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The Cardiac Ventricular Action Potential

Yoram Rudy

10.1002/cphy.cp020113

Source: Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart

Originally published: 2002

Published online: January 2011

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 13. 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 6,36,134; Ito, transient outward current; IKr, rapid delayed rectifier potassium current 21; IKs, slow delayed rectifier potassium current; IKl, inward rectifier potassium current 74; IKp, plateau potassium current (also known as ultra‐rapid current, Ikur) 5,147; IK(ATP), ATP‐sensitive potassium current 66,103,105,120; IK(Na) sodium‐activated potassium current 45,67,86,140; Ins(Ca), nonspecific calcium‐activated current (activated under conditions of calcium overload) 43; 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 24; Iup, calcium uptake from the myoplasm to network sarcoplasmic reticulum (NSR) 130; Irel, calcium release from juncitonal sarcoplasmic reticulum (JSR) 94; Ileak, calcium leakage from NSR to myoplasm; Itr, calcium translocation from NSR to JSR 149. 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 45,88,89,120,136,137,151). The model code can be downloaded from the Research Section of www.cwru.edu/med/CBRTC.

Experimental data are adapted from reference 13, 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 109 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 1). 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. 9).

Compiled from references 89,151, 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 151, 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 136, 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 136, 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 137, 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 137, 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 45, 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 120, 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 13. 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 6,36,134; Ito, transient outward current; IKr, rapid delayed rectifier potassium current 21; IKs, slow delayed rectifier potassium current; IKl, inward rectifier potassium current 74; IKp, plateau potassium current (also known as ultra‐rapid current, Ikur) 5,147; IK(ATP), ATP‐sensitive potassium current 66,103,105,120; IK(Na) sodium‐activated potassium current 45,67,86,140; Ins(Ca), nonspecific calcium‐activated current (activated under conditions of calcium overload) 43; 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 24; Iup, calcium uptake from the myoplasm to network sarcoplasmic reticulum (NSR) 130; Irel, calcium release from juncitonal sarcoplasmic reticulum (JSR) 94; Ileak, calcium leakage from NSR to myoplasm; Itr, calcium translocation from NSR to JSR 149. 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 45,88,89,120,136,137,151). The model code can be downloaded from the Research Section of www.cwru.edu/med/CBRTC.

Experimental data are adapted from reference 13, 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 109 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 1). 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. 9).

Compiled from references 89,151, 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 151, 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 136, 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 136, 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 137, 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 137, 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 45, 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 120, with permission
References
 1. Antzelevitch, C., G. Yan, W. Shimizu, A. Burashnikov. Electrical heterogeneity, the ECG, and cardiac arrhythmias. In: Cardiac Electrophysiology: From Cell to Bedside, edited by D. P. Zipes and J. Jalife. Philadelphia: W. B. Saunders, 1999: 222–238.
 2. Antzelevitch, C., S. Sicouri, S. H. Litovsky, et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ. Res. 69: 1427–1449, 1991.
 3. Anyukhovsky E. P., E. A. Sosunov, and M. R. Rosen. Regional differences in electrophysiologic properties of epicardium, midmyocardium, and endocardium: in vitro and in vivo correlations. Circulation 94: 1981–1988, 1996.
 4. Attali, B. Ion channels. A new wave for heart rhythms. Nature 384: 24–25, 1996.
 5. Backx, P. H. and E. Marban. Background potassium current active during the plateau of the action potential in guinea pig ventricular myocytes. Circ. Res. 72: 890–900, 1993.
 6. Balke, C. W., W. C. Rose, E. Marban, and W. G. Wier. Macroscopic and unitary properties of physiological ion flux through T‐type Ca2+ channels in guinea‐pig heart cells. J. Physiol. (Lond.) 456: 247–265, 1992.
 7. Barinaga, M. Tracking down mutations that can stop the heart. Science 281: 32–34, 1998.
 8. Barry, D. M. and J. M. Nerbonne. Myocardial potassium channels: electrophysiological and molecular diversity. Annu Rev. Physiol. 58: 363–394, 1996.
 9. Benardeau, A., S. N. Hatem, C. Ruecker‐Martin, et al. Contribution of Na+/Ca+ exchange to action potential of human atrial myocytes. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H1151–H1161, 1996.
 10. Bennett, P. B., K. Yazawa, N. Makita, and A. L. George, Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature 376: 683–685, 1995.
