Biomedical Engineering Reference
In-Depth Information
Table 6.11.
Ion currents that underlie the pacemaker function. Action potential of sinoatrial
cells can be decomposed into 3 phases: slow and rapid depolarization and repolarization (
i
f
:
hyperpolarization-activated inward Na
+
and K
+
current;
i
sus
: sustained inward Na
+
(essentially)
current;
i
Ca
,
L
,
i
Ca
,
T
: inward L- and T-type Ca
2
+
currents;
i
Ca
,
b
:inwardCa
2
+
background current;
i
Kto
: transient outward K
+
current;
i
Kto
(
r
/
s
)
: rapid/slow K
+
delayed rectifier current;
i
Ksus
: sustained
K
+
current;
i
Na
,
b
:inwardNa
+
background current;
i
NaCa
:Na
+
-Ca
2
+
exchanger current;
i
NaK
:
Na
+
-K
+
pump current). The bulk background current comprises background Ca
2
+
,-K
+
,and-
Na
+
currents as well as
i
NaK
current. Background Ca
2
+
current is needed to keep the diastolic level
of the intracellular free calcium concentration. Background conductance involves also spontaneous
opening of ACh- and ATP-sensitive K
+
channels (
i
K
ACh
and
i
K
AT P
as well as Na
+
-Ca
2
+
exchangers
(
i
NaCa
). Depolarization activates Ca
V
1 channels (
i
Ca
,
L
). This event is followed by a gradual
activation of the delayed rectifier K
+
current. The major component of the delayed rectifying
K
+
current (
i
K
) in pig and rabbit sinoatrial cells are
i
Ks
and
i
Kr
, respectively. Sustained K
+
current
(
i
Ksus
) occurs through K
V
1.5 in human atriomyocytes that underlie the ultrarapid delayed rectifier
K
+
+ current (
i
Kur
). Tra
nsient outward K
+
current (
i
Kto
) is related to K
V
4.2
and K
V
4.3 sununits.
Stage
Ion currents
Slow depolarization
i
f
,
i
sus
,
i
Ca
,
T
;
i
Na
,
b
,
i
Ca
,
b
,
i
NaK
AT P
,
i
NaCaX
Rapid depolarization
i
Na
,
i
Ca
,
L
Repolarization
i
K
,
to
,
i
K
,
r
/
s
,
i
K
,
sus
,
i
Ca
,
L
Hyperpolarization-activated current, an inward depolarizing current, is due to
flux of Na
+
and other ions. Hyperpolarization-activated cyclic nucleotide-gated
cation channel HCN4 is involved in the Cl
−
-sensitive, Ca
2
+
-dependent, inward
“funny” current (
i
f
) of cardiac pacemaker activity.
57
In mouse embryos, HCN4 serves as a powerful cardiac pacemaker when it is
stimulated by cAMP [
606
]. Moreover, HCN4 channel activity initiated by cAMP is
required for embryo viability.
58
Acute stress stimulates
-adrenergic receptors that activate HCN4 via cyclic
adenosine monophosphate and provokes increased heart rate, as sinoatrial nodal
cells generate faster action potentials. However, in some circumstances, HCN4
can be dispensable for fight-or-flight response. Increase in intracellular Ca
2
+
concentration by a release from sarcoplasmic reticulum stores can contribute to an
i
f
-independent mechanism that accelerates cardiac frequency during
β
-adrenoceptor
stimulation. Ca
2
+
-calmodulin-dependent protein kinase-2 and phosphatase mod-
ulate the function of sarcoplasmic reticulum in nodal cells and cardiomyocytes.
Kinase CamK2 is a mediator of
β
β
-adrenoceptors that contributes to speeding up
57
During development, HCN4 location becomes restricted to the dorsal wall of the right atria, then
to the junction of the right atrial appendage and the superior vena cava, where the sinoatrial node
appears [
605
]. HCN4 channels are highly expressed in the adult sinoatrial node.
58
In adult mice, HCN4 channel does not contribute to cardiac pacemaking, but prevents sinus
pauses during and after adrenergic stimulation stress. In humans, the role of HCN4 channels is
different, as the cardiac frequency is higher in mice than in humans.
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