Biomedical Engineering Reference
In-Depth Information
very low, with potential being determined by a delicate balance between small
inward and outward currents. The major inward plateau current is
I
Ca,L
, and major
outward plateau currents are generated by the rapid and slow-activating delayed
outward rectifier K
+
currents
I
Kr
and
I
Ks
, respectively, and the plateau K
+
current
I
Kp
. Finally, repolarization Phase 3 is produced by the hyperpolarizing activated
inward rectifier K
+
current
I
K1
.
Three major ion transporters and exchangers play a critically important role
in shaping properties of the cardiac AP, Ca
2+
transient, and in long-term regula-
tion of intracellular ion concentrations. These are the sarcolemmal Na
+
-K
+
pump, the sarcolemmal Na
+
-Ca
2+
exchanger, and the SR Ca
2+
-ATPase. The sar-
colemmal Na
+
-K
+
pump, present in virtually all mammalian cell membranes,
extrudes 3 Na
+
ions while importing 2 K
+
ions on each cycle. This pump func-
tions to keep intracellular Na
+
low, thereby maintaining the external versus in-
ternal gradient of Na
+
, by extruding Na
+
that enters during each AP. Cycling of
this pump requires hydrolysis of 1 ATP molecule, and generates a net outward
movement of 1 positive charge, thus contributing to outward membrane current
and influencing resting membrane potential.
The sarcolemmal Na
+
-Ca
2+
exchanger imports three Na
+
ions for every Ca
2+
ion extruded, yielding a net charge movement. It is driven by both transmem-
brane voltage and intra- and extracellular Na
+
and Ca
2+
ion concentrations. It
functions in forward mode during diastole, in which case it extrudes Ca
2+
and
imports Na
+
, thus generating a net inward current. It is the principal means by
which Ca
2+
is extruded from the myocyte following each AP, particularly during
the diastolic interval. Due to the voltage- and Ca
2+
-sensitivity of the exchanger,
experimental evidence indicates that it can function in reverse mode during the
plateau phase of the AP, in which case it extrudes Na
+
and imports Ca
2+
, thus
generating a net outward current.
A second major cytoplasmic Ca
2+
extrusion mechanism is the SR Ca
2+
-
ATPase. This ATPase pumps Ca
2+
from the cytosol into the NSR. The SR Ca
2+
-
ATPase has both forward and reverse components (7), with the reverse compo-
nent serving to prevent overloading of the SR with Ca
2+
at rest. An additional
Ca
2+
extrusion mechanism is the sarcolemmal Ca
2+
-ATPase. This Ca
2+
pump
hydrolyzes ATP to transport Ca
2+
out of the cell. However, it contributes a sar-
colemmal current that is small relative to that of the Na
+
-Ca
2+
exchanger, with
estimates indicating perhaps that as little as 3% of Ca
2+
extrusion from the myo-
cyte is mediated by this pump.
2.2. The Structure of Myocyte Models
Development of myocyte models began in the early 1960s with publication
of Purkinje fiber AP models. Subsequent elaboration of these models led to de-
velopment of the first biophysically based cell model describing interactions