 11. Berman, M. F., J. S. Camardo, R. B. Robinson, and S. A. Siegel‐baum. Single sodium channels from canine ventricular myocytes: voltage dependence and relative rates of activation and inactivation. J. Physiol. (Lond.) 415: 503–531, 1989.
 12. Bers, D. M., W. J. Lederer, and J. R. Berlin. Intracellular Ca transients in rat cardiac myocytes: role of Na‐Ca exchange in excitation‐contraction coupling. Am. J. Physiol. 258 (Cell Physiol. 27): C944–C954, 1990.
 13. Beuckelmann, D. J. and W. G. Wier. Mechanism of release of calcium from sarcoplasmic reticulum of guinea‐pig cardiac cells. J. Physiol. (Lond.) 405: 233–255, 1988.
 14. Beuckelmann, D. J. and W. G. Wier. Sodium‐calcium exchange in guinea‐pig cardiac cells, exchange current and changes in intracellular Ca2+. J. Physiol. (Lond.) 414: 499–520, 1989.
 15. Blaustein, M. P. and W. J. Lederer. Sodium/calcium exchange: its physiological implications. Physiol. Rev. 79: 763–854, 1999.
 16. Blaustein, M. P., R. DiPolo, and J. P. Reeves. Sodium/calcium exchange. Ann. N.Y. Acad. Sci. 639: 1–671, 1991.
 17. Brahmajothi, M. V., M. J. Morales, K. A. Reimer, and H. C. Strauss. Regional localization of ERG, the channel protein responsible for the rapid component of the delayed rectifier, K+ current in the ferret heart. Circ. Res. 81: 128–135, 1997.
 18. Bridge, J. H. B., J. R. Smolley, and K. W. Spitzer. The relationship between charge movements associated with ICa and INaCa in cardiac myocytes. Science 248: 376–378, 1990.
 19. Brugada, P. and J. Brugada. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report. J. Am. Coll. Cardiol. 20: 1391–1396, 1992.
 20. Brill, D. M. and J. A. Wasserstrom. Intracellular sodium and the positive inotropic effect of veratridine and cardiac glycoside in sheep Purkinje fibers. Circ. Res. 58: 109–119, 1986.
 21. Campbell, D. L., R. L. Rasmusson, M. B. Comer, and H. C. Strauss. The cardiac calcium‐independent transient outward potassium current: kinetics, molecular properties, and role in ventricular transient repolarization. In: Cardiac Electrophysiology: From Cell to Bedside, edited by D. P. Zipes and J. Jalife. Philadelphia: WB Saunders, 1995: 83–96.
 22. Capogrossi, M. C., M. D. Stern, H. A. Spurgeon, and E. G. Lakatta. Spontaneous Ca2+ release from the sarcoplasmic reticulum limits Ca2+‐dependent twitch potentiation in individual cardiac myocytes: a mechanism for maximum inotropy in the myocardium. J. Gen. Physiol. 91: 133–155, 1988.
 23. Carmeliet, E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol. Rev. 79: 917–1017, 1999.
 24. Caroni, P., M. Zurini, A. Clark, and E. Carafoli. Further characterization and reconstitution of the purified Ca‐pumping ATP‐ase of heart sarcolemma. J. Biol. Chem. 258: 7305–7310, 1983.
 25. Cascio, W. E., T. A. Johnson, and L. S. Gettes. Electrophysiologic changes in ischemic ventricular myocardium: I. Influence of ionic, metabolic and energetic changes. J. Cardiovasc. Electro‐physiol. 6: 1039–1062, 1995.
 26. Chandra, R., F. Starmer, and A. O. Grant. Multiple effects of KPQ delection mutation in gating of human cardiac Na+ channels expressed in mammalian cells. Am. J. Physiol. 274 (Heart Circ. Physiol. 43): H1643–H1654, 1998.
 27. Chinn, K. Two delayed rectifiers in guinea pig ventricular myocytes distinguished by tail current kinetics. J. Pharmacol. Exp. Ther. 264: 553–560, 1993.
 28. Chouabe C., N. Neyroud, P. Guicheney, et al. Properties of KvLQT1 K+ channel mutations in Romano‐Ward and Jervell and Lange‐Nielsen inherited cardiac arrhythmias. EMBO J. 16: 5472–5479, 1997.
