Pacemaker Shift in the Rabbit Sinoatrial Node in Response to Vagal Nerve Stimulation

Shibata, Nitaro; Inada, Shin; Mitsui, Kazuyuki; Honjo, Haruo; Yamamoto, Masahito; Niwa, Ryoko; Boyett, Mark R.; Kodama, Itsuo

doi:10.1113/eph8602100

Cited by 50 publications

(45 citation statements)

References 17 publications

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“…Activation originated in the anatomically defined SAN near the SVC with a wide wavefront that spread anisotropically throughout the RA and LA. Delayed activation in the septal margin of the SAN was observed in all mice, as has been previously shown in the mouse (26,33) and in other mammals (12,14,27,32). We observed a "typical" stable monofocal position of the leading pacemaker in all seven WT preparations under control conditions (blue circles in Fig.…”

Section: Resultssupporting

confidence: 59%

Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

Glukhov

Fedorov

Anderson

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Glukhov AV, Fedorov VV, Anderson ME, Mohler PJ, Efimov IR. Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice. Am J Physiol Heart Circ Physiol 299: H482-H491, 2010. First published June 4, 2010; doi:10.1152/ajpheart.00756.2009.-The mouse is widely used as a genetic platform to investigate the molecular mechanisms of sinoatrial node (SAN) pacemaking. Recently, it has been shown that isolated SAN cells from the ankyrin-B (AnkB)-deficient mice display severe pacemaking dysfunction similar to individuals harboring ankyrin 2 allele variants. However, these results have been limited to isolated SAN cells only and thus did not evaluate the functional anatomy of the widely distributed atrial pacemaker complex (e.g., the dynamic interaction of primary and subsidiary pacemakers). We studied pacemaker function in an intact mouse atrial preparation, which included the SAN, atrioventricular junction (AVJ), and both atria, excluding most of the septum. Optical mapping with a voltage-sensitive dye and CMOS camera ULTIMA-L was used to map spontaneous pacemaker activity with or without autonomic modulation in wild-type (WT) mice (n ϭ 7) and in the AnkB heterozygous (AnkB ϩ/Ϫ ; n ϭ 9) mouse model of human SAN disease. In WT mice, isoproterenol accelerated the SAN rate (for 10 M: from 325 Ϯ 19 to 510 Ϯ 33 beat/min, P Ͻ 0.01) and shifted the leading pacemaker site superiorly by 0.77 Ϯ 0.11 mm within the SAN. ACh decreased the SAN rate (from 333 Ϯ 26 to 96 Ϯ 22 beats/min, P Ͻ 0.01) and shifted the leading pacemaker either inferiorly within the SAN or abruptly toward the AVJ. After isoproterenol, AnkB ϩ/Ϫ mice exhibited a larger beat-to-beat variability (SD of a cycle length: 13.4 Ϯ 3.6 vs. 2.5 Ϯ 0.8 ms, P Ͻ 0.01 vs. WT mice), disorganized shift of the leading pacemaker (2.04 Ϯ 0.37 mm, P Ͻ 0.05 vs. WT mice), and competing multiple pacemakers, resulting in beat-to-beat changes of the leading pacemaker location site between the SAN and AVJ regions. Notably, AnkB ϩ/Ϫ mice also displayed a reduced sensitivity to ACh (rate slowing by 32 Ϯ 12% vs. 67 Ϯ 4%, P Ͻ 0.05, AnkB ϩ/Ϫ vs. WT mice, respectively). In conclusion, AnkB dysfunction results in SAN abnormalities in an isolated mouse atria preparation. While AnkB dysfunction dramatically alters single SAN cell function, the mechanisms underlying cardiac automaticity are clearly complex, and phenotypes may be partially compensated by the dynamic interaction of cells within the pacemaker complex. These new findings highlight the importance of the functional anatomy of the entire atrial distributed pacemaker complex, including the SAN and AVJ, and clearly demonstrate the role of AnkB in cardiac automaticity.pacemaker; autonomic control; action potential; sinoatrial node DESPITE THE CRITICAL IMPORTANCE of sinoatrial node (SAN) cardiac pacing, relatively little is known about SAN physiology or SAN cell biology compared with our more complete understanding of ventricular and atrial myocardium (4,8,9,12,14). To investigate the basic molecu...

