scholarly journals Isoprenaline: A Potential Contributor in Sick Sinus Syndrome—Insights from a Mathematical Model of the Rabbit Sinoatrial Node

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Xiang Li ◽  
Ji-qian Zhang ◽  
Jian-wei Shuai
Keyword(s):  
Action Potential ◽  
Sinoatrial Node ◽  
Sick Sinus Syndrome ◽  
Surrounding Tissue ◽  
Pacemaker Activity ◽  
Histological Structure ◽  
Cell Models ◽  
Peripheral Cell ◽  
Positive Effects ◽  
Rabbit Sinoatrial Node

The mechanism of isoprenaline exerting its effects on cardiac pacemaking and driving in sick sinus syndrome is controversial and unresolved. In this paper, mathematical models for rabbit sinoatrial node cells were modified by incorporating equations for the known dose-dependent actions of isoprenaline on various ionic channel currents, the intracellular Ca2+transient, andiNachanges induced by SCN5A gene mutations; the cell models were also incorporated into an intact SAN-atrium model of the rabbit heart that is based on both heterogeneities of the SAN electrophysiology and histological structure. Our results show that, in both central and peripheral cell models, isoprenaline could not only shorten the action potential duration, but also increase the amplitude of action potential. The mutation impaired the SAN pacemaking. Simulated vagal nerve activity amplified the bradycardic effects of the mutation. However, in tissue case, the pacemaker activity may show temporal, spatial, or even spatiotemporal cessation caused by the mutation. Addition of isoprenaline could significantly diminish the bradycardic effect of the mutation and the SAN could restart pacing and driving the surrounding tissue. Positive effects of isoprenaline may primarily be attributable to an increase iniNaandiCa,Twhich were reduced by the mutation.

Regional differences in effects of 4-aminopyridine within the sinoatrial node

1998 ◽  
Vol 275 (4) ◽  
pp. H1158-H1168 ◽  
Author(s):  
M. R. Boyett ◽  
H. Honjo ◽  
M. Yamamoto ◽  
M. R. Nikmaram ◽  
R. Niwa ◽  
...  
Keyword(s):  
Action Potential ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Outward Current ◽  
Peripheral Tissue ◽  
Transient Outward Current ◽  
Pacemaker Activity ◽  
Small Ball ◽  
Tissue Differences ◽  
Rabbit Sinoatrial Node

4-Aminopyridine (4-AP)-sensitive transient outward current ( I to) has been observed in the sinoatrial node, but its role is unknown. The effect of block of I to by 5 mM 4-AP on small ball-like tissue preparations (diameter ∼0.3–0.4 mm) from different regions of the rabbit sinoatrial node has been investigated. 4-AP elevated the plateau, prolonged the action potential, and decreased the maximum diastolic potential. Effects were greater in tissue from the periphery of the node than from the center. In peripheral tissue, 4-AP abolished the action potential notch, if present. 4-AP slowed pacemaker activity of peripheral tissue but accelerated that of central tissue. Differences in the response to 4-AP were also observed between tissue from more superior and inferior regions of the node. In the intact sinoatrial node, 4-AP resulted in a shift of the leading pacemaker site consistent with the regional differences in the response to 4-AP. It is concluded that 4-AP-sensitive outward current plays a major role in action potential repolarization and pacemaker activity in the sinoatrial node and that its role varies regionally.

Downward gradient in action potential duration along conduction path in and around the sinoatrial node

1999 ◽  
Vol 276 (2) ◽  
pp. H686-H698 ◽  
Author(s):  
M. R. Boyett ◽  
H. Honjo ◽  
M. Yamamoto ◽  
M. R. Nikmaram ◽  
R. Niwa ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Sinoatrial Node ◽  
Pacemaker Activity ◽  
Similar Data ◽  
Conduction Path ◽  
Crista Terminalis ◽  
Conduction Pathway ◽  
Pacemaker Shift ◽  
Rabbit Sinoatrial Node

Regional differences in electrical activity in rabbit sinoatrial node have been investigated by recording action potentials throughout the intact node or from small balls of tissue from different regions. In the intact node, action potential duration was greatest at or close to the leading pacemaker and declined markedly in all directions from it, e.g., by 74 ± 4% (mean ± SE, n = 4) to the crista terminalis. Similar data were obtained from the small balls. The gradient is down the conduction pathway and will help prevent reentry. In the intact node, a zone of inexcitable tissue with small depolarizations of <25 mV or stable resting potentials was discovered in the inferior part of the node, and this will again help prevent reentry. The intrinsic pacemaker activity of the small balls was slower in tissue from more inferior (as well as more central) parts of the node [e.g., cycle length increased from 339 ± 13 ms ( n = 6) to 483 ± 13 ms ( n = 6) in transitional tissue from more superior and inferior sites], and this may help explain pacemaker shift.

