Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K+ channel

Chromanol 293B and dofetilide are inhibitors of IK_s and IK_r, i.e., of the slow and the rapid component of the delayed rectifier potassium current. The specificity of these drugs was tested by investigating their effects on the delayed rectifier potassium current in vascular smooth muscle, regulating the tone of blood vessels. Using depolarizing step protocols with asymmetrical potassium concentrations (135/4.5 mM K⁺ in pipette/bath), voltage-dependent K⁺ currents (IK_v) of enzymatically dispersed guinea pig portal vein cells were studied in the whole-cell patch-clamp technique. Peak currents were obtained within 20 ms (at +50 mV) after activation. During a 10 s test pulse to +60 mV, these currents exhibited a relatively fast inactivation with time constants of 384 ms (τ_fast) and 4505 ms (τ_slow). Dofetilide was totally ineffective in modulating currents; in contrast, after application of chromanol 293B, a steady-state block of IK_v developed within 135 s. The block was concentration-dependent with an IC₅₀ of 7.4 μM. Chromanol did not produce any shift in the normalized steady-state activation and inactivation curves and the recovery from inactivation was not significantly changed. Chromanol 293B similarly inhibited delayed rectifier K⁺ channels whether in their closed or open state, and produced an “apparent” acceleration of inactivation, i.e., the drug accelerated the faster time constant of inactivation during a 10 s test pulse from 384 ms (control) to 149 ms (100 μM chromanol). In recent studies, chromanol was described as a specific blocker of slowly activating delayed rectifier potassium channels (IK_s) in cardiomyocytes. The results of this study, however, extend the inhibitory spectrum of the drug and demonstrate block of closed and open state delayed rectifier K⁺ currents in portal vein vascular smooth muscle. Such a block could possibly contribute to the generation of portal hypertension. Received: 2 March 2001, Returned for 1. revision: 22 March 2001, 1. Revision received: 9 May 2001, Returned for 2. revision: 16 May 2001, 2. Revision received: 3 August 2001, Accepted: 20 August 2001     

Hemodynamic effects of antiarrhythmic drugs

In order to use antiarrhythmic drugs safely, one must understand their hemodynamic effects. Quinidine and the calcium antagonists have direct cardiac effects and frequently opposing autonomically mediated or indirect cardiac effects. Lidocaine is exceptionally well tolerated, even by patients with severe left ventricular dysfunction. Phenytoin and procainamide have the potential for serious adverse effects, but are generally well tolerated at usual doses. Disopyramide causes serious depression of left ventricular function in many patients because of its direct myocardial depressant and peripheral vasoconstricting actions. Although bretylium causes an immediate increase in contractility, it can ultimately result in important hypotension. In this review the in vitro and in vivo hemodynamic effects of these and other antiarrhythmic drugs are discussed to provide information that will assist the clinician in using these drugs properly.     

Proarrhythmic effects of antiarrhythmic drugs

Antiarrhythmic agents can worsen existing arrhythmias by increasing their duration or frequency, increasing the number of premature complexes or couplets, altering the rate of the arrhythmia or causing new, previously unexperienced arrhythmias. QT prolongation occurs in many settings, not all of which are associated with increased arrhythmia development. Arrhythmogenesis in the setting of a long QT interval may be related to marked asynchrony of repolarization. The role of afterdepolarizations is still being investigated. No correlation has been established between the occurrence of torsades de pointes, a specific degree of QT prolongation and either the dose or serum concentration of any of the antiarrhythmic agents. In 30 patients who experienced drug-induced ventricular fibrillation, the median time to ventricular fibrillation was only 3 days after drug treatment began. Significant caution must be exercised in determining the need for antiarrhythmic therapy and in monitoring patients after treatment has begun.     