 29. Clancy, C. E. and Y. Rudy. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature 400: 566–569, 1999.
 30. Clark, R. B., R. A. Bouchard, E. Salinas‐Stefanon, et al. Heterogeneity of action potential waveforms and potassium currents in rat ventricle. Cardiovasc. Res. 27: 1795–1799, 1993.
 31. Cranefield, F. P. and R. S. Aronson. Cardiac Arrhythmias: The Role of Triggered Activity and Other Mechanisms. Mt, Kisco, NY: Futura Publishing Company, 1988.
 32. Crespo, L. M., C. J. Grantham, and M. B. Cannell. Kinetics, stoichiometry and role of the Na‐Ca exchange mechanism in isolated cardiac myocytes. Nature 345: 618–621, 1990.
 33. Curran, M. E., I. Splawski, K. W. Timothy, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80: 795–803, 1995.
 34. Daut, J. The energetics of the Na,K‐pump in cardiac muscle. In: Fortschritte der Zoologie, Luttgau (Hrsg): Volume 33, Membrane Control. Stuttgart/New York: Gustav Fischer Verlag, 1986: 419–427.
 35. Doerr, T., R. Denger, A. Doerr, and W. Trautwein. Ionic currents contributing to the action potential in single ventricular myocytes of the guinea pig studied with action potential clamp. Pflugers Arch. 416: 230–237, 1990.
 36. Droogmans, G. and B. Nilius. Kinetic properties of the cardiac T‐type calcium channel in the guinea‐pig. J. Physiol (Lond.) 419: 627–650, 1989.
 37. Drouin, E., F. Charpentier, C. Gauthier, K. Laurent, and H. Le Marec. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: evidence for presence of M cells. J. Am. Coll. Cardiol. 26: 185–192, 1995.
 38. Dumaine, R., J. A. Towbin, P. Brugada, M. Vatta, D. V. Nester‐enko, V. V. Nesterenko, J. Brugada, R. Brugada, and C. Antzelevitch. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ. Res. 85: 803–809, 1999.
 39. Dumaine, R., Q. Wang, M. T. Keating, et al. Multiple mechanisms of sodium channel‐linked long QT syndrome. Circ. Res. 78: 916–924, 1996.
 40. Earm, Y. E., W. K. Ho, and I. S. So. Inward current generated by Na‐Ca exchange during the action‐potential in single atrial cells of the rabbit. Proc. R. Soc Lond. B. Biol. Sci. 240: 61–81, 1990.
 41. Eddlestone, G. T., A. C. Zygmont, and C. Antzelevitch. Larger late sodium current contributes to the longer action potential of the M‐cell in canine ventricular myocardium. PACE 19: 569 (Abstract), 1996.
 42. Egan, T. M., D. Noble, S. J. Noble, et al. Sodium‐calcium exchange during the action‐potential in guinea‐pig ventricular cells. J. Physiol. 411: 639–661, 1989.
 43. Ehara, T., A. Noma, and K. Ono. Calcium‐activated nonselective cation channel in ventricular cells isolated from adult guinea‐pig hearts. J. Physiol. (Lond.) 403: 117–133, 1988.
 44. Eisner, D. A. and W. J. Lederer. Na‐Ca exchange: stoichiometry and electrogenicity. Am. J. Physiol. 236 (Cell Physiol. 5): C189–C202, 1985.
 45. Faber, G. M. and Y. Rudy. Action potential contractility changes in [Na+]i overloaded cardiac myocytes: a simulation study. Biophys. J. 78: 2392–2404, 2000.
 46. Fabiato, A. Simulated calcium current can both cause calcium loading in and trigger calcium release from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J. Gen. Physiol. 85: 291–320, 1985.
 47. Faivre, J. F. and I. Findlay. Action potential duration and activation of ATP‐sensitive potassium current in isolated guinea‐pig ventricular myocytes. Biochim. Biophys. Acta 1029: 167–172, 1990.
 48. Fedida, D. and W. R. Giles. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J. Physiol. (Lond.) 442: 191–209, 1991.
 49. Fedida, D., D. Noble, Y. Shimoni, and A. J. Spindler. Inward current related to contraction in guinea‐pig ventricular myocytes. J. Physiol. (Lond). 385: 565–589, 1987.
 50. Fozzard, H. A. and D. A. Hanck. Structure and function of voltage‐dependent sodium channels: comparison of brain II and cardiac isoforms. Physiol. Rev. 76: 887–926, 1996.
