Victor Elharrar

Alterations in canine myocardial excitability during ischemia.

SUMMARY Changes in the ventricular diastolic excitability threshold following occlusion of the left anterior descending coronary artery (LAD) were studied in open-chest anesthetized dogs by using a new automatic threshold-following pacemaker (ATFP). The ATFP measures the diastolic excitability threshold by successively decreasing the duration of regularly occurring pacing stimuli until the ventricle fails to respond. Under control conditions, the threshold stimulus duration was 60 ± 4 (mean ± SEM) &mgr;sec. In the first 1–3 minutes following occlusion of the LAD, the diastolic excitability threshold in the ischemic zone (IZ) decreased to 51 ± 5 &mgr;sec and then rapidly increased to 600 &mgr;sec at 5 minutes. The initial decrease in excitability threshold at IZ could be abolished by elevating the serum K+ concentration prior to the LAD occlusion. These changes in excitability threshold at IZ could be prevented by infusing nonoxygenated solutions into the LAD at a site distal to the occlusion. As the excitability threshold increased in IZ during ischemia, the earliest time at which IZ could be reactivated by a stimulus with a voltage equal to twice the preligation diastolic voltage threshold was increased. In nine of 16 dogs, after 5 minutes of LAD ligation, the IZ to normal zone (NZ) activation time (when stimulating at IZ) exceeded the NZ to IZ activation time (when stimulating at NZ) by an average of 9 msec. We also found that in four dogs the NZ to IZ activation time exceeded the IZ to NZ activation time by an average of 10 msec. We conclude from these findings that a gradient of increasing excitability threshold exists as one moves from normally perfused toward more ischemic tissue, passing through a heterogeneous border zone that manifests some areas which have a decreased excitability threshold and other areas which have an increased excitability threshold, and that these changes in excitability importantly influence the determination of refractory period durations and conduction times.

Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs

The effects of various drugs on delayed activation of the ischemic myocardium and the incidence of ventricular arrhythmias were studied in 34 open-chest anesthetized dogs. The left anterior descending coronary artery was occluded for 6 minutes before and 42 minutes after administration of aprindine (2.85 mg/kg body weight), quinidine (8 mg/kg) and verapamil (0.2 mg/kg) and during infusion of isoproterenol (0.2 microng/min). The time intervals from the onset of the QRS complex to the major deflection of the bipolar electrograms recorded within the normal and ischemic zones were measured at cycle lengths of 500, 400 and 300 msec and were correlated with the development of ventricular arrhythmias. At a cycle length of 500 msec, aprindine increased by 19.5 msec the delay in activation time produced by coronary ligation alone (P less than 0.05), whereas verapamil reduced by 10 msec the extent of ischemia-induced conduction delay (P less than 0.05). The delay in activation time in the ischemic zone was not significantly altered by quinidine or isoproterenol. The incidence of ventricular arrhythmias was increased by aprindine (from 1 in 11 to 8 in 11 dogs), decresed by verapamil (from 3 in 7 to 0 in 7 dogs) and was not changes by quinidine or isoproterenol. Thus, delayed activation of the ischemic myocardium appears to play an important role in the genesis of early arrhythmias due to myocardial ischemia, and drugs that significantly depress conduction in the ischemic myocardium may predispose to the development of ventricular arrhythmia whereas those that improve conduction may be protective. Contrary to their effects on slow channel-dependent conduction, verapamil improved and isoproterenol worsened conduction during ischaemia.

Effect of Antiarrhythmic Drugs on the Cycle Length-dependent Action Potential Duration in Dog Purkinje and Ventricular Muscle Fibers

Summary: We examined the steady-state action potential duration (APD) within a wide range of cycle lengths (CL) in cardiac dog Purkinje (P) and ventricular (V) muscle fibers in the presence of: lidocaine (L) 4 and 8 μg/ml, mexiletine (M) 4 and 8 μg/ml, flecainide (F) 1 and 4 μg/ml, disopyramide (D) 3.1 and 10 μg/ml, quinidine (Q) 2.5, 5, and 10 μg/ml, bretylium tosylate (B) 5 and 10 μgl ml, and sotalol (S) 5 μg/ml. In the P fibers, all drugs except for B and S shortened plateau duration, increased slope of phase 2 and decreased slope of phase 3 repolarization, and either shortened (L, M, Q, F) or prolonged (D) APD. B and S lengthened APD and did not change significantly the slopes of phase 2 and 3 of repolarization. Each drug altered the relation between APD and CL according to one of the following three patterns: (a) L, M, Q, and F shortened APD more at long than at short CL; (b) D lengthened APD more at short than at long CL; (c) B and S lengthened APD more at long that at short CL. In the V fibers, APD was lengthened by F, Q, and B, and shortened by L and M. The drug-induced changes in the relation between APD and CL were as in the P fibers. The results suggest that the drug-induced changes in the relation between APD and CL can be predicted from the drug effects on the course of repolarization.

