Early Afterdepolarizations Amplitude Research Articles

Prostaglandin modulation of early afterdepolarizations and ventricular tachyarrhythmias induced by cesium chloride combined with efferent cardiac sympathetic stimulation in dogs

Prostaglandins inhibit efferent cardiac sympathetic nerve effects by acting at presynaptic sites and may act to suppress some arrhythmias. In the present study, the effects of intravenous administration of prostacyclin (PGI2) and prostaglandin E2(PGE2) on early afterdepolarization and ventricular tachycardia induced by cesium chloride (0.5 mmol/liter per kg body weight intravenously) combined with stimulation of bilateral ansae subclaviae in anesthetized dogs were examined. The right atrium was paced at a constant cycle length of 600 ms. A left ventricular endocardia! monophasic action potential catheter was used to detect early afterdepolarizations.Prostacyclin (0.2 μg/kg per min) reduced the amplitude of the early afterdepolarizations (39.2 ± 8.4% of the monophasic action potential amplitude during control study to 28.7 ± 5.5%, n = 10; p < 0.001) as well as the prevalence of ventricular tachycardia (11 of 14 dogs during control study to 5 of 14 dogs; p = 0.031). Prostaglandin E2(0.2 to 0.6 μg/kg per min) did not significantly reduce the early afterdepolarization amplitude (34.7 ± 8.9% to 25.1 ± 10.7%, n = 8; p = 0.085) or the prevalence of ventricular tachycardia (8 of 10 versus 6 of 10 dogs; p = 0.50).Alpha- and beta-adrenoceptor blockade with combined intravenous administration of propranolol (0.5 mg/kg) and phentolamine (0.3 mg/kg) decreased the amplitude of the early afterdepolarizations induced by cesium chloride and bilateral ansae subclaviae stimulation from 38.6 ± 11.2% to 18.8 ± 3.3% (n = 6; p = 0.005). Additional administration of PGI2further reduced the early afterdepolarization amplitude from 18.8 ± 3.3% to 9.8 ± 4.8% (n = 6; p = 0.001). In control dogs, the amplitude of the early afterdepolarizations and the prevalence of ventricular tachycardia did not change over time with repeated doses of cesium chloride and bilateral ansae subclaviae stimulation.Thus, exogenous PGI2suppresses early afterdepolarization amplitude and reduces the prevalence of ventricular tachycardia induced by cesium chloride combined with bilateral ansae subclaviae stimulation in dogs, even after alpha- and beta-adrenoceptor blockade. A direct action on the cesium chloride-induced repolarization abnormality, unrelated or in addition to sympathetic neural modulation, is likely to be involved in the PGI2effect.

Alpha-adrenoceptor stimulation and blockade modulates cesium-induced early afterdepolarizations and ventricular tachyarrhythmias in dogs.

In 84 open-chest dogs, we studied the effects on early afterdepolarizations (EADs) and ventricular tachyarrhythmias (VTs) induced by cesium chloride (168 mg/kg i.v.) of alpha-adrenoceptor stimulation with phenylephrine (100 micrograms plus 0.25 microgram/kg/min i.v.) and with left ansa subclavia stimulation (LAS; 2 Hz, 4 msec, 2 mA) after propranolol (0.5 mg/kg) administration. We also studied the effects of alpha-adrenoceptor blockade with phentolamine (3 mg/kg), prazosin (25-500 micrograms/kg), yohimbine (10-500 micrograms/kg), WB 4101 (2 mg/kg), and benoxathian (2 mg/kg) during decentralized LAS. EAD amplitude, presented as a percentage of monophasic action potential amplitude, was recorded simultaneously with contact electrodes from the right and left ventricular endocardium. Phenylephrine and LAS plus propranolol increased EAD amplitude (31.5 +/- 8.8% to 47.8 +/- 9.7% and 34.8 +/- 4.1% to 46.1 +/- 6.4%, respectively) and the prevalence of VT (from three to nine of 11 dogs and from the three to five of six dogs, respectively). Prazosin produced a dose-response decrease in EAD amplitude and reduced the prevalence of VT. Yohimbine did not alter the amplitude of EADs or the prevalence of VT. WB 4101 and phentolamine reduced the amplitude of EADs produced by cesium and LAS (from 44.3 +/- 10.2% to 32.6 +/- 9.4% and from 39.8 +/- 6.9% to 30.3 +/- 6.3%, respectively) and the prevalence of VT (from eight to one of 10 dogs and from 13 to 5 of 20 dogs, respectively). Benoxathian did not alter significantly the amplitude of EADs (41.6 +/- 11.4% to 37.5 +/- 9.4%) or the prevalence of VT (from six to five of 10 dogs).(ABSTRACT TRUNCATED AT 250 WORDS)

Early afterdepolarizations induced in vivo by reperfusion of ischemic myocardium. A possible mechanism for reperfusion arrhythmias.