Block of cardiac sodium channels by antiarrhythmic drugs

The effects of seven Class-I antiarrhythmic drugs on the maximum upstroke velocity (Vmax) of action potential were examined in isolated guinea pig ventricular muscles in order to characterize their use- and state-dependent sodium channel blocking action. From the onset and offset kinetics of the use-dependent Vmax inhibition during stimulation trains, the seven drugs were subdivided into two groups; fast drugs (lidocaine, mexiletine, and tocainide), and slow drugs (quinidine, aprindine, disopyramide and flecainide). In experiments to assess the state-dependent sodium channel block, a conditioning clamp pulse to 0 mV was applied by using the single sucrose-gap voltage-clamp technique, and the Vmax of test action potential 100 msec after the clamp pulse was measured. The decrease in Vmax by 10 msec clamp pulse was defined as the activated channel block (ACB), and the decrease in Vmax as the clamp pulse duration was prolonged from 10 to 500 msec was defined as the inactivated channel block (ICB). The ratio of ICB to ACB was less than 1.0 for quinidine, disopyramide and flecainide, and much greater than 1.0 for aprindine, lidocaine, mexiletine, and tocainide. These characteristics may contribute to the differences in efficacy of each drug in treating various types of arrhythmias.     

The proarrhythmic effects of antiarrhythmic drugs

Although antiarrhythmic drugs are effective for controlling cardiac arrhythmias, they may also induce or exacerbate them. Case reports have appeared implicating all classes of antiarrhythmic drugs. It is difficult to assess the size of the problem in practice, as it varies with different subgroups of patients, but rates of up to 13% have been found where proarrhythmic effects were actively sought. Their occurrence is affected both by the electrophysiologic characteristics of the drugs and by the arrhythmia substrate. Mechanisms of proarrhythmic effects may be classified according to the electrophysiologic and hemodynamic effects of the drugs. Detection of drug-induced arrhythmias depends on appreciation of the problem by physicians and, although there are few clear predictors, some form of monitoring of antiarrhythmic drug treatment is recommended. Management of such arrhythmias when they occur involves withdrawal of the offending agent, correcting contributory factors, and reassessing the initial arrhythmia and the strategy for its management.     

Modulation of potassium channels by antiarrhythmic and antihypertensive drugs.

Agents that modulate cardiac and smooth muscle K+ channels have stimulated considerable interest in recent years because of their therapeutic potential in a number of cardiovascular diseases. Foremost among these drugs are the so-called Class III antiarrhythmic agents, which act by prolonging cardiac action potentials, and K+ channel openers, which hyperpolarize and thereby relax smooth muscle cells. Many of the newly developed Class III antiarrhythmic agents probably act by specific block of one subtype of delayed rectifier K+ current, IKr, whereas other agents block more than one type of cardiac K+ current. Much controversy exists over the specific type of K+ channel (or channels) in smooth muscle that are activated by the K+ channel openers. Both groups of K+ channel modulators have great therapeutic promise, but the Class III antiarrhythmic agents may suffer from a side-effect that is directly linked to their specific mechanism of action.     

Hemodynamic effects of newer antiarrhythmic drugs

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodynamic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodynamic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verapamil are administered either acutely by the intravenous route or chronically by the oral route.     

The electrophysiologic effects of antiarrhythmic drugs

In this review antiarrhythmic agents are classified into 3 groups: (1) those that remove or prevent the factors responsible for the electrophysiologic abnormality underlying an arrhythmia; (2) those that enhance the effects of acetylcholine either by increasing parasympathetic effects or by decreasing sympathetic effects; and (3) those that directly alter the electrophysiologic properties of cardiac cells. If bretylium and propranolol are excluded from the drugs in group 3, then all of the drugs within this group have in common the ability to suppress diastolic depolarization and to shift the membrane potential during repolarization from which the earliest premature response can originate to a more negative value. By so doing, the rate of depolarization of the earliest premature response may be increased, in spite of a rightward shift of the membrane responsiveness curve. The importance of these effects is discussed in terms of current concepts of the genesis of arrhythmias.     

