help slowing tachyarrhythmias. These advantages may make potassium channel blockers a very useful alternative in the treatment of patients with cardiac arrhythmias.

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