Page 11 - YORAM RUDY BOOK FINAL

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2.3 Generation of an Action Potential by the Cardiac Cell

The cardiac action potential is generated by a single myocyte; it is a process that involves a

dynamic interplay between different ion channels, pumps, exchangers and the dynamically
changing ionic milieu of the cell. The integrated behavior of the cell determines the action
potential properties and its response to various physiological and pathological conditions.
Figure 2.1 (p. 12) is a schematic diagram of a ventricular myocyte and its electrophysiological
components. It also serves to describe mathematical models of the cell that will be used

extensively throughout this chapter. The Luo-Rudy dynamic (LRd) model 14,14a,15 is based on
single-cell and single channel data from the guinea pig, while the Hund-Rudy dynamic (HRd)
model 16,17 simulates the canine ventricular myocyte. A model of the human ventricular myocyte, the

O’Hara – Rudy dynamic (ORd) model was developed and published later ; it is described in section
18
2.6 (p. 26). Included in these models are the species-specific membrane ionic currents, pumps
and exchangers. Processes that regulate dynamic concentration changes of sodium, calcium and
potassium are also represented. The calcium-induced-calcium-release process (CICR) from the
19
sarcoplasmic reticulum (SR) is simulated and generates the calcium transient during the action

potential. Important properties that are represented in the models include: (1) I , the sodium
Na
current, characterized by fast activation and by fast and slow inactivation processes 20,21,22,23 ; I Na,L is
the slowly-inactivating late component of the sodium current. (2) The L-type calcium current, I Ca,L , is

inactivated by both voltage-dependent and calcium-dependent processes. 24,25,26,27,28,29 (3) The
model includes the two-components of the delayed rectifier potassium current, I (rapid) and I
Ks
Kr
(slow) 30,31,32 (4) Conductances of I , I , and I K(ATP) increase with extracellular potassium concentration,
Kr
K1
[K+] . 33,34,45,36 (5) Conductance of I increases with intracellular calcium concentration, [Ca ]. i 37,38
2+
0
Ks
(6) I , the transient outward potassium current, is present in canine and human epicardium and
to1
mid-myocardium, but not in guinea pig myocardium or canine endocardium. 39,40 Later versions
of the models 16,17,41,42,43 include processes of chloride homeostasis, a subsarcolemnal restricted
subspace for calcium distribution where L-type calcium channels and ryanodine receptors interact
during the CICR process, the Ca /calmodulin-dependent protein kinase (CaMKII) regulatory
2+
pathway and the ß -adrenergic cascade. The subsarcolemmal restricted space represents regions
along T-tubules where the junctional SR membrane abuts the sarcolemma, creating close proximi-
ty between ryanodine receptors and L-type calcium channels.

In Figure 2.2 (p. 13), the canine epicardial cell model is used to describe the role played by
various ionic currents in generating the action potential and determining its shape and duration.
The action potential (V ) and calcium transient ([Ca ]) are shown together with selected currents.
2+
m
i
The fast upstroke of the action potential (maximum dV /dt ~ 390 volts/sec) is generated by the
m
fast inward sodium current, I . It is followed by activation of I , the transient outward current that
to1
Na
repolarizes V to generate the action potential “notch”. When V reaches about -40 mV, inward I Ca,L
m
m