An ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes

EP Europace ◽  
2005 ◽  
Vol 7 (s2) ◽  
pp. S128-S134 ◽  
Author(s):  
Sarah N. Healy ◽  
Andrew D. McCulloch
Keyword(s):  
Action Potential ◽  
Safety Factor ◽  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Ionic Model ◽  
Rabbit Ventricular Myocytes ◽  
Induced Changes ◽  
Transmural Heterogeneity ◽  
Action Potential Shortening

Abstract Aims To develop an ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes consistent with experimental observations, that can be used to investigate the role of these currents in intact myocardium. Methods and results A non-specific cation-selective stretch-activated current Ins, was incorporated into the Puglisi–Bers ionic model of epicardial, endocardial and midmyocardial ventricular myocytes. Using the model, we predict a reduction in action potential duration at 20% repolarization (APD20) and action potential amplitude, an elevated resting transmembrane potential and either an increase or decrease in APD90, depending on the reversal potential of Ins. A stretch-induced decrease in IK1 (70%), plus a small Ins current (gns=10 pS), results in a reduction in APD20 and increase in APD90, and a reduced safety factor for conduction. Increasing IK1 (150%) plus a large Ins current (gns=40 pS), also leads to a reduction in APD20 and increase in APD90, but with a greater safety factor. Endocardial and midmyocardial cells appear to be the most sensitive to stretch-induced changes in action potential. The addition of the K+-specific stretch-activated current (SAC) IKo results in action potential shortening. Conclusion Transmural heterogeneity of IKo may reduce repolarization gradients in intact myocardium caused by intrinsic ion channel densities, nonuniform strains and electrotonic effects.

Modeling transmural heterogeneity of KATP current in rabbit ventricular myocytes

2007 ◽  
Vol 293 (2) ◽  
pp. C542-C557 ◽  
Author(s):  
Anushka Michailova ◽  
William Lorentz ◽  
Andrew McCulloch
Keyword(s):  
Ventricular Myocytes ◽  
Regulatory Subunit ◽  
Metabolic Coupling ◽  
Epicardial Cells ◽  
Channel Opening ◽  
Nucleotide Regulation ◽  
Metabolic Interactions ◽  
Rabbit Ventricular Myocytes ◽  
Transmural Heterogeneity ◽  
Action Potential Shortening

To investigate the mechanisms regulating excitation-metabolic coupling in rabbit epicardial, midmyocardial, and endocardial ventricular myocytes we extended the LabHEART model (Puglisi JL and Bers DM. Am J Physiol Cell Physiol 281: C2049–C2060, 2001). We incorporated equations for Ca2+ and Mg2+ buffering by ATP and ADP, equations for nucleotide regulation of ATP-sensitive K+ channel and L-type Ca2+ channel, Na+-K+-ATPase, and sarcolemmal and sarcoplasmic Ca2+-ATPases, and equations describing the basic pathways (creatine and adenylate kinase reactions) known to communicate the flux changes generated by intracellular ATPases. Under normal conditions and during 20 min of ischemia, the three regions were characterized by different INa, Ito, IKr, IKs, and IKp channel properties. The results indicate that the ATP-sensitive K+ channel is activated by the smallest reduction in ATP in epicardial cells and largest in endocardial cells when cytosolic ADP, AMP, PCr, Cr, Pi, total Mg2+, Na+, K+, Ca2+, and pH diastolic levels are normal. The model predicts that only KATP ionophore (Kir6.2 subunit) and not the regulatory subunit (SUR2A) might differ from endocardium to epicardium. The analysis suggests that during ischemia, the inhomogeneous accumulation of the metabolites in the tissue sublayers may alter in a very irregular manner the KATP channel opening through metabolic interactions with the endogenous PI cascade (PIP2, PIP) that in turn may cause differential action potential shortening among the ventricular myocyte subtypes. The model predictions are in qualitative agreement with experimental data measured under normal and ischemic conditions in rabbit ventricular myocytes.