Roles of hyperpolarization-activated current If in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models

2010 ◽  
Vol 298 (6) ◽  
pp. H1748-H1760 ◽  
Author(s):  
Yasutaka Kurata ◽  
Hiroyuki Matsuda ◽  
Ichiro Hisatome ◽  
Toshishige Shibamoto
Keyword(s):  
Mathematical Models ◽  
Sinoatrial Node ◽  
Equilibrium Points ◽  
Pacemaker Activity ◽  
Potential Region ◽  
Peripheral Cell ◽  
Constant Bias ◽  
State Potential ◽  
Hyperpolarization Activated Current ◽  
Acetylcholine Concentration

To elucidate the roles of hyperpolarization-activated current ( If) in sinoatrial node (SAN) pacemaking, we theoretically investigated 1) the effects of If on stability and bifurcation during hyperpolarization of SAN cells; 2) combined effects of If and the sustained inward current ( Ist) or Na+ channel current ( INa) on robustness of pacemaking against hyperpolarization; and 3) whether blocking If abolishes pacemaker activity under certain conditions. Bifurcation analyses were performed for mathematical models of rabbit SAN cells; equilibrium points (EPs), periodic orbits, and their stability were determined as functions of parameters. Unstable steady-state potential region determined with applications of constant bias currents shrunk as If density increased. In the central SAN cell, the critical acetylcholine concentration at which bifurcations, to yield a stable EP and quiescence, occur was increased by smaller If, but decreased by larger If. In contrast, the critical acetylcholine concentration and conductance of gap junctions between SAN and atrial cells at bifurcations progressively increased with enhancing If in the peripheral SAN cell. These effects of If were significantly attenuated by eliminating Ist or INa, or by accelerating their inactivation. Under hyperpolarized conditions, blocking If abolished SAN pacemaking via bifurcations. These results suggest that 1) If itself cannot destabilize EPs; 2) If improves SAN cell robustness against parasympathetic stimulation via preventing bifurcations in the presence of Ist or INa; 3) If dramatically enhances peripheral cell robustness against electrotonic loads of the atrium in combination with INa; and 4) pacemaker activity of hyperpolarized SAN cells could be abolished by blocking If.

Regional differences in effects of E-4031 within the sinoatrial node

1999 ◽  
Vol 276 (3) ◽  
pp. H793-H802 ◽  
Author(s):  
I. Kodama ◽  
M. R. Boyett ◽  
M. R. Nikmaram ◽  
M. Yamamoto ◽  
H. Honjo ◽  
...  
Keyword(s):  
Action Potential ◽  
Electrical Activity ◽  
Spontaneous Activity ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Peripheral Tissue ◽  
Delayed Rectifier ◽  
Small Ball ◽  
Rabbit Sinoatrial Node ◽  
Diastolic Potential

Effects of block of the rapid delayed rectifier K+current ( I K,r) by E-4031 on the electrical activity of small ball-like tissue preparations from different regions of the rabbit sinoatrial node were measured. The effects of partial block of I K,r by 0.1 μM E-4031 varied in different regions of the node. In tissue from the center of the node spontaneous activity was generally abolished, whereas in tissue from the periphery spontaneous activity persisted, although the action potential was prolonged, the maximum diastolic potential was decreased, and the spontaneous activity slowed. After partial block of I K,r, the electrical activity of peripheral tissue was more like that of central tissue under normal conditions. One possible explanation of these findings is that the density of I K,r is greater in the periphery of the node; this would explain the greater resistance of peripheral tissue to I K,r block and help explain why, under normal conditions, the maximum diastolic potential is more negative, the action potential is shorter, and pacemaking is faster in the periphery.

scholarly journals Computational evaluation of the roles of Na+ current, iNa, and cell death in cardiac pacemaking and driving

2007 ◽  
Vol 292 (1) ◽  
pp. H165-H174 ◽  
Author(s):  
H. Zhang ◽  
Y. Zhao ◽  
M. Lei ◽  
H. Dobrzynski ◽  
J. H. Liu ◽  
...  
Keyword(s):  
Cell Population ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Rabbit Heart ◽  
Pacemaker Activity ◽  
Histological Structure ◽  
Conduction Time ◽  
Functional Roles ◽  
Sa Node ◽  
Computational Evaluation