Recent studies in vitro have shown that afterdepolarizations may develop during reperfusion after hypoxia, thus suggesting that these afterdepolarizations may contribute to the genesis of reperfusion arrhythmias. We recorded monophasic action potentials (MAPs) during myocardial ischemia and reperfusion to investigate whether afterdepolarizations develop in vivo when reperfusion arrhythmias occur. In 15 anesthetized cats, 24 trials of 10 minutes of occlusion of the left anterior descending coronary artery were followed by reperfusion. In 13 of 24 (54%) trials, afterdepolarizations developed at the moment of reperfusion, with a mean amplitude of 2.4 +/- 1.1 mV (13 +/- 8% of MAP amplitude). When cycle length was either increased by vagal stimulation or decreased by atrial pacing, early afterdepolarization (EAD) amplitude was modified, according to what has been described for EAD in vitro, with a positive linear correlation between cycle length and EAD amplitude (r = 0.91, p less than 0.0001). The occurrence of EAD was not related to rapid changes in left ventricular pressure. In the eight of 13 (62%) cases in which EAD development was associated with reperfusion arrhythmias, the coupling interval of the EAD and of premature ventricular contractions showed a significant correlation (r = 0.86, p less than 0.0001). However, in five of 13 (38%) cases, occurrence of reperfusion arrhythmias was not accompanied by the presence of EAD on the MAP recording. In two animals, a 2:1 block of EAD conduction was observed, and this was reflected on the intracavitary electrocardiogram as T wave alternans. Thus, EADs occur frequently after reperfusion in vivo, with a time course that parallels the onset of reperfusion arrhythmias. This finding further supports the role of triggered activity in the genesis of reperfusion arrhythmias in vivo.

Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current.

Early afterdepolarizations (EADs) are a type of triggered activity found in heart muscle. We used voltage-clamped sheep cardiac Purkinje fibers to examine the mechanism underlying EADs induced near action potential plateau voltages with the Ca2+ current agonist Bay K 8644 and the effect of several interventions known to suppress or enhance these EADs. Bay K 8644 produced an inward shift of the steady-state current-voltage relation near plateau voltages. Tetrodotoxin, lidocaine, verapamil, nitrendipine, and raising [K]o abolish EADs and shift the steady-state current-voltage relations outwardly. Using a two-pulse voltage-clamp protocol, an inward current transient was present at voltages where EADs were induced. The voltage-dependence of availability of the inward current transient and of EAD induction were similar. The time-dependence of recovery from inactivation of the inward current transient and of EAD amplitude were nearly identical. Without recovery of the inward current transient, EADs could not be elicited. The inward current transient was enhanced with Bay K 8644 and blocked by nitrendipine, but was not abolished by tetrodotoxin or replacement of [Na]o with an impermeant cation. These results support a hypothesis that the induction of EADs near action potential plateau voltages requires 1) a conditioning phase controlled by the sum of membrane currents present near the action potential plateau and characterized by lengthening and flattening of the plateau within a voltage range where, 2) recovery from inactivation and reactivation of L-type Ca2+ channels to carry the depolarizing charge can occur. Our results suggest an essential role for the L-type Ca2+ "window" current and provide a framework for understanding the role of several membrane currents in the induction and block of EADs.

Differential response to right and left ansae subclaviae stimulation of early afterdepolarizations and ventricular tachycardia induced by cesium in dogs.

Early afterdepolarizations (EADs) are depolarizing potentials that occur before complete repolarization. They may be important in the acquired and possibly the idiopathic long QT syndrome and associated ventricular tachycardia (VT). The purpose of these experiments was to study in 20 open-chest dogs the effects of sympathetic stimulation on EADs and VT produced with cesium chloride (84 mg/kg i.v.) alone or combined with left (LAS), right (RAS), or bilateral (BAS) ansae subclaviae stimulation (2 Hz, 4 msec, 2 mA). We compared the EAD amplitude and area as a percentage of monophasic action potential amplitude and area, respectively, recorded simultaneously with contact electrodes from right (RV) and left ventricular (LV) endocardium and recorded the prevalence of VT induction during each intervention. Both LAS and BAS produced left ventricular EADs with larger amplitudes and areas than did RAS or cesium alone. BAS and LAS produced larger EADs recorded from the LV than from the RV. Cesium produced VT in six of 20 dogs, RAS in three of 20, BAS in 12 of 20, and LAS in 16 of 20. Norepinephrine (0.1-1.5 micrograms/kg/min) caused VT in all dogs by producing a dose-related increase in EAD amplitude that was similar in RV and LV, suggesting that the response of RV and LV EADs to catecholamine stimulation was not intrinsically different. During stimulation of left ansae subclaviae at increasing frequencies (1, 2, 4, and 6 Hz), EADs were significantly larger in LV than in RV at all stimulus frequencies, and the amplitude of EADs in both ventricles increased with increasing stimulus frequencies. Based on the increased LV amplitude and area of cesium chloride-induced EADs during LAS and BAS, with EAD amplitude dependent on the frequency of LAS but with an equal RV and LV EAD amplitude during norepinephrine infusion, it is possible that more norepinephrine released into the LV during LAS and BAS compared with RAS causes larger amplitude LV EADs that reach threshold to cause VT more often. Thus, quantitative differences between the effects of left and right stellate ganglia stimulation rather than qualitative differences or imbalance may account for the arrhythmogenic potential of the left stellate ganglion.