Biomedical Engineering Reference
In-Depth Information
In rabbits, the threshold of cholinergic agonist (carbachol) concentration to
reduce the beating rate is approximately 10 nmol [
611
]. Half-maximal inhibition
that is achieved at 100 nmol lowers phospholamban phosphorylation by PKA by
approximately 50%. In addition, this dose causes a time-dependent reduction in
the number and magnitude of rhythmic, spontaneous, local Ca
2
+
releases, but an
augmentation of the period of local Ca
2
+
releases. A dose of 1,000 nmol stops
spontaneous beating. On the other hand,
i
f
blockade does not affect the reduction
of cardiac frequency caused by cholinergic signals at any cholinergic agonist
concentration.
Initiation of acetylcholine-activated current
i
K
ACh
happens from cholinergic
agonist concentration greater than 30 nmol. Numerical simulations point out that
Ca
2
+
cycling is modulated by cholinergic input via activation of
i
NaCaX
current
primed by local Ca
2
+
releases [
611
]. The cholinergic control operates via Gi
activation. The extent of Gi coupling to Ca
2
+
cycling results from PKA signaling as
well as activation acetylcholine-activated K
+
current when the stimulation reaches
a given threshold (
>
30 nmol).
6.4.2
Ventriculomyocytes
Mathematical models of the ventricular action potential are aimed at reproduc-
ing the different action potential shapes corresponding to the 3 transmyocardial
regions (endo-, epi-, and midmyocardia) of ventricles and their different rate
dependencies [
603
,
612
]. Basal models of ventricular myocyte functioning comprise
3 major components: (1) membrane ion currents (fast sodium, L-type calcium,
transient outward potassium, rapid and slow delayed rectifier potassium, inward
rectifier potassium, sodium-calcium exchanger, sodium-potassium pump, calcium
and potassium plateau, and background currents; Fig.
6.5
)[
612
]; (2) intracellular
calcium compartments (subspace between the T tubule and junctional sarcoplasmic
reticulum,
60
junctional and network sarcoplasmic reticulum, sarcomere, and bulk
myoplasm); and (3) calcium buffers (mainly the sarcoplasmic Ca
2
+
buffer cal-
modulin, sarcomeric Ca
2
+
buffer troponin, and sarcoplasmic reticulum Ca
2
+
buffer
calsequestrin).
Very small inward currents of sodium and calcium ions maintain a long plateau of
depolarization. The action potential plateau is also maintained by the activity of the
sodium-calcium exchanger, driven by transmembrane voltage and Na
+
and Ca
2
+
concentration gradients. During the plateau phase of the action potential, the Na
+
-
Ca
2
+
exchanger initially works in reverse mode, importing Ca
2
+
and exporting Na
+
,
afterward it switches to forward mode, extruding Ca
2
+
.
60
Sarcoplasmic reticulum calcium channel respond to increase in calcium ion concentration in the
subspace caused by the local sarcolemmal influx.
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