A mathematical model of a rabbit sinoatrial node cell

1994 ◽  
Vol 266 (3) ◽  
pp. C832-C852 ◽  
Author(s):  
S. S. Demir ◽  
J. W. Clark ◽  
C. R. Murphey ◽  
W. R. Giles
Keyword(s):  
Mathematical Model ◽  
Sinoatrial Node ◽  
Surface Membrane ◽  
Recent Experimental Data ◽  
Pacemaker Cells ◽  
Diffusion Limited ◽  
Electrophysiological Responses ◽  
Sinoatrial Node Cell ◽  
Rabbit Sinoatrial Node

A mathematical model for the electrophysiological responses of a rabbit sinoatrial node cell that is based on whole cell recordings from enzymatically isolated single pacemaker cells at 37 degrees C has been developed. The ion channels, Na(+)-K+ and Ca2+ pumps, and Na(+)-Ca2+ exchanger in the surface membrane (sarcolemma) are described using equations for these known currents in mammalian pacemaker cells. The extracellular environment is treated as a diffusion-limited space, and the myoplasm contains Ca(2+)-binding proteins (calmodulin and troponin). Original features of this model include 1) new equations for the hyperpolarization-activated inward current, 2) assessment of the role of the transient-type Ca2+ current during pacemaker depolarization, 3) inclusion of an Na+ current based on recent experimental data, and 4) demonstration of the possible influence of pump and exchanger currents and background currents on the pacemaker rate. This model provides acceptable fits to voltage-clamp and action potential data and can be used to seek biophysically based explanations of the electrophysiological activity in the rabbit sinoatrial node cell.

Removal of sialic acid alters both T- and L-type calcium currents in cardiac myocytes

1991 ◽  
Vol 260 (3) ◽  
pp. H735-H743 ◽  
Author(s):  
B. Fermini ◽  
R. D. Nathan
Keyword(s):  
Sialic Acid ◽  
Sinoatrial Node ◽  
Calcium Currents ◽  
Pacemaker Cells ◽  
Patch Clamp Technique ◽  
Inactivation Curve ◽  
Node Removal ◽  
Rabbit Sinoatrial Node ◽  
Ca2 Channels ◽  
In Cells

The whole cell configuration of the patch-clamp technique was used to test the hypothesis that the presence of sialic acid residues influences both T- and L-type Ca2+ currents (ICa,T and ICa,L) in cultured pacemaker cells isolated from the rabbit sinoatrial node. Removal of these anionic sugar moieties by neuraminidase (1.0 U/ml for 5-20 min) increased ICa,T in five of nine cells (by a factor of 2.2-5.1) and ICa,L in three of six cells (by a factor of 1.2-1.6). In cells that did not exhibit such an increase, the enzyme reduced ICa,T but had no significant effect on ICa,L. In cells that exhibited an increase in ICa,T, exposure to neuraminidase also shifted the activation curve to more negative potentials and increased the slope of the inactivation curve. The enzyme did not influence the gating of ICa,L or the rates of inactivation of either ICa,T or ICa,L. The enhancement of ICa,T and ICa,L could not be mimicked by including neuraminidase in the patch pipette or by adding a contaminant of the enzyme preparation, phospholipase C, to the bath. When external Ca2+ was replaced by Ba2+, neither ICa,T nor ICa,L was increased significantly by neuraminidase. It is proposed that by removing sialic acid residues neuraminidase might directly alter the gating of T-type Ca2+ channels. On the other hand, the increased amplitudes of ICa,T and ICa,L might be due to a rise in intracellular Ca2+.

scholarly journals Kinetics and rectification of the slow inward current in the rabbit sinoatrial node cell.

1981 ◽  
Vol 31 (4) ◽  
pp. 491-500 ◽  
Author(s):  
Akinori NOMA ◽  
Hiroshi KOTAKE ◽  
Shinichiro KOKUBUN ◽  
Hiroshi IRISAWA
Keyword(s):  
Sinoatrial Node ◽  
Slow Inward Current ◽  
Inward Current ◽  
Sinoatrial Node Cell ◽  
Rabbit Sinoatrial Node

Heterogeneity of 4-aminopyridine-sensitive current in rabbit sinoatrial node cells

1999 ◽  
Vol 276 (4) ◽  
pp. H1295-H1304 ◽  
Author(s):  
Haruo Honjo ◽  
Ming Lei ◽  
Mark R. Boyett ◽  
Itsuo Kodama
Keyword(s):  
Membrane Potential ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Pacemaker Cells ◽  
Electrophysiological Properties ◽  
Sa Node ◽  
Slope Factor ◽  
Ionic Mechanisms ◽  
Rabbit Sinoatrial Node ◽  
Cell Capacitance

