Biomedical Engineering Reference
In-Depth Information
retinal HCN channels [
70
-
72
]. These blocking characteristics on myocardial
I
k
and
retinal
I
h
limit the possible clinical applications of zatebradine. Cilobradine
appeared to be more specific than zatebradine without having any apparent effect
on action potential shape when tested at low concentration on guinea-pig Purkinje
fibers [
62
]. Experiments showed that cilobradine reduced heart rate in the rabbit
without producing any negative inotropic effect, and reduced angina pectoris [
73
].
On that account, cilobradine might be an interesting candidate molecule for thera-
peutic approaches to combat cardiac diseases.
6.3
Ivabradine (S 16257)
Given that an elevated heart rate correlates with increased mortality in some cardiac
diseases such as angina and heart failure, lowering heart rate is beneficial because of
the reduced associated demand for oxygen and improvement in diastolic
myocardial perfusion. To this extent, specific heart rate-reducing agents targeting
f-channels were developed for their ability to slow heart rate by suppressing the rate
of diastolic depolarization with limited side effects on action potential duration and
inotropic state [
74
]. Among these “pure bradycardic agents”, ivabradine (S 16257)
[
75
], a compound with highly specific f-channel binding properties and typical
reduction of
I
f
conductance, was the first
I
f
blocker used in clinical development and
therapeutic application (see Fig.
3
for its chemical structure).
Patch-clamp studies on rabbit sinus node cells showed a selective use-dependent
block of
I
f
in the same concentration range as that reducing the slope of spontaneous
diastolic depolarisation [
76
,
77
] (see Fig.
4a, b
). Also, for concentrations close to
the IC
50
of
I
f
inhibition, no effect was observed on I
Ca,L
,I
Ca,T
, and I
Kr
, suggesting a
specific action of ivabradine on
I
f
in sinoatrial cells. In general, the ivabradine effect
is comparable to that of zatebradine and cilobradine, since all of these drugs alter
I
f
by decreasing maximal conductance without changing the voltage dependence of
current activation. This heart rate-reducing agent interacts with f-channels from the
intracellular side [
76
]. Elegant studies performed on f-channels in SA node cells
have provided further evidence for the precise blocking mechanism of ivabradine
(for details see [
77
]). Ivabradine is an open-channel blocker with a block exerted
when channels deactivate on depolarization (see Fig.
4c
). This use-dependent
property of ivabradine corresponding to drug accumulation during repetitive activ-
ity is clinically useful with respect to the better efficiency obtained at higher heart
rates, when a bradycardic action is expected. The voltage-dependence of the block
is a major property of ivabradine block facilitation by channel open/close cycling,
with the block being stronger at depolarized voltages. The block of f-channels from
the intracellular side and a better efficiency obtained at depolarized than at
hyperpolarized voltages result from the chemical nature of ivabradine (positively
charged at physiological pH by the presence of a quaternary ammonium ion). The
action of ivabradine block can be described as “current”-dependent in that
ivabradine blocks current flow by entering the pore and competing with permeating