Proarrhythmic effects of antiarrhythmic drugs]

The proarrhythmic effects of antiarrhythmic drugs are complications which have been described over several decades but the mechanisms (reentry, increased automaticity, ectopic faci, induced repetitive activity, vagal or adrenergic triggers) and the predisposing factors (underlying cardiac disease, previous severe arrhythmia, metabolic disorders, ischaemia, etc...) have only recently been identified. The appreciation of their true frequency poses problems of methodology (mode of recruitment, therapeutic converse proof), of definitions and depends to a great extent on the methods of detection used. Their severity cannot be denied and has been demonstrated both in experience of isolated cases and in recent prospective studies, the conclusions of which must be interpreted critically. Proarrhythmic effects may be observed at atrial (vagal or sympathetic arrhythmias, 1/1 flutter, acceleration of atrial fibrillation in preexcitation syndromes), junctional (artificial unidirectional block created by the antiarrhythmic drug which may be very effective at higher dosages: biphasic effect) or ventricular (aggravation of ventricular extrasystoles, torsades de pointe, ventricular tachycardia/fibrillation) levels. It is curious that no antiarrhythmic drug seems to be statistically less exposed to this type of complication which may result from phenomena of toxicity or idiosyncrasy. Given the potential gravity measures must be taken to prevent this complication, by observing simple rules (respect of contraindication, use of progressive dosage regimens, avoidance of loading doses, elimination of predisposing factors and abstention from dangerous therapeutic associations) and by carefully following up high risk patients.     

Membrane perturbational effects of antiarrhythmic drugs.

The structural and functional consequences of the interaction of various antiarrhythmic agents with human erythrocyte membranes were analyzed using drug concentrations influencing the stability of intact erythrocytes to hypotonic lysis, with the assumption that such stabilization may bear some molecular analogy to the stabilizing properties of these molecules in excitable tissues. Most of the agents tested, including quinidine, lidocaine, the verapamil analogue D-600 and the two quaternary analogues QX-572 and pranolium, produced concentration-dependent perturbations of membrane structural components as reflected by increases in the incorporation of 5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) and trinitrobenzenesulfonic acid (TNBS) into membrane sulfhydryl and amino groups respectively. Practolol, a β-adrenergic antagonist which, unlike the foregoing agents, lacks significant cardiodepressant actions, did not appreciably modify the membrane incorporation of TNBS or DTNB, despite the fact that this molecule possessed marked antihemolytic properties. It, therefore, appears that the membrane perturbational actions of antiarrhythmics as analyzed here by means of group-specific chemical probes are a better index of the direct myocardial membrane actions than erythrocyte stabilization. The diverse perturbational characteristics of the various antiarrhythmics studied, as revealed by their different effects on the incorporation of TNBS into membrane protein and phospholipid components suggested the possibility that the molecular mechanisms by which these drugs alter cardiac automaticity may not be identical. This, in turn, might underlie the different spectra of clinical effectiveness exhibited by these agents.     

Hemodynamic effects of antiarrhythmic drugs in acute myocardial infarction

The hemodynamic effects induced by an i.v. administration of Amiodarone (5 mg/Kg in 10 min + continuous infusion of 0.6 mg/min for 4-40 hrs), Propafenone (1-2 mg/Kg in 5 min + continuous infusion of 10-15 mcg/Kg/min for 24 hrs) and Mexiletine (250 mg in 15 min + 250 mg in 1 hr) have been evaluated in patients with acute myocardial infarction complicated by sinus tachycardia and hyperdynamic pattern, ventricular or supraventricular arrhythmias. The hemodynamic serial determinations have been comprehensive of: heart rate; systolic, diastolic and mean pressure; central venous pressure; arterial and wedge pulmonary pressure; cardiac output and cardiac index; vascular systemic resistences; left ventricular stroke work index; left ventricular mean ejection rate; double and triple product. In all of the three groups we observed: a reduction of cardiac index associated with an increase of left and right ventricular filling pressure and a reduction either of left ventricular stroke work index and left ventricular mean ejection rate; these hemodynamic changes were less significant after Mexiletine than after Amiodarone or Propafenone. These data confirm the negative inotropic effect of the three drugs; anyhow, these changes are usually well tolerated by patients affected by AMI with a sufficiently preserved ventricular function. The authors, however, reccommend an accurate hemodynamic monitoring of the effects of the drugs also to identify patients with a not overt ventricular failure which may become manifest after drug administration.     