Altered K+ current profiles underlie cardiac action potential shortening in hyperkalemia and β-adrenergic stimulation

2019 ◽  
Vol 97 (8) ◽  
pp. 773-780 ◽  
Author(s):  
Bence Hegyi ◽  
Ye Chen-Izu ◽  
Leighton T. Izu ◽  
Tamás Bányász
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Delayed Rectifier ◽  
Adrenergic Stimulation ◽  
Compensatory Mechanisms ◽  
Phase 3 ◽  
K Current ◽  
Rabbit Ventricular Myocytes ◽  
Action Potential Shortening ◽  
Stimulation Of

Hyperkalemia is known to develop in various conditions including vigorous physical exercise. In the heart, hyperkalemia is associated with action potential (AP) shortening that was attributed to altered gating of K+ channels. However, it remains unknown how hyperkalemia changes the profiles of each K+ current under a cardiac AP. Therefore, we recorded the major K+ currents (inward rectifier K+ current, IK1; rapid and slow delayed rectifier K+ currents, IKr and IKs, respectively) using AP-clamp in rabbit ventricular myocytes. As K+ may accumulate at rapid heart rates during sympathetic stimulation, we also examined the effect of isoproterenol on these K+ currents. We found that IK1 was significantly increased in hyperkalemia, whereas the reduction of driving force for K+ efflux dominated over the altered channel gating in case of IKr and IKs. Overall, the markedly increased IK1 in hyperkalemia overcame the relative decreases of IKr and IKs during AP, resulting in an increased net repolarizing current during AP phase 3. β-Adrenergic stimulation of IKs also provided further repolarizing power during sympathetic activation, although hyperkalemia limited IKs upregulation. These results indicate that facilitation of IK1 in hyperkalemia and β-adrenergic stimulation of IKs represent important compensatory mechanisms against AP prolongation and arrhythmia susceptibility.

Modulation of membrane potential by an acetylcholine-activated potassium current in trout atrial myocytes

2007 ◽  
Vol 292 (1) ◽  
pp. R388-R395 ◽  
Author(s):  
Cristina E. Molina ◽  
Hans Gesser ◽  
Anna Llach ◽  
Lluis Tort ◽  
Leif Hove-Madsen
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Atrial Myocytes ◽  
Atrial Tissue ◽  
Isolated Cardiac Myocytes ◽  
Inwardly Rectifying

Application of the current-clamp technique in rainbow trout atrial myocytes has yielded resting membrane potentials that are incompatible with normal atrial function. To investigate this paradox, we recorded the whole membrane current ( Im) and compared membrane potentials recorded in isolated cardiac myocytes and multicellular preparations. Atrial tissue and ventricular myocytes had stable resting potentials of −87 ± 2 mV and −83.9 ± 0.4 mV, respectively. In contrast, 50 out of 59 atrial myocytes had unstable depolarized membrane potentials that were sensitive to the holding current. We hypothesized that this is at least partly due to a small slope conductance of Im around the resting membrane potential in atrial myocytes. In accordance with this hypothesis, the slope conductance of Im was about sevenfold smaller in atrial than in ventricular myocytes. Interestingly, ACh increased Im at −120 mV from 4.3 pA/pF to 27 pA/pF with an EC50 of 45 nM in atrial myocytes. Moreover, 3 nM ACh increased the slope conductance of Im fourfold, shifted its reversal potential from −78 ± 3 to −84 ± 3 mV, and stabilized the resting membrane potential at −92 ± 4 mV. ACh also shortened the action potential in both atrial myocytes and tissue, and this effect was antagonized by atropine. When applied alone, atropine prolonged the action potential in atrial tissue but had no effect on membrane potential, action potential, or Im in isolated atrial myocytes. This suggests that ACh-mediated activation of an inwardly rectifying K+ current can modulate the membrane potential in the trout atrial myocytes and stabilize the resting membrane potential.