 51. Fozzard, H. A. and G. Lipkind. Ion channels and pumps in cardiac function. Adv. Exp. Med. Biol. 382: 3–10, 1995.
 52. Furukawa, T., R. J. Myerburg, N. Furukawa, et al. Differences in transient outward currents of feline endocardial and epicardial myocytes. Circ. Res. 67: 1287–1291, 1990.
 53. Gadsby, D. C. and M. Nakao. Steady‐state current‐voltage relationship of the Na/K pump in guinea pig ventricular myocytes. J. Gen. Physiol. 94: 511–537, 1989.
 54. Gettes, L. S. and W. E. Cascio. Effect of acute ischemia on cardiac electrophysiology. In: The Heart and Cardiovascular System, edited by H. A. Fozzard, R. B. Jennings, E. Haber, A. M. Katz, and H. E. Morgan. New York: Raven Press, 1992: 2021–2054.
 55. Grantham, C. J. and M. D. Cannell. Ca2+ influx during the cardiac action potential in guinea pig ventricular myocytes. Circ. Res. 79: 194–200, 1965.
 56. Habbab, M. A. and N. El‐Sherif. Drug‐induced torsades de pointes: role of early afterdepolarizations and dispersion of repolarization. Am. J. Med. 89: 241–246, 1990.
 57. Hadley, R. W. and W. J. Lederer. Ca2+ and voltage inactivate Ca2+ channels in guinea‐pig ventricular myocytes through independent mechanisms. J. Physiol. (Lond.) 444: 257–268, 1991.
 58. Harrison, S. M., E. McCall, and M. R. Boyett. The relationship between contraction and intracellular sodium in rat and guinea‐pig ventricular myocytes. J. Physiol. (Lond). 449: 517–550, 1992.
 59. Hess, P., J. B. Lansman, and R. W. Tsien. Calcium channel selectivity for divalent and monovalent cations, voltage and concentration dependence of single channel current in ventricular heart cells. J. Gen. Physiol. 88: 293–319, 1986.
 60. Hodgkin, A. L. and A. F. Huxley. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. (Lond.) 117: 500–544, 1952.
 61. Horie, M., S. Hayashi, and C. Kawai. Two types of delayed rectifying K+ channels in atrial cells of guinea pig heart. Jpn. J. Physiol. 40: 479–490, 1990.
 62. Irisawa H. and R. Sato. Intra‐ and extracellular actions of proton on the calcium current of isolated guinea pig ventricular cells. Circ. Res. 59: 348–355, 1986.
 63. January, C. T., and J. M. Riddle. Early afterdepolarizations: mechanism of induction and block: a role of L‐type Ca2+ current. Circ. Res. 64: 977–989, 1989.
 64. January, C. T., J. M. Riddle, and J. J. Salata. A model for early afterdepolarizations: induction with the Ca2+ channel agnoist Bay K8644. Circ. Res. 62: 563–571, 1988.
 65. Kagiyama, Y., J. L. Hill, and L. S. Gettes. Interaction of acidosis and increased extracellular potassium on action potential characteristics and conduction in guinea pig ventricular muscle. Circ. Res. 51: 614–623, 1982.
 66. Kakei, M., A. Noma, and T. Shibasaki. Properties of adenosine‐triphosphate‐regulated potassium channels in guinea‐pig ventricular cells. J. Physiol. (Lond.) 363: 441–462, 1985.
 67. Kameyama, M., M. Kakei, R. Sato, T. Shibasaki, H. Matsuda, and H. Irisawa. Intracellular Na+ activates a K+ channel in mammalian cardiac cells. Nature 309: 354–356, 1984.
 68. Kass, R. S. and M. P. Davies. The roles of ion channels in an inherited heart disease: molecular genetics of the long QT syndrome. Cardiovasc. Res. 32: 443–454, 1996.
 69. Kass, R. S. and M. C. Sanguinetti. Inactivation of calcium channel current in the calf cardiac Purkinje fiber: evidence for voltage‐ and calcium‐mediated mechanisms. J. Gen. Physiol. 84: 705–726, 1984.
 70. Keating, M. T. and M. C. Sanguinetti. Molecular genetic insights into cardiovascular disease. Science 272: 681–685, 1996.
