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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 5, September/October 2019
268
AFRICA
Effects of atorvastatin on time-dependent change of fast
sodium current in simulated acute ischaemic ventricular
myocytes
Hongshi Li, Zheng Wan, Xiaolong Li, Tianming Teng, Xin Du, Jing Nie
Abstract
Introduction:
Our previous experiments showed that the tran-
sient sodium current (
I
Na
) was abnormally increased in early
ischaemia and atorvastatin could inhibit
I
Na
. The aim of this
study was to observe the time-dependent effects of simulated
ischaemia on
I
Na
and characterise the direct effects of atorvas-
tatin on ischaemic
I
Na
.
Methods:
Left ventricular myocytes were isolated fromWistar
rats and randomly divided into two groups: a control group
(normal to simulated ischaemia) and a statin group (normal
to simulated ischaemia with 5 μmol/l atorvastatin). The
I
Na
was recorded under normal conditions (as baseline) by whole-
cell patch clamp and recorded from three to 21 minutes in the
next phase of simulated ischaemic conditions.
Results:
In the control group, normalised
I
Na
(at –40 mV)
was increased to the peak (1.15
±
0.08 mA) at three minutes
of ischaemia compared with baseline (0.95
±
0.04 mA,
p
<
0.01), it subsequently returned to baseline levels at nine
and 11 minutes of ischaemia (0.98
±
0.12 and 0.92
±
0.12
mA, respectively), and persistently decreased with prolonged
ischaemic time. In the statin group, there were no differences
between baseline and the early stages of ischaemia (0.97
±
0.04 mA at baseline vs 0.92
±
0.12 mA in ischaemia for three
minutes,
p
>
0.05).
Conclusion:
Our results suggest that, in the early stages of
ischaemia, changes in
I
Na
in ventricular myocytes are time-
dependent, showing an initial increase followed by a decrease,
while atorvastatin inhibited the transient increase in
I
Na
and
made the change more gradual.
Keywords:
ventricular myocytes, sodium, ventricular arrhythmia,
membrane potential, statin
Submitted 11/7/18, accepted 25/4/19
Published online 28/7/19
Cardiovasc J Afr
2019;
30
: 268–274
www.cvja.co.zaDOI: 10.5830/CVJA-2019-021
Clinically, acute ischaemia is one of the common causes of
malignant ventricular arrhythmias.
1
A retrospective study showed
that 7.5% of patients with acute myocardial infarction developed
ventricular arrhythmias, most of which (78%) occurred within
the first 48 hours of ischaemic symptoms,
2
suggesting that
electrical activities are very unstable in the early stage of
ventricular ischaemia.
Sodium current (
I
Na
) is the starting current of the action
potential and affects the shape and conduction of the action
potential.
3
It is one of the most common targets to cause
and treat arrhythmias. Animal experiments found that in an
aconitine-induced arrhythmia model,
4
increased
I
Na
could lead to
pre-contraction and even ventricular arrhythmias. Therefore
I
Na
plays an important role in arrhythmogenesis.
Previous studies have shown that
I
Na
would be decreased
or Nav1.5, which is the ion channel protein of
I
Na
, would be
downregulated in the ischaemic condition.
5,6
However in our
pre-experiment of simulated ischaemia, peak
I
Na
was transiently
increased in the very early stage of ischaemia (three to five
minutes), suggesting unstable early ischaemic electrical activity.
As the decreased
I
Na
demonstrated in ischaemia or simulated
ischaemia usually needs myocyte exposure for more than 10
minutes,
5
this indicates that time is a key factor affecting
I
Na
in
the ischaemic state.
On the other hand, as the basic therapeutic agents of
acute coronary syndrome, statins may reduce the incidence of
ischaemic ventricular arrhythmias
7,8
and can prevent sudden
cardiac death,
9
as well as other cardiovascular events. However,
the mechanisms are controversial. One view is that electrical
protection from the statin is secondary to a decrease in low-density
lipoprotein cholesterol, whereas another view is that statins act
as an upstream protection on the basis of pleiotropic effects.
10
In addition, Vaquero
et al
.
11
confirmed that atorvastatin and
simvastatin had an inhibitory effect on atrial plateau currents
[hKv1.5 and Kv4.3 channels, while
I
Ca,L
(L-type calcium current)
could also be blocked by simvastatin acid] at the cellular level.
Similarly, there is a direct electrical effect on the
I
Na
of ventricular
myocytes in the early stage of ischaemia only.
We assumed that the effect of ischaemia on
I
Na
was time-
dependent, that
I
Na
may be transiently increased during the first
10 minutes of ischaemia, and that atorvastatin could inhibit this
phenomenon. Therefore we used a patch-clamp technique to
observe the time-dependent effects of simulated ischaemia on
I
Na
in ventricular myocytes by setting the observation interval
to two minutes. In addition, we also applied atorvastatin on the
above basis, in order to observe its direct effect on
I
Na
in the early
ischaemic condition.
Methods
Thirty Wistar rats (300
±
50 g, male and female) were purchased
from the Chinese Academy of Medical Sciences Institute of
Department of Cardiology, Tianjin Medical University General
Hospital, Tianjin Medical University, Tianjin 300070, PR China
Hongshi Li, MD
Zheng Wan, MD,
wanzh_md@126.comXiaolong Li
Tianming Teng
Xin Du, MD
Jing Nie, MD