The intrinsic cycle length in small pieces isolated from the rabbit sinoatrial node

Opthof, Tobias; VanGinneken, Antoni C.G.; Bouman, L. N.; Jongsma, Habo J.

doi:10.1016/s0022-2828(87)80621-1

Cited by 52 publications

(36 citation statements)

References 23 publications

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“…This evidence can also be explained by the altered intracellular Ca 2ϩ concentration transients in AnkB ϩ/Ϫ SAN cells (20). Additionally, it can be referred to the functional heterogeneity of the SAN (22,28) as well as its heterogeneous innervation (3,12). It has been previously demonstrated in the rabbit SAN that after severing the superior from the inferior part of the SAN preparation, the AChinduced deceleration was smaller in the inferior part than in the superior part (22).…”

Section: Discussionmentioning

confidence: 95%

“…To investigate the basic molecular mechanisms of SAN biology and disease, the mouse SAN is widely used as a genetic platform, allowing the modification of the expression and/or function of different genes that encode the corresponding ionic channels or Ca 2ϩ -handling proteins (20). However, many of these studies were performed using isolated SAN (21,22,28) or isolated cell (20, 23) preparations and therefore lack critical data regarding the interaction of the intact SAN with the surrounding atrial myocardium and atrioventricular (AV) …”

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confidence: 99%

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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: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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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“…Until now, atrio-sinus interaction has been studied by isolating the nodal area from the atrium. 2,3 Our approach was to selectively depolarize the SA node without affecting the hyperpolarizing load of the atrium. We demonstrate that the hyperpolarizing current from the atrium can effectively counteract sinus arrest of the central nodal area induced by blockade of I K,r .…”

Section: Discussionmentioning

confidence: 99%

“…2 When the rabbit SA node is fragmented into small isolated pieces, fragments from the tissue close to the crista terminalis (CT) show the highest beating rate and the fastest diastolic depolarization. 3 In contrast, in the intact node, fibers close to the CT have a much slower diastolic depolarization than fibers in the center of the node. 4 It is assumed that the center of the node is too far from the atrium for the hyperpolarizing current to be effective.…”

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confidence: 97%

Atrio-Sinus Interaction Demonstrated by Blockade of the Rapid Delayed Rectifier Current

2002

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Background-Proper pacemaking of the heart requires a specific organization of the sinoatrial (SA) node. The SA node drives the surrounding atrium but needs to be protected from its hyperpolarizing influence, which tends to suppress pacemaker activity. It has been suggested that the hyperpolarizing atrial influence is minimal at the site of the central nodal area. Methods and Results-Atrio-sinus interaction was assessed by specific depolarization of the SA node by blocking the HERG-encoded rapid delayed rectifier current (I K,r ) with the drug E-4031. In the SA node, E-4031 (1 mol/L) changed action potential configuration drastically but never resulted in pacemaker arrest. In the atrium, E-4031 did not affect the membrane resting potential, thereby leaving the normal hyperpolarizing load on the SA node intact. When the SA node was sectioned into strips and subsequently separated from the atrium, spontaneous electrical activity of the strip containing the primary pacemaker ceased on I K,r blockade. When not separated from the atrium, I K,r blockade never resulted in pacemaker arrest. A similar effective atrio-sinus interaction was demonstrated in computer simulations. Conclusions-Our results demonstrate that the atrium provides an effective hyperpolarizing load on the central SA nodal area and is at least one of the controlling mechanisms for normal pacemaking function. The present study can be of help in understanding why patients with long-QT2 syndrome secondary to a mutation in HERG do not show sinus arrest.

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“…Figure 1A shows cycle length (time between successive spontaneous action potentials) of small tissue samples from the rabbit SA node plotted against the distance of the tissue from the crista terminalis (marks approximate boundary between SA node and atrial muscle): the solid circles show data from Kodama and Boyett 12 ; solid squares, data from Opthof et al 13 ; and solid triangles, data from Kodama et al 14 These 3 independent data sets (albeit from 2 groups) show an increase in cycle length from peripheral (0 mm) to central (Ϸ1.5 mm) tissue. The example of action potentials from small tissue samples from the periphery and center of the rabbit SA node in Figure 1B shows the characteristic difference in cycle length.…”

Section: Regional Differences In Intrinsic Pacemaker Activitymentioning

confidence: 99%

Gradient Model Versus Mosaic Model of the Sinoatrial Node

2001

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Background-A radical reinterpretation (mosaic model) of the makeup of the sinoatrial (SA) node has been proposed to explain the characteristic regional differences in electrical activity between the periphery and center of the SA node. According to the mosaic model, the differences result from a change in the mix of atrial cells and uniform SA node cells from periphery to center, whereas according to the alternative gradient model, there are no atrial cells within the functional SA node, and the differences result from a change in the intrinsic properties of SA node cells from periphery to center. Methods and Results-A mosaic model of peripheral and central tissue has been constructed computationally by use of a coupled ordinary differential equation network (CODE) in a 2D lattice (20ϫ20), with each node of the lattice designated randomly as an atrial cell or SA node cell (in correct proportions for periphery and center). The mosaic model fails to predict the characteristic differences in action potential rate and shape between the periphery and center, whereas the existing gradient model can do so. Conclusions-The mosaic model of the SA node is untenable, and the SA node is adequately described by the gradient model. (Circulation. 2001;103:584-588.)

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The intrinsic cycle length in small pieces isolated from the rabbit sinoatrial node

Cited by 52 publications

References 23 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

Atrio-Sinus Interaction Demonstrated by Blockade of the Rapid Delayed Rectifier Current

Gradient Model Versus Mosaic Model of the Sinoatrial Node

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