Comprehensive Physiology Wiley Online Library

The Cardiac Ventricular Action Potential

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Fundamental Principles
2 The Ventricular Cell is A Complex Interactive System
3 Ionic Basis of the Action Potential
3.1 The Normal Action Potential
3.2 The Premature Action Potential and Adaptation to Rate
4 Heterogeneity of Ventricular Action Potentials
5 Abnormal Repolarization. Example—Early Afterdepolarizations
6 Effects of Ionic Concentrations on the Action Potential. Example—Sodium Overload
7 Pathological Action Potential Changes. Example—Acute Ischemia
8 Epilogue
Figure 1. Figure 1.

Top: Schematic diagram of the dynamic Luo‐Rudy (LRd) ventricular cell model. Bottom: Action potential and calcium transient, [Ca2+]i, simulated by the model are shown in comparison with experimental data from Beuckelmann and Wier . Note that simulations are conducted at 37°C and experiments at 27°C and are shown on different scales (200 ms bars). The scales become identical, and the close similarity of simulated and measured data is preserved when the appropriate Q10 is used to correct for the temperature difference. Definitions: INa, fast sodium current; ICa(L), calcium current through L‐type calcium channels; ICa(T), calcium current through T‐type calcium channels ; Ito, transient outward current; IKr, rapid delayed rectifier potassium current ; IKs, slow delayed rectifier potassium current; IKl, inward rectifier potassium current ; IKp, plateau potassium current (also known as ultra‐rapid current, Ikur) ; IK(ATP), ATP‐sensitive potassium current ; IK(Na) sodium‐activated potassium current ; Ins(Ca), nonspecific calcium‐activated current (activated under conditions of calcium overload) ; INa,b, sodium background current; ICa,b, calcium background current; INaK, sodium‐potassium pump current; INaCa, sodium–calcium exchange current; IP(Ca), calcium pump in the sarcolemma ; Iup, calcium uptake from the myoplasm to network sarcoplasmic reticulum (NSR) ; Irel, calcium release from juncitonal sarcoplasmic reticulum (JSR) ; Ileak, calcium leakage from NSR to myoplasm; Itr, calcium translocation from NSR to JSR . Calmodulin and troponin represent calcium buffers in the myoplasm. Calsequestrin is a calcium buffer in the JSR. (Details of the LRd model can be found in references ). The model code can be downloaded from the Research Section of www.cwru.edu/med/CBRTC.

Experimental data are adapted from reference , with permission
Figure 2. Figure 2.

Example of interactive processes in a single ventricular myocyte. ICa(L) triggers Ca2+ release from the sarcoplasmic reticulum (SR). Ca2+, in turn, activates INaCa and augments IKs (+ indicates a positive, enhancing effect). Ca2+ also acts to inactivate ICa(L) in a “ negative feedback” process (indicated by ‐). Ca2+ has multiple other actions, not shown in the scheme.

From reference with permission
Figure 3. Figure 3.

Major ionic currents during the action potential (AP). Shown are the AP (repeated at top of both columns for reference), the calcium transient (free calcium in the myoplasm during the AP, [Ca2+]i), and selected ionic currents that determine the AP morphology (current symbols are defined in Figure ). INa is also shown on an expanded time scale (inset). All quantities are simulated using the LRd model. The cell has reached steady state during pacing at a constant BCL of 1000 ms. (BCL is basic cycle length, the interval between pacing stimuli). Note that Ito (which is absent from guinea pig myocardium and is prominent in epicardium of certain species) is not included in this simulation. Its role will be considered in the context of AP heterogeneity (Fig. ).

Compiled from references , with permission
Figure 4. Figure 4.

Repolarizing outward potassium currents during the action potential. IKr and IKs are the rapid and slow delayed rectifier currents, respectively. Their sum constitutes IK (IK = IKr + IKs), originally termed the delayed rectifier K+ current. IKl, the inward rectifier, is time‐independent. IKp, the plateau current, is also known as the ultra‐rapid K+ current IKur. From reference , with permission.

Figure 5. Figure 5.

Membrane potential and selected ionic currents during a fully recovered and a premature action potential. The premature AP is stimulated 15 msec after return of the previous AP to rest potential.

Figure 6. Figure 6.

Action potentials and selected ionic currents at slow (BCL = 1000 msec, black line) and fast (BCL = 200 msec, gray line) pacing rates.

Figure 7. Figure 7.

