Biomedical Engineering Reference
In-Depth Information
AR-mediated cardiac frequency. Greater rates in Ca
2
+
uptake
and discharge from the sarcoplasmic reticulum can help sinoatrial nodal cells trigger
shorter depolarization waves.
The other important ion channel in cardiac pacemaking is voltage-dependent
Ca
2
+
channel Ca
V
1.3 that carries
i
Ca
,
L
current activated during the early phase of the
diastolic depolarization. In addition to
i
f
and
i
Ca
,
L
, other ionic currents contribute to
the regulation of the heart frequency, such as
i
Ca
,
T
that is almost exclusively due to
Ca
V
3.1 channels, sustained inward current, and electrogenic Na
+
-Ca
2
+
exchange
that are caused by rhythmic cortical Ca
2
+
oscillations due to spontaneous opening
of ryanodine receptors.
Sodium fluxes lead to several currents, a small fast inward Na
+
,aNa
+
-Ca
2
+
exchange , a Na
+
-K
+
pump, and a Na
+
background current. Among the voltage-
dependent K
+
currents, the outward K
+
delayed rectifier current plays a major
role in pacemaker activity. Only a small fraction of nodal cells of the sinoatrial
node yields a transient outward K
+
current. Furthermore, inward rectifier K
+
current, although observed in the atrium and part of the atrioventricular node, is
not found in the sinoatrial node, whereas it is the dominant background current in
ventriculomyocytes. Additional K
+
currents are provided by ligand-gated channels
(ATP-, adenosine-, and acetylcholine-sensitive channels).
59
Transient and long-
lasting Ca
2
+
currents have been recorded in the sinoatrial node through Ca
V
3and
Ca
V
1 channels. A stretch-activated Cl
−
channel can provide an inward background
current. The decay in outward K
+
current and inward background current leads to
initial cell depolarization to the threshold. The hyperpolarization-activated current
modulates pacemaker depolarization. Ca
2
+
current is a main factor during late
depolarization. ATP-sensitive K
+
channels are activated by ATP depletion. Na
+
-
K
+
pumps and Na
+
-Ca
2
+
exchangers influence pacemaker activity. Intracellular
ion concentrations and regulators affect the functioning of pacemaker ion carriers
(Table
6.13
).
β
maximal increase in
6.4.1.1
Parasympathetic Control
In sinoatrial cells, cholinergic signals activate Gi-coupled M
2
cholinergic receptors
that decrease cAMP level, thus suppressing activation of protein kinase-A and
slowing pacemaker rate. In addition, these receptors activate acetylcholine-activated
potassium channels (K
IR
3).
On the other hand, adrenergic cues activate
-adrenergic receptors in pacemaker
cells, thereby increasing cAMP concentration, activating PKA, and raising the
pacemaker frequency. Protein kinase-A regulates numerous proteins in nodal cells,
especially ion channels such as Ca
V
1 channel and phospholamban.
β
59
The activity of both adenosine- and acetylcholine-sensitive K
+
channels involves GTP-binding
proteins. Both ATP and Mg
2
+
are cofactors of acetylcholine-sensitive K
+
channels.
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