 71. Kimura, J., S. Miyamae, and A. Noma. Identification of sodium‐calcium exchange current in single ventricular cells of guinea‐pig. J. Physiol. (Lond.) 384: 199–222, 1987.
 72. Kléber, A. G. Resting membrane potential, extracellular potassium activity, and intracellular sodium activity during acute global ischemia in isolated perfused guinea pig hearts. Circ. Res. 52: 442–450, 1983.
 73. Kunze, D. L., A. E. Lacerda, D. L. Wilson, and A. M. Brown. Cardiac Na currents and the inactivating, reopening, and waiting properties of single cardiac Na channels. J. Gen. Physiol. 86: 691–719, 1985.
 74. Kurachi, Y. Voltage‐dependent activation of the inward‐rectifier potassium channel in the ventricular cell membrane of guineapig heart. J. Physiol. (Lond.) 366: 365–385, 1985.
 75. Lagnado, L. and P. A. McNaughton. Electrogenic properties of the Na,Ca exchange. J. Membr. Biol. 113: 177–191, 1990.
 76. Lawrence, J. H., D. T. Yue, W. C. Rose, and E. Marban. Sodium channel inactivation from resting states in guinea‐pig ventricular myocytes. J. Physiol. (Lond.) 443: 629–650, 1991.
 77. Lee, K. S., E. Marban, and R. W. Tsien. Inactivation of calcium channels in mammalian heart cells: joint dependence on membrane potential and intracellular calcium. J. Gen. Physiol. 364: 395–411, 1985.
 78. Levi, A. The effect of strophanthidin on action potential, calcium current and contraction in isolated guinea‐pig ventricular myocytes. J. Physiol. (Lond.) 443: 1–23, 1991.
 79. Levi, A. J., G. R. Dalton, J. C. Hancox, J. S. Mitcheson, J. Issberner, J. A. Bates, S. J. Evans, F. C. Howarth, I. A. Hobai, and J. V. Jones. Role of intracellular sodium overload in the genesis of cardiac arrhythmias. J. Cardiovasc. Electrophysiol. 8: 700–721, 1997.
 80. Lipp, P. and M. D. Bootman. The physiology and molecular biology of cardiac Na/Ca exchange. In: Cardiac Electrophysiology: From Cell to Bedside, edited by D. P. Zipes and J. Jalife. Philadelphia: WB Saunders, 1999: 41–51.
 81. Lipp, P., S. Mechmann, and L. Pott. Effects of calcium release from sarcoplasmic reticulum on membrane currents in guinea pig atrial cardioballs. Pflugers Arch. 410: 121–131, 1987.
 82. Litovsky, S. H. and C. Antzelevitch. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ. Res. 62: 116–126, 1988.
 83. Litovsky, S. H. and C. Antzelevitch. Rate dependence of action potential duration and refractoriness in canine ventricular endocardium differs from that of epicardium: role of the transient outward current. J. Am. Coll. Cardiol. 14: 1053–1066, 1989.
 84. Liu, D. W., G. A. Gintant, and C. Antzelevitch. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ. Res. 72: 671–687, 1993.
 85. Liu, D. W. and C. Antzelevitch. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes: a weaker IKs contributes to the longer action potential of the M cell. Circ. Res. 76: 351–365, 1995.
 86. Luk, H. N. and E. Carmeliet. Na+‐activated K+ current in cardiac cells: rectification, open probability, block and role in digitalis toxicity. Pflugers Arch. 416: 766–769, 1990.
 87. Lukas, A. and C. Antzelevitch. Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia. The antiarrhythmic effects of 4‐aminopyridine. Cardiovasc. Res. 32: 593–603, 1996.
 88. Luo, C. and Y. Rudy. A model of the ventricular cardiac action potential: depolarization, repolarization and their interaction. Circ. Res. 68: 1501–1526, 1991.
 89. Luo, C. and Y. Rudy. A dynamic model of the cardiac ventricular action potential: I. Simulations of ionic currents and concentration changes. Circ. Res. 74: 1071–1096, 1994.
 90. Luo, C. and Y. Rudy. A dynamic model of the cardiac ventricular action potential: II. Afterdepolarizations, triggered activity and potentiation. Circ. Res. 74: 1097–1113, 1994.
 91. Marban, E., S. W. Robinson, and W. G. Wier. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. Clin. Invest. 78: 1185–1192, 1986.
