Modulation of Electrophysiological Properties of Neonatal Canine Heart by Tonic Parasympathetic Stimulation

The effects of tonic right and left vagal stimulation (RVS and LVS) on electrophysiological properties of the immature myocardium and specialized conduction system were evaluated in 11 neonatal canines pretreated with propranolol (1 mg/kg iv). Electrophysiological studies were performed by recording intracardiac electrograms from multiple endocardial catheters during programmed electrical stimulation. Assessments were made of sinus node function, intra-atrial, atrioventricular (AV) nodal and His-Purkinje conduction, and atrial and ventricular refractoriness in the control state and during RVS and LVS at 4-12 Hz. Vagal stimulation prolonged the sinus cycle length; RVS produced a 38% increase and LVS a 25% increase at 8 Hz (P \u3c 0.01). There were no changes in the intra-atrial or His-Purkinje conduction times. Comparable increases occurred during RVS and LVS in the paced cycle length resulting in AV nodal Wenckebach, the AV nodal conduction time at a paced cycle length of 340 ms, and the effective and functional refractory periods of the AV node, suggesting symmetrical influences of the right and left vagus on neonatal AV nodal function. Right atrial effective and functional refractory periods shortened significantly during vagal stimulation (ERP, 36% RVS and 23% LVS; FRP, 27% RVS and 15% LVS), and in 5 of 11 neonates, a sustained regular atrial tachyarrhythmia was induced during atrial extrastimulation. Small yet significant increases were observed in the right ventricular ERP and FRP during vagal stimulation. This study provides information regarding the functional integrity of the parasympathetic nervous system and its potential rose as a modulator of the electrophysiological properties of the newborn heart. Developmental differences in parasympathetic influence on the sinus node, atrium, AV node, and ventricle of the newborn are demonstrated. Information concerning autonomic modulation of the electrophysiology of the neonatal heart may be of importance in understanding the natural history of certain dysrhythmias observed in the neonatal period

Ibutilide Induced Intraatrial Wenckebach Periodicity in the Neonatal Canine Heart

In nine anesthetized canine neonates, the high right atrium was paced at progressively shorter cycle lengths while recording high right atrial electrograms and left atrial appendage monophasic action potentials before and after the administration of the new Class III agent, ibutilide. Prior to ibutilide administration, 1:1 conduction was maintained from the high right atrium to the left atrial appendage at all paced cycle lengths, down to 160 ms. Following ibutilide, a pattern of intraatrial conduction was observed in two of nine neonates at a cycle length of 160 ms that was consistent with the development of intraatrial Wenckebach periodicity. This represents one of the only demonstrations of drug induced intraatrial Wenckebach periodicity in vivo and suggests that this rarely reported form of atrial conduction block might play a role in ibutilide\u27s clinical efficacy against atrial arrhythmias

Comparison of the Rate Dependent Effects of Dofetilide and Ibutilide in the Newborn Heart

This study compared the rate dependent changes in atrial and ventricular monophasic action potential duration in the newborn canine heart in response to two Class III antiarrhythmic agents: dofetilide, a pure Ikr blocker, and ibutilide, a Na+ channel opener. Newborn dogs were anesthetized with pentobarbital, vagotomized, and given propranolol to eliminate autonomic responses. A 4 Fr electrical catheter was placed in the right atrium for pacing. Monophasic action potential durations (APDs) at 90% repolarization (APD90) were recorded from the epicardial surface of the left ventricle and atrium with Ag-AgCl2 suction electrodes. APD90 was measured as cardiac cycle length was shortened by pacing, in the control condition and following two doses of dofetilide (n = 8) or ibutilide (n = 9). Slopes of the APD90 versus decreasing paced cycle length (PCL) relationships were then compared. Large dose dependent increases in atrial and ventricular APD90 were observed after dofetilide and ibutilide. In the neonatal atrium, there were no changes in the APD90 versus PCL relationship with either drug, indicating no rate dependency of drug effect. In contrast, in the ventricle, a steeper APD90 versus PCL slope was noted after dofetilide and ibutilide, indicating a significant loss of drug effect at faster heart rates (i.e., reverse rate dependency). In spite of probable different cellular mechanisms of action, the rate dependent characteristics of dofetilide and ibutilide are identical in the neonatal heart. There is no evidence of (reverse) rate dependency in the atrium, predicting that both agents would be effective at rapid atrial tachycardia rates. For both, however, marked reverse rate dependency is observed in the neonatal ventricle