K+-induced dilation of hamster cremasteric arterioles involves both the Na+/K+-ATPase and inward-rectifier K+ channels

OBJECTIVE: The mechanism by which elevated extracellular potassium ion concentration ([K+]o) causes dilation of skeletal muscle arterioles was evaluated. METHODS: Arterioles (n = 111) were hand-dissected from hamster cremaster muscles, cannulated with glass micropipettes and pressurized to 80 cm H2O for in vitro study. The vessels were superfused with physiological salt solution containing 5 mM KCl, which could be rapidly switched to test solutions containing elevated [K+]o and/or inhibitors. The authors measured arteriolar diameter with a computer-based diameter tracking system, vascular smooth muscle cell membrane potential with sharp micropipettes filled with 200 mM KCl, and changes in intracellular Ca2+ concentration ([Ca2+]i) with Fura 2. Membrane currents and potentials also were measured in enzymatically isolated arteriolar muscle cells using patch clamp techniques. The role played by inward rectifier K+ (KIR) channels was tested using Ba2+ as an inhibitor. Ouabain and substitution of extracellular Na+ with Li+ were used to examine the function of the Na+/K+ ATPase. RESULTS: Elevation of [K+]o from 5 mM up to 20 mM caused transient dilation of isolated arterioles (27 +/- 1 microm peak dilation when [K+]o was elevated from 5 to 20 mM, n = 105, p <.05). This dilation was preceded by transient membrane hyperpolarization (10 +/-1 mV, n = 23, p <.05) and by a fall in [Ca2+]i as indexed by a decrease in the Fura 2 fluorescence ratio of 22 +/- 5% (n = 4, p <.05). Ba(2+) (50 or 100 microM) attenuated the peak dilation (40 +/- 8% inhibition, n = 22) and hyperpolarization (31 +/- 12% inhibition, n = 7, p <.05) and decreased the duration of responses by 37 +/-11% (n = 20, p < 0.05). Both ouabain (1 mM or 100 microM) and replacement of Na+ with Li+ essentially abolished both the hyperpolarization and vasodilation. CONCLUSIONS: Elevated [K+]o causes transient vasodilation of skeletal muscle arterioles that appears to be an intrinsic property of the arterioles. The results suggest that K+-induced dilation involves activation of both the Na+/K+ ATPase and KIR channels, leading to membrane hyperpolarization, a fall in [Ca2+]i, and culminating in vasodilation. The Na+/K+ ATPase appears to play the major role and is largely responsible for the transient nature of the response to elevated [K+]o, whereas KIR channels primarily affect the duration and kinetics of the response.     

Acid-sensing ion channels interact with and inhibit BK K+ channels

Acid-sensing ion channels (ASICs) are neuronal non-voltage-gated cation channels that are activated when extracellular pH falls. They contribute to sensory function and nociception in the peripheral nervous system, and in the brain they contribute to synaptic plasticity and fear responses. Some of the physiologic consequences of disrupting ASIC genes in mice suggested that ASIC channels might modulate neuronal function by mechanisms in addition to their H(+)-evoked opening. Within ASIC channel's large extracellular domain, we identified sequence resembling that in scorpion toxins that inhibit K(+) channels. Therefore, we tested the hypothesis that ASIC channels might inhibit K(+) channel function by coexpressing ASIC1a and the high-conductance Ca(2+)- and voltage-activated K(+) (BK) channel. We found that ASIC1a associated with BK channels and inhibited their current. Reducing extracellular pH disrupted the association and relieved the inhibition. BK channels, in turn, altered the kinetics of ASIC1a current. In addition to BK, ASIC1a inhibited voltage-gated Kv1.3 channels. Other ASIC channels also inhibited BK, although acidosis-dependent relief of inhibition varied. These results reveal a mechanism of ion channel interaction and reciprocal regulation. Finding that a reduced pH activated ASIC1a and relieved BK inhibition suggests that extracellular protons may enhance the activity of channels with opposing effects on membrane voltage. The wide and varied expression patterns of ASICs, BK, and related K(+) channels suggest broad opportunities for this signaling system to alter neuronal function.     

