Biomedical Engineering Reference
In-Depth Information
Fig. 4 (a) Recordings of spontaneous action potentials of rabbit sinus node preparation before and
during ivabradine (3
m
M) application (modified from [
68
]). (b) Use-dependent block of
I
f
by
ivabradine (3
m
M). Current was elicited by hyperpolarizing steps to
100 at 1/6 Hz. The graph
plots the current-amplitude before and during ivabradine application.
Inset figures
show a set of
three
I
f
traces specified on the graph (
a
,
b
,
c
). (c) Schematic representation of the specific
mechanism of
I
f
channel blockade by ivabradine. Ivabradine enters the channel pore from the
intracellular side of the channel and binds to a site in the ion permeation pathway
ions for a binding site along the permeation pathway when ions flow in the outward
direction. Unblocking takes place when the current is inward during hyperpolariza-
tion. The dependence of block upon current flow was limited to HCN4, the
predominant subtype present in the mammalian SAN, and is not significant for
HCN1 [
63
,
78
,
79
]. This feature distinguishes the action of ivabradine from the
other heart rate-reducing agents that reduce
I
f
in a voltage-dependent manner
independently of the electrochemical gradient.
The anti-ischemic efficacy of ivabradine was initially established in pig and dog
models mimicking exercise-induced angina pectoris [
80
-
82
], and was later con-
firmed in patients with stable angina [
83
,
84
]. Ivabradine is, at present, the only
member of the family of specific heart rate-reducing agents to have completed
clinical assessment for the treatment of stable angina. Ivabradine has no side effects