Comparison of the Rate Dependent Effects of Dofetilide and Ibutilide in the Newborn Heart

This study compared the rate dependent changes in atrial and ventricular monophasic action potential duration in the newborn canine heart in response to two Class III antiarrhythmic agents: dofetilide, a pure Ikr blocker, and ibutilide, a Na+ channel opener. Newborn dogs were anesthetized with pentobarbital, vagotomized, and given propranolol to eliminate autonomic responses. A 4 Fr electrical catheter was placed in the right atrium for pacing. Monophasic action potential durations (APDs) at 90% repolarization (APD90) were recorded from the epicardial surface of the left ventricle and atrium with Ag-AgCl2 suction electrodes. APD90 was measured as cardiac cycle length was shortened by pacing, in the control condition and following two doses of dofetilide (n = 8) or ibutilide (n = 9). Slopes of the APD90 versus decreasing paced cycle length (PCL) relationships were then compared. Large dose dependent increases in atrial and ventricular APD90 were observed after dofetilide and ibutilide. In the neonatal atrium, there were no changes in the APD90 versus PCL relationship with either drug, indicating no rate dependency of drug effect. In contrast, in the ventricle, a steeper APD90 versus PCL slope was noted after dofetilide and ibutilide, indicating a significant loss of drug effect at faster heart rates (i.e., reverse rate dependency). In spite of probable different cellular mechanisms of action, the rate dependent characteristics of dofetilide and ibutilide are identical in the neonatal heart. There is no evidence of (reverse) rate dependency in the atrium, predicting that both agents would be effective at rapid atrial tachycardia rates. For both, however, marked reverse rate dependency is observed in the neonatal ventricle

Modulation of Electrophysiological Properties of Neonatal Canine Heart by Tonic Parasympathetic Stimulation

The effects of tonic right and left vagal stimulation (RVS and LVS) on electrophysiological properties of the immature myocardium and specialized conduction system were evaluated in 11 neonatal canines pretreated with propranolol (1 mg/kg iv). Electrophysiological studies were performed by recording intracardiac electrograms from multiple endocardial catheters during programmed electrical stimulation. Assessments were made of sinus node function, intra-atrial, atrioventricular (AV) nodal and His-Purkinje conduction, and atrial and ventricular refractoriness in the control state and during RVS and LVS at 4-12 Hz. Vagal stimulation prolonged the sinus cycle length; RVS produced a 38% increase and LVS a 25% increase at 8 Hz (P \u3c 0.01). There were no changes in the intra-atrial or His-Purkinje conduction times. Comparable increases occurred during RVS and LVS in the paced cycle length resulting in AV nodal Wenckebach, the AV nodal conduction time at a paced cycle length of 340 ms, and the effective and functional refractory periods of the AV node, suggesting symmetrical influences of the right and left vagus on neonatal AV nodal function. Right atrial effective and functional refractory periods shortened significantly during vagal stimulation (ERP, 36% RVS and 23% LVS; FRP, 27% RVS and 15% LVS), and in 5 of 11 neonates, a sustained regular atrial tachyarrhythmia was induced during atrial extrastimulation. Small yet significant increases were observed in the right ventricular ERP and FRP during vagal stimulation. This study provides information regarding the functional integrity of the parasympathetic nervous system and its potential rose as a modulator of the electrophysiological properties of the newborn heart. Developmental differences in parasympathetic influence on the sinus node, atrium, AV node, and ventricle of the newborn are demonstrated. Information concerning autonomic modulation of the electrophysiology of the neonatal heart may be of importance in understanding the natural history of certain dysrhythmias observed in the neonatal period

Ibutilide Induced Intraatrial Wenckebach Periodicity in the Neonatal Canine Heart