 92. Matsuura, H., T. Ehara, and Y. Imoto. An analysis of the delayed outward current in single ventricular cells of the guinea‐pig. Pflugers Arch. 410: 596–603, 1987.
 93. McDonald, T. F., S. Pelzer, W. Trautwein, and D. J. Pelzer. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. 74: 365–507, 1994.
 94. Meissner, G. Sarcoplasmic reticulum ion channels. In: Cardiac Electrophysiology: From Cell to Bedside, edited by D. P. Zipes and J. Jalife. Philadelphia: W. B. Saunders, 1995: 51–58.
 95. Mechmann, S. and L. Pott. Identification of Na‐Ca exchange current in single cardiac myocytes. Nature 319: 597–599, 1986.
 96. Mitchell, M. R., T. Powell, D. A. Terrar, and V. W. Twist. The effect of ryanodine, EGTA and low‐sodium on action potentials in rat and guinea‐pig ventricular myocytes: evidence for two inward currents during the plateau. Br. J. Pharmacol. 81: 543–550, 1984.
 97. Mitsuiye, T. and A. Noma. Exponential activation of the cardiac Na+ current in single guinea‐pig ventricular cells. J. Physiol. (Lond.) 453: 261–277, 1992.
 98. Mullins, L. J. A mechanism for Na/Ca transport. J. Gen. Physiol. 70: 681–695, 1977.
 99. Mullins, L. J. The generation of electric currents in cardiac fibers by Na/Ca exchange. Am. J. Physiol. 236 (Cell Physiol. 5): C103–C110, 1979.
 100. Nabauer, M., D. J. Beuckelmann, P. Uberfuhr, and G. Steinbeck. Regional differences in current density and rate‐dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation 93: 168–177, 1996.
 101. Nakao, M. and D. C. Gadsby. [Na] and [K] dependence of the Na/K pump current‐voltage relationship in guinea‐pig ventricular myocytes. J. Gen. Physiol. 94: 539–565, 1989.
 102. Neely, A., R. Olcese, X. Wei, L. Birnbaumer, and E. Stefani. Ca2+ ‐dependent inactivation of a cloned cardiac Ca2+ channel α1 subunit (α1C) expressed in. Xenopus oocytes. Biophys. J. 66: 1895–1903, 1994.
 103. Nichols, C. G., C. Ripoll, W. J. Lederer. ATP‐sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ. Res. 68: 280–287, 1991.
 104. Nitta, J., T. Furukawa, F. Marumo, T. Sawanobori, and M. Hiraoka. Subcellular mechanism for Ca2+‐dependent enhancement of delayed rectifier K+ current in isolated membrane patches of guinea pig ventricular myocytes. Circ. Res. 74: 96–104, 1994.
 105. Noma, A. ATP‐regulated K+ channels in cardiac muscle. Nature 305: 147–148, 1983.
 106. Noma, A. and T. Shibasaki. Membrane current through adenosine‐triphosphate‐regulated potassium channels in guinea‐pig ventricular cells. J. Physiol. (Lond.) 363: 463–480, 1985.
 107. Ohya, Y. and N. Sperelakis. ATP regulation of the slow calcium channels in vascular smooth muscle cells of guinea pig mesenteric artery. Circ. Res. 64: 145–154, 1989.
 108. Priori, S. G. and P. B. Corr. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1796–H1805, 1990.
 109. Priori, S. G., J. Barhanin, R. N. W. Hauer, W. Haverkamp, H. J. Jongsma, A. G. Kleber, W. J. McKenna, D. M. Roden, Y. Rudy, K. Schwartz, P. J. Schwartz, J. A. Towbin, and A. M. Wilde. Genetic and molecular basis of cardiac arrhythmias, Part III. Circulation 99: 674–681, 1999.
 110. (Also published in Eur. Heart J. 20: 179–195, 1999.)
 111. Reeves, J. P. and C. C. Hale. The stoichiometry of the cardiac sodium‐calcium exchange system. J. Biol. Chem. 259: 7733–7739, 1984.
 112. Roden, D. M. and P. M. Spooner. Inherited long QT syndrome: a paradigm for understanding arrhythmogenesis. J. Cardiovasc. Electrophysiol. 10: 1664–1683, 1999.
 113. Rosen, M. R. The concept of afterdepolarizations. In: Cardiac Electrophysiology: A Textbook, edited by M. R. Rosen, M. J. Janse, A. L. Wit. Mount Kisco, NY: Futura, 1990: 267–271.