Frequency-dependent effects of several class I antiarrhythmic drugs on Vmax of action potential upstroke in canine cardiac purkinje fibers

Summary: &OV0312;max of the action potential upstroke in canine cardiac Purkinje fibers was studied in the presence of seven class I antiarrhythmic drugs—lidocaine (4 μg/ml), mexiletine (4 μg/ml), propranolol (0.9 μg/ml), procainamide (30 μg/ml), quinidine (5 μg/ml), flecainide (4 μg/ml), and disopyramide (3.1 μg/ml)—at constant cycle lengths (CCL) and after abrupt changes in cycle length (ACCL). The time constant of &OV0312;max recovery after ACCL at a basic cycle length of 500 ms was 0.09 ± 0.01 s for lidocaine, 0.18 ± 0.03 s for mexiletine, 1.35 ± 0.20 s for propranolol, 4.4 ± 0.8 s for procainamide, 8.3 ± 1.2 s for quinidine, 11.0 ± 0.9 s for flecainide, and 37.9 ± 9.4 s for disopyramide. These values were similar to those reported by others in guinea pig papillary muscle, and, with the exception of flecainide, conformed to the scheme proposed by Courtney (J Mol Cell Cardiol 1980;12:1273–86) based on the molecular weight and lipid solubility hypothesis. Each drug altered the &OV0312;max differently at CCL from after ACCL at the same diastolic intervals. The magnitude of these differences and the range of diastolic intervals at which they were present varied among different drugs. These observations explain differences in the drug effects on the &OV0312;max of the regularly and prematurely occurring depolarizations. In the presence of lidocaine and mexiletine, the recovery kinetics of &OV0312;max were not altered by CCL within the 300–1,500-ms range, and the magnitude of &OV0312;max depression was not influenced by action potential duration within the 200–270-ms range.

Use-dependent effects of amiodarone on V̇max in cardiac Purkinje and ventricular muscle fibers

Superfusion with 5 micrograms/ml amiodarone for 3-4 h induced use-dependent Vmax block in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was exponential with tau of 289 +/- 30 ms in Purkinje (n = 7) and 282 +/- 47 ms in muscle (n = 6) fibers. The onset of frequency-dependent Vmax block was rapid, i.e. reached steady state after 4.2 +/- 0.5 beats (n = 5). The combination of rapid interaction with sodium channel and the reported action potential lengthening make amiodarone unique among Class I antiarrhythmic drugs.

Adrenergically Mediated Ventricular Fibrillation in Probucol‐Treated Dogs: Roles of Alpha and Beta Adrenergic Receptors

A high incidence of sudden death due to ventricular fibrillation (VF) has been observed in dogs under chronic treatment with probucol, a new hypocholesterolemic agent. The present study describes the cardiac electrophysiologic properties of probucol‐treated dogs and characterizes the electrophysiological response of these animais to manipula‐tion of the autonomic nervous system. There was no significant difference in the spontaneous sinus cycle length, the QT interval, refractory period of the atrium, ventricle or A‐V junction between normal and probucol‐treated dogs. Epinephrine produced VF with few and sometimes no preceding premature ventricular extra‐systoles. Electrical stimulation of the left stellate ganglion induced VF in 16/19 dogs whereas stimulation of the right stellate ganglion induced VF in 1/19 dogs. Phenyl‐ephrine induced VF in 0/19 dogs, isoproterenol in 5/19 dogs, but phenylephrine + isoproterenol induced VF in 9/11 dogs in which isoproterenol did not produce VF. α(phentolaminej or β (propranolol) blockade prevented initiation of VF by epi‐nephrine, phenylephrine + isoproterenol, and left stellate stimulation but a blockade did not prevent induction of VF by isoproterenoJ when isoproterenol alone produced VF. In this nonischemic model, we conclude that left stellate stimulation is a far more potent initiator of VF than right stellate stimulation and that induction of VF appears to require both α and β adrenergic receptor stimulation.