In nine anesthetized canine neonates, the high right atrium was paced at progressively shorter cycle lengths while recording high right atrial electrograms and left atrial appendage monophasic action potentials before and after the administration of the new Class III agent, ibutilide. Prior to ibutilide administration, 1:1 conduction was maintained from the high right atrium to the left atrial appendage at all paced cycle lengths, down to 160 ms. Following ibutilide, a pattern of intraatrial conduction was observed in two of nine neonates at a cycle length of 160 ms that was consistent with the development of intraatrial Wenckebach periodicity. This represents one of the only demonstrations of drug induced intraatrial Wenckebach periodicity in vivo and suggests that this rarely reported form of atrial conduction block might play a role in ibutilide\u27s clinical efficacy against atrial arrhythmias

Characterization of Responses of Neonatal Sinus and Av Nodes to Critically Timed, Brief Vagal Stimuli

We studied the responses of sinus cycle length and atrioventricular (AV) nodal conduction to brief, critically timed vagal stimuli in 25 neonatal (9.6 ± 3.1 days) canines. Vagal stimuli were delivered to the right or left decentralized cervical vagosympathetic trunk as either a single, brief stimulus train or a repetitive, phase-coupled train with both stimulation paradigms programmed to scan the entire cardiac cycle. The effects of brief vagal stimuli on cardiac cycle length were measured while the heart was beating spontaneously, and the vagal effects on AV nodal conduction were measured while the cycle length was held constant by atrial pacing at 300 ms. Neither changes in sinus cycle length nor AV nodal conduction demonstrated classical phase dependency, i.e., a gradual increase in the magnitude of the vagal response as stimuli are delivered progressively later in the cardiac cycle until the latency period (that point in the cardiac cycle at which vagal stimulation no longer affects the next cardiac cycle) is reached. Phase-response curves (PRCs) to single and repetitive stimuli typically exhibited either a flat response or a small decrease in magnitude as the latency period of the PRC was approached. Thus the neonatal sinus and AV node PRCs exhibit a different configuration than that reported in the adult

Temperature Dependency of the Vagal Chronotropic Response in the Young Puppy: An \u27Environmental-Autonomic Interaction\u27

We investigated the effects of mild hypothermia (34.3 ± 0.2°C [mean ± SD]), hyperthermia (40.8 ± 0.2°C) and hypoxia (Pa(O2) = 43 ± 4 mmHg) on the response of heart rate to continuous right vagus nerve stimulation (the \u27vagal chronotropic response\u27) in young puppies, aged 5-22 days. Puppies were anesthetized with α-chloralose, vagotomized and pre-treated with propranolol (1 mg/kg i.v.) and phentolamine(1 mg/kg, 1-2 mg/kg/h i.v.). Hypoxia (n = 9) did not significantly alter the resting sinus cycle length and did not alter the response of sinus cycle length to a 30 s train of 8 Hz right vagal stimulation. Mild hypothermia (n = 8) increased the resting sinus cycle length by 16 ± 4% and greatly augmented the vagal chronotropic response (from 76 ± 27% change in the sinus cycle length (normothermia) to 155 ± 38% (hypothermia)). Both the sinus cycle length and the vagal chronotropic response returned towards pre-hypothermia values with rewarming. Mild hypothermia also increased the negative chronotropic response to 20 μg/kg/min i.v. of methacholine (12 ± 2% change in the sinus cycle length (normothermia) versus 24 ± 14% (hypothermia)), suggesting that a postsynaptic mechanism is involved in the hypothermia-induced augmentation of the cardiac vagal chronotropic response. In contrast to hypothermia, mild hyperthermia (n = 8) decreased the resting sinus cycle length slightly (-5 ± 5% change) and significantly attenuated the cardiac vagal chronotropic response (from 88 ± 28% change in sinus cycle length (normothermia) to 50 ± 26% (hyperthermia. These changes were also reversible with the re-establishment of normothermia. This demonstrates that clinically relevant, environmentally-induced changes in body temperature can directly and reversibly modify parasympathetic efferent responses