 114. Sakmann, B. and G. Trube. Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea‐pig heart. J. Physiol. (Lond.) 347: 641–657, 1984.
 115. Sanguinetti, M. C. and N. K. Jurkiewicz. Two components of cardiac delayed rectifier K+ current: differential sensitivity to block by class III antiarrhythmic agents. J. Gen. Physiol. 96: 195–215, 1990.
 116. Sanguinetti, M. C. and N. K. Jurkiewicz. Role of external Ca2+ and K+ in gating of cardiac delayed rectifier K+ currents. Pflugers Arch. 420: 180–186, 1992.
 117. Sanguinetti, M. C. Na+‐activated and ATP‐sensitive K+ channels in the heart. In: Potassium Channels: Basic Function and Therapeutic Aspects, edited by T. J. Colatsky. New York: Alan R. Liss, Inc., 1990: 85–109.
 118. Sanguinetti, M. C., M. E. Curran, P. S. Spector, et al. Spectrum of HERG K+ channel dysfunction in an inherited cardiac arrhythmia. Proc. Natl. Acad. Sci. U.S.A. 93: 2208–2212, 1996.
 119. Scanley, B. E., D. A. Hanck, T. Chay, and H. A. Fozzard. Kinetic analysis of single sodium channels from canine cardiac Purkinje cells. J. Gen. Physiol. 95: 411–447, 1990.
 120. Schwartz, P. J., S. G. Priori, and C. Napolitano. Long QT syndrome. In: Cardiac Electrophysiology: From Cell to Bedside, edited by D. P. Zipes and J. Jalife. Philadelphia: W. B. Saunders, 1999: 788–810.
 121. Shaw, R. M. and Y. Rudy. Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration. Cardiovasc. Res. 35: 256–272, 1997.
 122. Shimizu, W. and Anzelevitch, C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsades de pointes in LQT2 and LQT3 models of the long‐QT syndrome. Circulation 96: 2038–2047, 1997.
 123. Shirokov, R., R. Levis, N. Shirokova, and E. Rios. Ca2+‐dependent inactivation of cardiac L‐type Ca2+ channels does not affect their voltage sensor. J. Gen. Physiol. 102: 1005–1030, 1993.
 124. Sicouri, S., M. Quist, and C. Antzelevitch. Evidence for the presence of M cells in the guinea pig ventricle. J. Cardiovasc. Electrophysiol. 7: 503–511, 1996.
 125. Sicouri, S. and C. Antzelevitch. A subpopulation of cells with unique electrophysiological properties in the deep subepicar‐dium of the canine ventricle: the M cell. Circ. Res. 68: 1729–1741, 1991.
 126. Sipido, K. R., G. Callewaert, and E. Carmeliet. Inhibition and rapid recovery of Ca2+ current during release from sarcoplasmic reticulum in guinea pig ventricular myocytes. Circ. Res. 76: 102–109, 1995.
 127. Skinner, R. B., Jr., and D. L. Kunze. Changes in extracellular potassium activity in response to decreased pH in rabbit atrial muscle. Circ. Res. 39: 678–683, 1976.
 128. Splawski, I., M. Tristanti‐Firouzi, M. H. Lehmann, et al. Mutations in the. hminK gene cause long QT syndrome and suppress IKs function. Nat. Genet. 17: 338–340, 1996.
 129. Stern, M. D., M. C. Capogrossi, and E. G. Lakatta. Spontaneous calcium release from the sarcoplasmic reticulum in myocardial cells, mechanisms and consequences. Cell Calcium 9: 247–256, 1988.
 130. Szabo, B., T. Kovacs, and R. Lazzara. Role of calcium loading in early afterdepolarizations generated by Cs+ in canine and guinea pig Purkinje fibers. J. Cardiovasc. Electrophysiol. 6: 796–812, 1995.
 131. Tada, M., M. Shigekawa, M. Kadoma, and Y. Nimura. Uptake of calcium by sarcoplasmic reticulum and its regulation and functional consequences. In: Physiology and Pathophysiology of the Heart, edited by N. Sperelakis. Boston: Kluwer Academic Publishers, 1989: 267–290.
 132. Tani, M. and J. Neely. Na+ accumulation increases Ca2+ overload and impairs function in anoxic rat heart. J. Mol. Cell. Cardiol. 22: 57–72, 1990.