ROLE OF ACTION POTENTIAL SHORTENING IN THE PREVENTION OF ARRHYTHMIAS IN CANINE CARDIAC TISSUE

1999 ◽  
Vol 26 (12) ◽  
pp. 964-969 ◽  
Author(s):  
Kawonia P Mull ◽  
Qadriyyah Debnam ◽  
Syeda M Kabir ◽  
Mohit Lal Bhattacharyya
Keyword(s):  
Action Potential ◽  
Cardiac Tissue ◽  
Action Potential Shortening

Abstract 16953: Role of the Fast Transient Outward Current Ito,f in Shaping Action Potential Waveforms in Human iPSC-derived Cardiomyocytes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Scott Marrus ◽  
Steven Springer ◽  
Rita Martinez ◽  
Edward Dranoff ◽  
Rebecca Mellor ◽  
...  
Keyword(s):  
Action Potential ◽  
Potassium Current ◽  
Ventricular Myocytes ◽  
Current Clamp ◽  
Transient Outward Potassium Current ◽  
Fast Transient ◽  
Human Ipsc ◽  
Outward Potassium Current ◽  
Upstroke Velocity

Abnormalities of a key repolarizing cardiac potassium current, the fast transient outward potassium current, I to,f , are associated with both heart failure and congenital arrhythmia syndromes. However, the precise role of I to,f in shaping action potential waveforms remains unclear. This study was designed to define the functional role of the fast transient outward potassium current, I to,f , in shaping action potentials in human iPSC-derived cardiomyocytes (iPSC-CMs). Most iPSC-CMs (29 of 43 cells) demonstrated spontaneous electrical activity, slow upstroke velocity (63±71 V/s), a wide range of action potential durations (APD90 = 860±722 ms) and heterogeneous action potential waveforms. Using dynamic current clamp, a modeled human ventricular inwardly rectifying K + current, I K1 , was introduced into iPSC-CMs, resulting in silencing of spontaneous activity, hyperpolarization of the resting membrane potential (RMP = -90±3 mV), increased peak upstroke velocity (dV/dt = 346±71 V/s) and decreased APD90 (420±211 ms) to values similar to those recorded in isolated adult human ventricular myocytes (RMP = -84±3 mV, dV/dt = 348±101 V/s and APD90 = 468±133 ms, all p>0.05). Importantly, a ventricular-like action potential waveform was observed in 25 of the 26 cells studied following the dynamic clamp addition of I K1 . Using these cells as a model of human ventricular myocytes, further dynamic current clamp experiments introduced a modeled human fast transient outward K + current, I to,f , and revealed that increasing in the amplitude of I to,f results in an increase in the phase 1 notch and a progressive shortening of the action potential duration in iPSC-CMs. Together, the experiments here demonstrate that combining human iPSC-CMs with the power of the dynamic current clamp technique to modulate directly and precisely the “expression” of individual ionic currents provides a novel and quantitative approach to defining the roles of specific ionic conductances in regulating the excitability of human cardiomyocytes.

Mechanism of atrioventricular nodal facilitation in the rabbit heart: role of the distal AV node

1997 ◽  
Vol 272 (6) ◽  
pp. H2815-H2825 ◽  
Author(s):  
G. J. Fahy ◽  
I. Efimov ◽  
Y. Cheng ◽  
G. A. Kidwell ◽  
D. Van Wagoner ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Cellular Response ◽  
Rabbit Heart ◽  
Av Node ◽  
Microelectrode Recordings ◽  
Bundle Of His ◽  
Action Potential Shortening

We investigated whether atrioventricular (AV) nodal facilitation is the result of distal AV nodal action potential shortening. Atrial and bundle of His (H) electrograms and microelectrode recordings from proximal and distal AV nodal cells were analyzed in eight superfused rabbit AV node preparations in response to two pacing protocols. In the facilitation protocol, an atrial extrastimulus (A3) was preceded by an atrial impulse (A2) introduced 300, 200, 150, or 125 ms after 30 basic beats (A1). The preexcitation protocol differed from the facilitation protocol by the addition of a premature His depolarization (h2) such that the H1-h2 interval was shorter than the H1-H2 interval. Conduction curves (A3-H3 vs. H2-A3, h2-A3, and A2-A3 intervals) were constructed. Facilitation was demonstrated in all preparations when H2-A3 was used (P = 0.02) but not in the A2-A3 format. Compared with facilitation at the same A1-A2 intervals, preexcitation, despite shortening the distal cellular action potential duration, resulted in longer A3-H3 delays (P = 0.002), shorter A2-A3 intervals, and depression of the proximal nodal cellular response. Thus facilitation does not result from altered distal AV nodal characteristics and instead is a manifestation of an uncontrolled pacing protocol-dependent modulation of proximal AV nodal function.

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