Biomedical Engineering Reference
In-Depth Information
have been shown to modulate
I
f
via their modulation of intracellular cAMP levels
(see [
5
,
16
] for reviews). It has been reported that adenosine A1 receptors in
thalamic and mesopontine neurons, and
-opio¨d receptors in nodose ganglion
cells, are negatively coupled to adenylate cyclase, inducing a shift in the
I
h
activa-
tion curve [
41
,
42
]. As is the case in neurons,
I
f
in the heart is enhanced by the
stimulation of histamine H2 receptors and decreased by the action of adenosine [
43
,
44
]. The current can also be regulated in both brain [
45
] and heart [
46
] by nitric
oxide. This gas elevates cGMP levels by stimulation of soluble guanylate cyclase.
Subsequent studies have suggested that
I
h
activity may also be regulated by protein
phosphorylation and dephosphorylation [
47
]. A number of protein kinases have
been implicated, including PKA [
48
,
49
], PKC [
48
], and tyrosine kinases [
50
,
51
]. It
has also been shown that triiodothyronine (T3) enhances the pacemaker current in
SA node cells isolated from rabbit heart by increasing maximal conductance
without inducing a shift of the activation curve, signifying an overexpression of
f-channels that possibly leads to the acceleration of the resting heart rate observed
in hyperthyro¨dism [
52
]. This overexpression has been corroborated by Pachuki
et al. [
53
].
m
6 Pharmacology
6.1 Alinidine (ST567) and Clonidine
Alinidine (see Fig.
3
for chemical structure) is an antiarrhythmic drug that acts
primarily on the sinus node. This
N
-allyl derivative of clonidine, a well-known
a
2 adrenoreceptor agonist, is a specific bradycardic agent. In the rabbit SAN,
alinidine blocks
I
f
in the micromolar range [
54
]. This inhibition is associated with
a reduced slope of slow diastolic depolarization and slightly prolonged action
potential duration [
55
]. Experiments performed on sheep Purkinje fibers revealed
that
I
f
inhibition by alinidine is a consequence of a decreased maximal conductance
associated with a shift in the activation curve toward more negative potentials.
These effects do not appear to be use- or frequency-dependent [
56
]. At present,
despite its bradycardic action, alinidine is not used in therapy since it is not specific
enough for
I
f
. Indeed, this drug also has inhibitory properties on other ionic currents
as in the case, for example, of potassium and calcium conductances [
54
].
Recently, the
2 adrenoreceptor agonist clonidine was shown to have a direct
inhibitory effect on
I
f
[
57
]. In that study, using knockout mice for the three
a
a
2 adrenoreceptors, the authors showed that clonidine induced bradycardia.
Electrophysiological measurements in SAN cells confirmed that clonidine lowered
the frequency of pacemaker potentials through
I
f
inhibition with an IC
50
around
3
M. HCN2 and HCN4 heterologously expressed in HEH293 cells present a
similar sensitivity to clonidine, with an IC
50
of 10
m
M. This inhibition was
associated with a shift in the activation curve toward more negative potentials.
m