Voltage-dependent sodium (Na+) channels are heterogeneously distributed through the pacemaker of the heart, the sinoatrial node (SA node). The measured sodium channel current ( iNa) density is higher in the periphery but low or zero in the center of the SA node. The functional roles of iNa in initiation and conduction of cardiac pacemaker activity remain uncertain. We evaluated the functional roles of iNa by computer modeling. A gradient model of the intact SA node and atrium of the rabbit heart was developed that incorporates both heterogeneities of the SA node electrophysiology and histological structure. Our computations show that a large iNa in the periphery helps the SA node to drive the atrial muscle. Removal iNa from the SA node slows down the pacemaking rate and increases the sinoatrial node-atrium conduction time. In some cases, reduction of the SA node iNa results in impairment of impulse initiation and conduction that leads to the SA node-atrium conduction exit block. Decrease in active SA node cell population has similar effects. Combined actions of reduced cell population and removal of iNa from the SA node have greater impacts on weakening the ability of the SA node to pace and drive the atrium.

Parasympathetic modulation of sinoatrial node pacemaker activity in rabbit heart: a unifying model

1999 ◽  
Vol 276 (6) ◽  
pp. H2221-H2244 ◽  
Author(s):  
Semahat S. Demir ◽  
John W. Clark ◽  
Wayne R. Giles
Keyword(s):  
Sinoatrial Node ◽  
Vagal Stimulation ◽  
Full Range ◽  
Rabbit Heart ◽  
Pacemaker Activity ◽  
Membrane Hyperpolarization ◽  
Different Types ◽  
Cardiac Pacemaking ◽  
Rabbit Sinoatrial Node ◽  
Diastolic Potential

We have extended our compartmental model [ Am. J. Physiol. 266 ( Cell Physiol. 35): C832–C852, 1994] of the single rabbit sinoatrial node (SAN) cell so that it can simulate cellular responses to bath applications of ACh and isoprenaline as well as the effects of neuronally released ACh. The model employs three different types of muscarinic receptors to explain the variety of responses observed in mammalian cardiac pacemaking cells subjected to vagal stimulation. The response of greatest interest is the ACh-sensitive change in cycle length that is not accompanied by a change in action potential duration or repolarization or hyperpolarization of the maximum diastolic potential. In this case, an ACh-sensitive K+ current is not involved. Membrane hyperpolarization occurs in response to much higher levels of vagal stimulation, and this response is also mimicked by the model. Here, an ACh-sensitive K+ current is involved. The well-known phase-resetting response of the SAN cell to single and periodically applied vagal bursts of impulses is also simulated in the presence and absence of the β-agonist isoprenaline. Finally, the responses of the SAN cell to longer continuous trains of periodic vagal stimulation are simulated, and this can result in the complete cessation of pacemaking. Therefore, this model is 1) applicable over the full range of intensity and pattern of vagal input and 2) can offer biophysically based explanations for many of the phenomena associated with the autonomic control of cardiac pacemaking.

scholarly journals Pharmacologic Approach to Sinoatrial Node Dysfunction

2021 ◽  
Vol 61 (1) ◽  
pp. 757-778
Author(s):  
Pietro Mesirca ◽  
Vadim V. Fedorov ◽  
Thomas J. Hund ◽  
Angelo G. Torrente ◽  
Isabelle Bidaud ◽  
...  
Keyword(s):  
Clinical Practice ◽  
General Population ◽  
Action Potential ◽  
Sinoatrial Node ◽  
Sick Sinus Syndrome ◽  
Current Knowledge ◽  
Systemic Disease ◽  
Age Related ◽  
Sinoatrial Node Dysfunction ◽  
Pharmacologic Therapies

The spontaneous activity of the sinoatrial node initiates the heartbeat. Sino-atrial node dysfunction (SND) and sick sinoatrial (sick sinus) syndrome are caused by the heart's inability to generate a normal sinoatrial node action potential. In clinical practice, SND is generally considered an age-related pathology, secondary to degenerative fibrosis of the heart pacemaker tissue. However, other forms of SND exist, including idiopathic primary SND, which is genetic, and forms that are secondary to cardiovascular or systemic disease. The incidence of SND in the general population is expected to increase over the next half century, boosting the need to implant electronic pacemakers. During the last two decades, our knowledge of sino-atrial node physiology and of the pathophysiological mechanisms underlying SND has advanced considerably. This review summarizes the current knowledge about SND mechanisms and discusses the possibility of introducing new pharmacologic therapies for treating SND.

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