Heterogeneity of APD in three cell types in relation to IKr and IKs. A: Simulated APs of the three cell types at BCL of 2000 msec. B: Corresponding IKr. C: Corresponding IKs. Dotted lines denote magnitudes of IKr and IKs at membrane potential of 10 mV. Epi, epicardial; M, midmyocardial; Endo, endocardial.

From reference , with permission
Figure 8. Figure 8.

Rate dependence of APD in the three cell types. M‐cells prolong their APD dramatically compared with epicardial and endocardial cells with slowing of rate. APs at progressively decreasing rate (BCL = 300, 500, 1000, and 2000 msec) are shown for each cell type.

From reference , with permission
Figure 9. Figure 9.

Simulated epicardial AP (A) and the corresponding Ito (B). An endocardial AP, in which Ito is not expressed, is shown in panel C for comparison.

Figure 10. Figure 10.

Pause‐induced early afterdepolarizations (EADs). Action potentials from epicardial and mid‐myocardial cells are overlaid for comparison. A: control conditions for wild‐type (WT) ion channels. B: reduced IKs simulating LQT1. C: reduced IKr simulating LQT2. D: enhanced late INa simulating LQT3. The pause only causes slight prolongation of the APD of WT M‐cell, but results in development of multiple EADs in the mutant M cells.

From reference , with permission
Figure 11. Figure 11.

Ionic mechanism of pause‐induced EADs. A: The last pre‐pause AP (thin line) and a post‐pause AP developing plateau EADs (bold line). The arrows indicate the start of secondary membrane depolarization (EAD). B: Corresponding ICa(L). Arrows indicate ICa(L) reactivation, which generates the EADs.

From reference , with permission
Figure 12. Figure 12.

Effect of elevated [Na+]i on the action potential. Action potentials (AP) and selected corresponding ionic currents are shown for two different concentrations of intracellular Na+, [Na+]i = 10 mM (control, thin lines) and [Na+]i = 20 mM (high Na+, thick lines). Inset in B shows INa on an expanded time scale. IK(Na) is the Na+‐activated K+ current that is augmented by Na+ overload.

Adapted from reference , with permission
Figure 13. Figure 13.

Action potential (AP) and major ionic currents during acute ischemia. An ischemic AP (A) and the principal ionic currents (B‐E) are shown for conditions of elevated [K+]o = 12 mM, reduced pH=6.5, and reduced [ATP]i = 3 mM. A control, nonischemic AP (F) and corresponding ionic currents (G‐J) are shown for comparison.

From reference , with permission


Figure 1.

Top: Schematic diagram of the dynamic Luo‐Rudy (LRd) ventricular cell model. Bottom: Action potential and calcium transient, [Ca2+]i, simulated by the model are shown in comparison with experimental data from Beuckelmann and Wier . Note that simulations are conducted at 37°C and experiments at 27°C and are shown on different scales (200 ms bars). The scales become identical, and the close similarity of simulated and measured data is preserved when the appropriate Q10 is used to correct for the temperature difference. Definitions: INa, fast sodium current; ICa(L), calcium current through L‐type calcium channels; ICa(T), calcium current through T‐type calcium channels ; Ito, transient outward current; IKr, rapid delayed rectifier potassium current ; IKs, slow delayed rectifier potassium current; IKl, inward rectifier potassium current ; IKp, plateau potassium current (also known as ultra‐rapid current, Ikur) ; IK(ATP), ATP‐sensitive potassium current ; IK(Na) sodium‐activated potassium current ; Ins(Ca), nonspecific calcium‐activated current (activated under conditions of calcium overload) ; INa,b, sodium background current; ICa,b, calcium background current; INaK, sodium‐potassium pump current; INaCa, sodium–calcium exchange current; IP(Ca), calcium pump in the sarcolemma ; Iup, calcium uptake from the myoplasm to network sarcoplasmic reticulum (NSR) ; Irel, calcium release from juncitonal sarcoplasmic reticulum (JSR) ; Ileak, calcium leakage from NSR to myoplasm; Itr, calcium translocation from NSR to JSR . Calmodulin and troponin represent calcium buffers in the myoplasm. Calsequestrin is a calcium buffer in the JSR. (Details of the LRd model can be found in references ). The model code can be downloaded from the Research Section of www.cwru.edu/med/CBRTC.

Experimental data are adapted from reference , with permission


Figure 2.