 133. Tohse, N. Calcium‐sensitive delayed rectifier potassium current in guinea pig ventricular cells. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1200–H1207, 1990.
 134. van Echteld, C., J. Kirkels, M. Eijgelshoven, P. van der Meer, and T. Ruigrok. Intracellular sodium during ischemia and calcium‐free perfusion: a 23Na NMR study. J. Mol. Cell. Cardiol. 23: 297–307, 1991.
 135. Vassort, G. and J. Alvarez. Cardiac T‐type calcium current: pharmacology and roles in cardiac tissues. J. Cardiovasc. Electrophysiol. 5: 376–393, 1994.
 136. Veldkamp, M. W., J. Vereecke, and E. Carmeliet. Effects of intracellular sodium and hydrogen ion on the sodium activated potassium channel in isolated patches from guinea pig ventricular myocytes. Cardiovasc. Res. 28: 1036–1041, 1994.
 137. Viswanathan, P. C., R. M. Shaw, and Y. Rudy. Effects of IKr and IKs heterogeneity on action potential duration and its rate‐dependence: A simulation study. Circulation 99: 2466–2474, 1999.
 138. Viswanathan, P. C. and Y. Rudy. Pause induced early afterdepolarizations in the long QT syndrome: A simulation study. Cardiovasc. Res. 42: 530–542, 1999.
 139. Viswanathan, P. C. and Y. Rudy. Cellular arrhythmogenic effects of the congenital and acquired long QT syndrome in the heterogeneous myocardium. Circulation 101: 1192–1198, 2000.
 140. Vos, M. A., S. C. Verduyn, A. P. Gorgels, G. C. Lipcsei, and H. J. J. Wellens. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d‐sotalol and pacing in dogs with chronic atrioventricular block. Circulation 91: 864–872, 1995.
 141. Wang, Z., T. Kimitsuki, and A. Noma. Conductance properties of the Na+‐activated K+ channel in guinea‐pig ventricular cells. J. Physiol. (Lond.) 433: 241–257, 1991.
 142. Weirich, J., R. Bernhardt, N. Loewen, et al. Regional‐ and species‐dependent effects of K+‐channel blocking agents on subendocardium and mid‐wall slices of human, rabbit, and guinea pig myocardium. Pflugers Arch. 431: R130 (Abstract), 1996.
 143. Weiss, J. N., N. Venkatesh, and S. T. Lamp. ATP‐sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J. Physiol. (Lond.) 447: 649–673, 1992.
 144. Welsh, J. J. and T. Hoshi. Molecular cardiology. Ion channels lose the rhythm. Nature 376: 640, 1995.
 145. Wettwer E., G. J. Amos, H. Posival, and U. Ravens. Transient outward current in human ventricular myocytes of subepicar‐idal and subendocardial origin. Circ. Res. 75: 473–482, 1994.
 146. Wier, W. and P. Hess. Excitation‐contraction coupling in cardiac Purkinje fibers. Effects of cardiotonic steroids on the intracellular [Ca 2+] transient, membrane potential, and contraction. J. Gen. Physiol. 83: 395–415, 1984.
 147. Wit, A. L. and M. J. Janse. The ventricular arrhythmias of ischemia and infarction: electrophysiological mechanisms. Mt. Kisco, NY: Futura Publishing Company, 1992.
 148. Yue, D. T. and E. Marban. A novel cardiac potassium channel that is active and conductive at depolarized potentials. Pflugers Arch. 413: 127–133, 1988.
 149. Yue, D. T., P. H. Backx, and J. P. Imredy. Calcium‐sensitive in‐activation in the gating of single calcium channels. Science 250: 1735–1738, 1990.
 150. Yue, D. T., D. Burkhoff, M. R. Franz, W. C. Hunter, and K. Sagawa. Postextrasystolic potentiation of the isolated canine left ventricle: relationship to mechanical restitution. Circ. Res. 56: 340–350, 1985.
 151. Zeng, J. and Y. Rudy. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys. J. 68: 949–964, 1995.
 152. Zeng, J., K. R. Laurita, D. S. Rosenbaum, and Y. Rudy. Two components of the delayed rectifer K+ current in ventricular myocytes of the guina pig type: theoretical formulation and their role in repolarization. Circ. Res. 77: 1–13, 1995.

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Article Title: The Cardiac Ventricular Action Potential
 

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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