Voltage Modulation of Automaticity in Cardiac Purkinje Fibers

The sino atrial pacemaker dominates subsidiary pacemakers through the process of overdrive suppression. Subsidiary pacemakers that demonstrate spontaneous diastolic depolarization are located in specialized atrial and ventricular fibers. Diastolic depolarization is normally absent in ordinary atrial and ventricular fibers, although under certain experimental conditions, considered by Surawicz [l], these fibers may develop diastolic depolarization and spontaneous automaticity. The purpose of this chapter is to review the mechanisms responsible for diastolic depolarization and spontaneous automaticity in cardiac Purkinje fibers, with particular emphasis on the effects that pharmacologic agents exert on automaticity that occur at high and low levels of transmembrane potential.

Effect of altered repolarization course induced by antiarrhythmic drugs and constant current pulses on duration of premature action potentials in canine cardiac Purkinje fibers.

Summary: The purpose of this study was to elucidate the mechanism of the upward shift of the electrical restitution curve, i.e., the lengthening of premature action potential duration (APDt) expressed as percentage of basic APD, induced by class I antiarrhythmic drugs in dog Purkinje fibers. In this study, six class I antiarrhythmic drugs lengthened APDt at a diastolic interval of 20 ms by 2.5–14.1%. The drugs also decreased the ratio of APD at 50% to APD at 90% of repolarization from 70.8 ± 1.8% (n = 60) to 47.4 – 60.8%. The relation between the decrease in the ratio of APD50 to APD90 of the basic AP and lengthening of the normalized APDt was linear (r = 0.92; p < 0.01). We attributed the lengthening of normalized APDt to the decreased ratio of APD50 to APD90, and applied repolarizing current pulses in short (≤2 mm) fibers to simulate the drug-induced decrease in the ratio of APD50 to APD90. The altered repolarization course of basic AP by the current pulse during late plateau and early phase 3 caused APDt lengthening. The relation between the current-induced decrease in the ratio of APD50 to APD90 of the basic AP and the lengthening of normalized APDt was linear (r = 0.91; p < 0.01). The slope of regression line describing this relation was similar to that in the presence of drugs. These results suggest that lengthening of the normalized APDt by class I antiarrhythmic drugs results from a more rapid repolarization during phase 2 of the preceding basic AP, possibly due to lesser influence of the delayed outward rectifying current. The lengthening of APDt by class I drugs may contribute to their antiarrhythmic action.

Effect of mexiletine, amiodarone and disopyramide on the excitability and refractoriness of canine cardiac fibers: possible relation to antiarrhythmic drug action and classification.

SummaryWe tested the hypothesis of Campbell [1] that the effect of the sodium channel-blocking antiarrhythmic drugs on postrepolarization refractoriness i.e., relation between action potential duration (APD) and effective refractory period (ERP) is determined by the drugs effect on the recovery from Vmax block. We studied the effects of two antiarrhythmic drugs with fast (mexiletine, amiodarone), and one with slow (disopyramide) kinetics of recovery from Vmax block, at two different basic cycle lengths (BCL), on ERP/APD ratio in cardiac dog Purkinje and ventricular muscle fibers. ERP was measured using stimuli of 2 ms duration and 1.0 to 5.0 times diastolic threshold strength. The three drugs altered the kinetics of recovery from Vmax block in the manner previously reported by us and other investigators. In both fiber types, mexiletine increased and the other two drugs did not change the ERP/APD ratio. We concluded that the magnitude of postrepolarization refractoriness could not be predicted from the kinetics of the Vmax block. Also, the effect of the drug on the ERP/APD ratio could be altered by changes in the stimulus strength and the BCL.

Effect of Various Interventions on Myocardial Activation During Ischemia

For several years, investigators have studied the effects of various interventions on the electric properties of ischemic myocardium. Several important observations have emerged. First, the ischemic myocardium appears more sensitive to the effects of antiarrhythmic agents than does the normal myocardium. Drugs that influence the normal myocardium minimally may profoundly affect conduction or refractoriness in ischemic tissue (1–6). Second, drugs that have a negative dromotropic action are capable of increasing ischemia-induced conduction delay. An increase in conduction delay has been associated with an increase in the spontaneous development of ventricular tachyarrhythmias following administration of aprindine (3), ethmozin (4), quinidine (6), mexiletine (6), and other agents (5,6). Conversely, drugs that reduce ischemia-induced conduction delay, like verapamil, appear to prevent ventricular arrhythmias following acute coronary artery occlusion (3). Verapamil, given after coronary artery occlusion, may produce different effects compared to its administration prior to coronary artery occlusion (7).