A receptor for type I antiarrhythmic drugs associated with rat cardiac sodium channels

We assessed the effects of type I antiarrhythmic drugs on the binding of ligands to receptors on voltage-sensitive sodium channels of rat cardiac myocytes. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTXB), a toxin that binds to the sodium channel. The 8 drugs tested inhibited [3H]BTXB binding in a dose-dependent fashion with IC50 values from 1.34 microM for O-demethylencainide to 811 microM for procainamide. A log-log plot of IC50 versus mean therapeutic serum concentration yielded a regression line with slope of 1.17 and r of 0.95. Scatchard analysis of [3H]BTXB binding showed that lidocaine reduced the maximal binding without altering the KD for [3H]BTXB binding, indicating allosteric inhibition. The inhibition by lidocaine of [3H]BTXB binding was reversible within 30 minutes when the samples were diluted from 390 to 39 microM lidocaine. In other studies, the stereoisomers of tocainide were shown to have a threefold to fourfold difference in IC50 for inhibition of [3H]BTXB binding. The binding of antiarrhythmic drugs to this site is saturable, reversible, and stereospecific and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. This suggests that binding at this site relates to pharmacologic activity.     

K+ channel openers activate brain sulfonylurea-sensitive K+ channels and block neurosecretion.

Vascular K+ channel openers such as cromakalim, nicorandil, and pinacidil potently stimulate 86Rb+ efflux from slices of substantia nigra. This 86Rb+ efflux is blocked by antidiabetic sulfonylureas, which are known to be potent and specific blockers of ATP-regulated K+ channels in pancreatic beta cells, cardiac cells, and smooth muscle cells. K0.5, the half-maximal effect of the enantiomer (-)-cromakalim, is as low as 10 nM, whereas K0.5 for nicorandil is 100 nM. These two compounds appear to have a much higher affinity for nerve cells than for smooth muscle cells. Openers of sulfonylurea-sensitive K+ channels lead to inhibition of gamma-aminobutyric acid release. There is an excellent relationship between potency to activate 86Rb+ efflux and potency to inhibit neurotransmitter release.     

Future of antiarrhythmic drugs

PURPOSE OF REVIEW: This article briefly summarizes the principal mechanisms of action of contemporary antiarrhythmic agents, delineates their limitations in the treatment of cardiac arrhythmias, and discusses why there is a need for new cardiac antiarrhythmic drugs. RECENT FINDINGS: In recent years, the limited efficacy and proarrhythmic potential of classic antiarrhythmic drugs have focused attention on nonpharmacologic approaches to treatment of cardiac arrhythmias. Despite the current success of ablative therapy and implantable defibrillators, the need is still pressing for new antiarrhythmic drugs. Evolving knowledge about the molecular mechanisms of cardiac arrhythmias provides innovative strategies for discovering new cardiac antiarrhythmic drugs. Some of these have already led to the development of new compounds on the verge of clinical use, and others hold great promise for future drug development. SUMMARY: Cardiac arrhythmias are associated with significant morbidity and mortality in developed countries. Antiarrhythmic drug therapy was traditionally the mainstay of arrhythmia treatment; however, the inefficacy of drug treatment and the potential that antiarrhythmic drugs can provoke life-threatening arrhythmias have generated interest in new approaches to antiarrhythmic drug development. Improved understanding of the cellular and molecular basis of cardiac arrhythmias holds the promise of identifying novel approaches for the treatment of cardiac arrhythmias. These approaches may target traditional and newly discovered cardiac ion channels, as well as new molecular and signaling pathways that modulate arrhythmic substrates.