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Section: Resultssupporting

confidence: 59%

Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

Glukhov

Fedorov

Anderson

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…3; online Supplemental Movie Control-LPS). With a superior LPS, activation rapidly propagated over the superior free wall and appendage, in agreement with experiments (35). With a central LPS, activation spread radially along the inferior and superior SAN, reaching the free wall and subsequently the appendage (16).…”

Section: Resultssupporting

confidence: 70%

“…4A). as observed in vivo (2, 31) and in vitro (16,35). Less frequently, vagal stimulation induced double breakouts (Fig.…”

Section: Resultsmentioning

confidence: 64%

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Munoz

Kaur

Vigmond

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Muñoz MA, Kaur J, Vigmond EJ. Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study. Am J Physiol Heart Circ Physiol 301: H1974-H1983, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00059.2011.-Neuronal modulation of the sinoatrial node (SAN) plays a crucial role in the initiation and maintenance of atrial arrhythmias (AF), although the exact mechanisms remain unclear. We used a computer model of a rabbit right atrium (RA) with a heterogeneous SAN and detailed ionic current descriptions for atrial and SAN myocytes to explore reentry initiation associated with autonomic activity. Heterogeneous acetylcholine (ACh)-dependent ionic responses along with L-type Ca current (ICa,L) upregulation were incorporated in the SAN only. During control, activation was typical with the leading pacemaker site located close to the superior vena cava or the intercaval region. With cholinergic stimulation, activation patterns frequently included caudal shifts of the leading pacemaker site and occasional double breakouts. The model became increasingly arrhythmogenic for the ACh concentration Ͼ20 nM and for large ICa,L conductance. Reentries obtained included counterclockwise rotors in the free wall, clockwise reentry circulating between the SAN and free wall, and typical flutter. The SAN was the cause of reentry with a common leading sequence of events: a bradycardic beat with shifting in the caudal direction, followed by a premature beat or unidirectional block within the SAN. Electrotonic loading, and not just overdrive pacing, squelches competing pacemaker sites in the SAN. Cholinergic stimulation concomitant with I Ca,L upregulation shifts leading pacemaker site and can lead to reentry. A heterogeneous response to autonomic innervation, a large myocardial load, and an extensive SAN in the intercaval region are required for neurally induced SAN-triggered reentry. electrophysiology; reentry; autonomic innervation ATRIAL FIBRILLATION (AF) is the most common and diverse cardiac arrhythmia (21). Experimental observations have illustrated the crucial role that neuronal mechanisms have in its initiation and maintenance (33). Atrial arrhythmias can be induced in dogs by localized electrical stimuli applied to nerve branches of the thoracic vagosympathetic complex (31) or mediastinal nerves (2, 31). Experiments show that acetylcholine (ACh) can trigger reentry and AF in the right atrium (RA) and that adrenergic stimulation facilitates both AF initiation and maintenance (33). Atropine completely abolishes bradycardia and subsequent tachyarrhythmias, indicating that cholinergic efferents play a predominant role in induction (33).Different studies describe a similar sequence of events for arrhythmias originating in the RA that were induced by neural stimulation: cycle length (CL) prolongation, often with leading pacemaker site (LPS) shifting, followed by an atrial premature beat (APB), and subsequent tachyarrhythmia (1, 2, 31, 33). The escape beat initiating the tachyarr...

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“…[15][16][17] We refer to "apparent origin" because it would be an oversimplification to suppose that the area leading the depolarization uniquely determines what happens (see also elsewhere 18 ). Electric current flows between any two connected cells that are at different potentials, and this current must influence the leading cells (by slowing them down) as much as they influence the follower cells (by speeding them up).…”

Section: Insights From Tissue Studies and From Development Of The Heartmentioning

confidence: 99%

Competing Oscillators in Cardiac Pacemaking

Noble

Fink

2010

Circulation Research

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Key Words: cardiac pacemaker Ⅲ heart models Ⅲ calcium oscillator Ⅲ membrane oscillator T he earliest models of cardiac rhythm, beginning with that of Noble, 1 were restricted to interactions between surface membrane ion channels. The first cardiac cell model to incorporate the intracellular calcium signaling system involved in excitation-contraction coupling was that of DiFrancesco and Noble. 2 That model was developed for sheep Purkinje fibers, and it was the first to predict a large role for sodium/calcium exchange current during the action potential. In fact it identified the slower components of inward current that had previously been attributed to calcium channel current as being attributable instead to the exchanger. Pacemaker activity in that model was attributed almost entirely to the slow onset of the nonspecific cation current, i f, activated by hyperpolarization. The exchange current was not predicted to play any role in pacemaker rhythm in that case.However, the DiFrancesco-Noble Purkinje fiber model was almost immediately developed to create the first mathematical model to reproduce voltage waveforms similar to those observed in rabbit sinoatrial node (SAN) cells. 3 It was also developed later to create the first models of rabbit atrial cells. 4,5 For the intracellular calcium signaling mechanisms, the 1980s models were based on the work of Fabiato on calcium-induced calcium release. 6 The experimental basis of the SAN model was the work of Brown et al, 7,8 which revealed the presence of very slow components of inward current similar to that predicted for the Original

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Pacemaker Shift in the Rabbit Sinoatrial Node in Response to Vagal Nerve Stimulation

Cited by 50 publications

References 17 publications

Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Competing Oscillators in Cardiac Pacemaking

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