The electrophysiological properties of sinoatrial (SA) node pacemaker cells vary in different regions of the node. In this study, we have investigated variation of the 4-aminopyridine (4-AP)-sensitive current as a function of the size (as measured by the cell capacitance) of SA node cells to elucidate the ionic mechanisms. The 10 mM 4-AP-sensitive current recorded from rabbit SA node cells was composed of transient and sustained components ( I trans and I sus, respectively). The activation and inactivation properties [activation: membrane potential at which conductance is half-maximally activated ( V h) = 19.3 mV, slope factor ( k) = 15.0 mV; inactivation: V h= −31.5 mV, k = 7.2 mV] as well as the density of I trans (9.0 pA/pF on average at +50 mV) were independent of cell capacitance. In contrast, the density of I sus (0.97 pA/pF on average at +50 mV) was greater in larger cells, giving rise to a significant correlation with cell capacitance. The greater density of I sus in larger cells (presumably from the periphery) can explain the shorter action potential in the periphery of the SA node compared with that in the center. Thus variation of the 4-AP-sensitive current may be involved in regional differences in repolarization within the SA node.

Inward current of the rabbit sinoatrial node cell

1977 ◽  
Vol 372 (1) ◽  
pp. 43-51 ◽  
Author(s):  
A. Noma ◽  
K. Yanagihara ◽  
H. Irisawa
Keyword(s):  
Sinoatrial Node ◽  
Inward Current ◽  
Sinoatrial Node Cell ◽  
Rabbit Sinoatrial Node

scholarly journals The Functional Role of Hyperpolarization Activated Current (If) on Cardiac Pacemaking in Human vs. in the Rabbit Sinoatrial Node: A Simulation and Theoretical Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiangyun Bai ◽  
Kuanquan Wang ◽  
Mark R. Boyett ◽  
Jules C. Hancox ◽  
Henggui Zhang
Keyword(s):  
Low Dose ◽  
Sinoatrial Node ◽  
Cell Model ◽  
Bradycardic Agent ◽  
Diastolic Depolarization ◽  
Cardiac Pacemaking ◽  
Resultant Increase ◽  
Model Independent ◽  
Rabbit Sinoatrial Node

The cardiac hyperpolarization-activated “funny” current (If), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of If in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human If formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of If reduction with the total inward depolarising current (Itotal) during diastolic depolarization. Replacing the rabbit If formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% If reduction (a level close to the inhibition of If by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit If formulation; however, the effect was doubled (~12.4%) for the human If formulation, even though the latter has smaller If density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% If reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of Itotal during diastolic depolarization phase: a smaller If in the model resulted in a smaller Itotal amplitude, resulting in a slower pacemaking rate; and the same reduction in If resulted in a more significant change of CL in the cell model with a smaller Itotal. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.

scholarly journals Bi-directional flow of the funny current (If) during the pacemaking cycle in murine sinoatrial node myocytes

2021 ◽  
Author(s):  
Colin H. Peters ◽  
Pin W. Liu ◽  
Stefano Morotti ◽  
Stephanie C. Gantz ◽  
Eleonora Grandi ◽  
...  
Keyword(s):  
Heart Rate ◽  
Conceptual Framework ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Charge Movement ◽  
Firing Cycle ◽  
Pacemaker Cells ◽  
Net Charge ◽  
Precise Role

AbstractSinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current, If, is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. We used the AP-clamp technique to quantify If during the cardiac cycle in mouse SAMs. We found that If is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of -30 mV. Despite operating at only 2-5% of its maximal conductance, If carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that β-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of If to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously-expressed HCN4 channels and by mathematical models of If. Modelling further suggested that the slow activation and deactivation of the HCN4 isoform underlie the persistent activity of If during the sinoatrial AP. These results establish a new conceptual framework for the role of If in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.Significance StatementCardiac pacemaker cells trigger each heartbeat by virtue of spontaneous oscillations in their membrane voltage. Although the funny current (If) is critical for these oscillations and for setting heart rate, its precise role remains an enigma because it activates mostly outside of the physiological voltage range and quite slowly relative to the pacemaker cycle. Here we show that If is persistently active in pacemaker cells; once opened, the small fraction of ion channels that conduct If do not re-close. Consequently, If flows both inward and outward to help propel the voltage oscillations and it paradoxically conducts a large fraction of the net charge movement. These results establish a new conceptual framework for the role of If in driving cardiac pacemaking.

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