Page 82 - YORAM RUDY BOOK FINAL

P. 82
current, a smaller and slower current under normal physiological conditions, provides a significant

portion of the depolarizing charge when I is suppressed. This issue is addressed by the simula-
Na
tions in Figure 3.6. In Panel A, SF is computed with (solid line) or without (dashed line) contribution
from I over a range of membrane excitability. For most of this range, SF is not influenced by the
Ca,L
presence or absence of I . Only at extreme levels of I suppression (<30% availability) contribution
Ca,L Na
from I augments SF slightly and occurrence of conduction failure is shifted to a slightly lower
Ca,L
excitability value (11% or 15% availability with or without I , respectively).
Ca,L

In further examination of I role in depressed conduction, we computed and compared its
Ca,L
depolarizing charge contribution to that of I . Figure 3.6B shows the action potential rising phase
Na
with (solid line) and without (dashed line) contribution from I for severely depressed membrane
Ca,L
excitability (20% I availability). The action potential amplitude between a given cell’s excitation (0
Na
msec) and excitation of its downstream neighboring cell (0.37 msec, marked by a thin vertical line)
is slightly higher when I is present. This increases the electrotonic driving force and axial
Ca,L
depolarizing current to downstream cells, augmenting SF slightly (a very small quantitative
effect). The inset bar graph in Figure 3.6B compares charge contributions from I (Q ) and from
Na Na
I (Q ) during the interval when a cell serves as a source of depolarizing charge for the fiber. As
Ca,L Ca,L
above, this interval is from the time of a cell’s excitation (determined from dV /dt ) to excitation
m max
of the adjoining cell; charge is computed by integrating the current over this time interval. The
ratio of charge contribution Q :Q is 75:1, indicating that even when I is greatly suppressed, its
Na Ca Na
contribution to conduction is much greater than that of I . Because the gap junction
Ca,L
conductance is normal, intercellular conduction delays are short and the source period of a cell is
also short (0.37 msec in the simulation). During this short interval I is near its maximum, while
Na
I is only beginning to activate, explaining the large Q :Q ratio even when I is suppressed.
Ca,L Na Ca,L Na
Clearly, I is the dominant current that maintains conduction in well coupled cardiac tissue, even
Na
when its availability is greatly reduced. Conceivably, enhancement of I in this condition could
Ca,L
increase Q and rescue conduction. This was achieved experimentally where addition of
Ca
epinephrine during severe hyperkalemia ([K ] =20 mM) produced I – dependent slow conduction
+
0 Ca,L
at a velocity of 10 cm/sec. 202

Acute Myocardial Ischemia

Acute myocardial ischemia is a pathophysiological condition that affects membrane ionic

currents and ion concentrations in the intra-and extra-cellular spaces. Consequently, it alters
membrane excitability, leading to abnormal action potential conduction and cardiac arrhythmias
that can be fatal. 206,207 During the acute phase of ischemia (first 10-15 min), electrophysiological

changes are mainly due to changes in membrane excitability, without appreciable changes in gap
junction coupling 208 . Therefore, the abnormal conduction and reentrant arrhythmias at this phase
provide an example of excitability-based mechanisms of a clinical rhythm disorder. The major
conditions associated with acute ischemia are elevated extracellular potassium [K ] , acidosis
+
0