Page 16 - YORAM RUDY BOOK FINAL

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reduced V at the notch inhibits reverse-mode I NaCa , an outward (repolarizing) current. This
m
contributes also to action potential prolongation at slow rates.

The above discussion highlights the complex multi-current interactions that determine
action potential repolarization and its rate dependence. The delicate balance of currents during

the plateau and repolarization phases of the action potential provides for tight control of APD,
an essential property for normal cardiac function over the physiological range of heart rates. In
contrast, the depolarization phase of a normal action potential (its upstroke) depends only on I , a
Na
single very large current that generates the action potential with a large margin of safety (an action

potential is generated even at only 11% of normal I peak magnitude). This property is consistent
Na
with the requirement that action potential generation should be a very robust “all or none”
process, rather than a precise process that depends on a delicate balance between small inward
and outward currents.

Acute ischemia affects both, excitability and repolarization. We simulated the effects of
acute ischemia using the LRd model cell. The three major component conditions of acute
50
ischemia were incorporated in the model: elevated extracellular K (hyperkalemia), acidosis and
+
anoxia. Hyperkalemia had a major negative effect on excitability by depolarizing resting
membrane potential, causing reduction in sodium channel availability. It also delayed recovery of
excitability after the AP, a phenomenon known as “post-repolarization refractoriness”, by causing
major slowing of sodium-channel recovery from inactivation. Anoxia, simulated by lowering cellular

ATP and activating the ATP-dependent potassium current, I K(ATP ), decreased APD greatly (activation
of only 1% of I K(ATP) channels was sufficient to shorten APD by ~ 50%) and caused AP shape changes
observed in ischemic myocytes.

2.5 Kinetics of Selected Ion Channels during the Action Potential

The previous section described the macroscopic transmembrane currents during the action
potential. Additional mechanistic insights into kinetic properties of ion channels that underlie the

action potential can be obtained by incorporating Markov models of the channels into the model
of the whole-cell action potential (in the LRd, HRd or ORd models, Hodgkin-Huxley or Markov
representations of currents can be used interchangeably). With this representation, the model can
be used to describe channel occupancies in specific kinetic states (closed, open, inactivated) and

the transitions between them during the action potential. This description provides a mechanistic
link between the action potential and the functioning of ion channels that generate it. In this
section, we examine the kinetic transitions of selected ion channels during the cardiac action
potential and their role in its rate dependence. The selected channels play an important role in

action potential generation and rate-adaptation; they are the sodium channel (I ), L-type calcium
Na
channel (I Ca,L ), and the rapid and slow delayed rectifier potassium channels (I and I ). The guinea
ks
kr
pig LRd model is used in the simulations.