Example of interactive processes in a single ventricular myocyte. ICa(L) triggers Ca2+ release from the sarcoplasmic reticulum (SR). Ca2+, in turn, activates INaCa and augments IKs (+ indicates a positive, enhancing effect). Ca2+ also acts to inactivate ICa(L) in a “ negative feedback” process (indicated by ‐). Ca2+ has multiple other actions, not shown in the scheme.

From reference with permission


Figure 3.

Major ionic currents during the action potential (AP). Shown are the AP (repeated at top of both columns for reference), the calcium transient (free calcium in the myoplasm during the AP, [Ca2+]i), and selected ionic currents that determine the AP morphology (current symbols are defined in Figure ). INa is also shown on an expanded time scale (inset). All quantities are simulated using the LRd model. The cell has reached steady state during pacing at a constant BCL of 1000 ms. (BCL is basic cycle length, the interval between pacing stimuli). Note that Ito (which is absent from guinea pig myocardium and is prominent in epicardium of certain species) is not included in this simulation. Its role will be considered in the context of AP heterogeneity (Fig. ).

Compiled from references , with permission


Figure 4.

Repolarizing outward potassium currents during the action potential. IKr and IKs are the rapid and slow delayed rectifier currents, respectively. Their sum constitutes IK (IK = IKr + IKs), originally termed the delayed rectifier K+ current. IKl, the inward rectifier, is time‐independent. IKp, the plateau current, is also known as the ultra‐rapid K+ current IKur. From reference , with permission.



Figure 5.

Membrane potential and selected ionic currents during a fully recovered and a premature action potential. The premature AP is stimulated 15 msec after return of the previous AP to rest potential.



Figure 6.

Action potentials and selected ionic currents at slow (BCL = 1000 msec, black line) and fast (BCL = 200 msec, gray line) pacing rates.



Figure 7.

Heterogeneity of APD in three cell types in relation to IKr and IKs. A: Simulated APs of the three cell types at BCL of 2000 msec. B: Corresponding IKr. C: Corresponding IKs. Dotted lines denote magnitudes of IKr and IKs at membrane potential of 10 mV. Epi, epicardial; M, midmyocardial; Endo, endocardial.

From reference , with permission


Figure 8.

Rate dependence of APD in the three cell types. M‐cells prolong their APD dramatically compared with epicardial and endocardial cells with slowing of rate. APs at progressively decreasing rate (BCL = 300, 500, 1000, and 2000 msec) are shown for each cell type.

From reference , with permission


Figure 9.

Simulated epicardial AP (A) and the corresponding Ito (B). An endocardial AP, in which Ito is not expressed, is shown in panel C for comparison.



Figure 10.

Pause‐induced early afterdepolarizations (EADs). Action potentials from epicardial and mid‐myocardial cells are overlaid for comparison. A: control conditions for wild‐type (WT) ion channels. B: reduced IKs simulating LQT1. C: reduced IKr simulating LQT2. D: enhanced late INa simulating LQT3. The pause only causes slight prolongation of the APD of WT M‐cell, but results in development of multiple EADs in the mutant M cells.

From reference , with permission


Figure 11.

Ionic mechanism of pause‐induced EADs. A: The last pre‐pause AP (thin line) and a post‐pause AP developing plateau EADs (bold line). The arrows indicate the start of secondary membrane depolarization (EAD). B: Corresponding ICa(L). Arrows indicate ICa(L) reactivation, which generates the EADs.

From reference , with permission


Figure 12.

Effect of elevated [Na+]i on the action potential. Action potentials (AP) and selected corresponding ionic currents are shown for two different concentrations of intracellular Na+, [Na+]i = 10 mM (control, thin lines) and [Na+]i = 20 mM (high Na+, thick lines). Inset in B shows INa on an expanded time scale. IK(Na) is the Na+‐activated K+ current that is augmented by Na+ overload.

Adapted from reference , with permission


Figure 13.

Action potential (AP) and major ionic currents during acute ischemia. An ischemic AP (A) and the principal ionic currents (B‐E) are shown for conditions of elevated [K+]o = 12 mM, reduced pH=6.5, and reduced [ATP]i = 3 mM. A control, nonischemic AP (F) and corresponding ionic currents (G‐J) are shown for comparison.

From reference , with permission
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Yoram Rudy. The Cardiac Ventricular Action Potential. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 531-547. First published in print 2002. doi: 10.1002/cphy.cp020113