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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 6, November/December 2015
246
AFRICA
the left ventricular (LV) maximum blood pressure (101.7
±
2.2
vs123.4
±
4.5 mmHg in the controls;
p
<
0.01), but not the LV
end-diastolic blood pressure. Mg
2+
pre-treatment did not reverse
or worsen the ISO-induced decrease in the LV maximum blood
pressure (107.4
±
6.4 mmHg; compared with the controls,
p
=
0.34; compared with ISO-treated,
p
=
0.98), or affect the LV
end-diastolic blood pressure. ISO significantly decreased the
minimal rate of LV pressure change (dP/dt min; –5479
±
203 vs
–7921
±
435 mmHg/s in controls;
p
<
0.001), but not the maximal
rate of LV pressure change (dP/dt max). Mg
2+
pre-treatment did
not reverse the ISO effects on dP/dt min or change the dP/dt
max. Mg
2+
pre-treatment did not affect diastolic duration, but
decreased the systolic duration in ISO-treated rats. Mg
2+
alone
did not alter LV blood pressures, LV maximal/minimal dP/dt, or
systolic/diastolic duration.
Effects of ISO and Mg
2+
on markers of lipid
peroxidation
Plasma CD and TBARS were measured 24 hours post-treatment
to evaluate the effects of ISO and Mg
2+
on oxidative stress.
Fig. 4 shows that ISO did not alter CD and TBARS plasma
concentrations significantly, suggesting that infarction occurred
early, in which case the measured concentrations of CD and
TBARS may not have reflected the concentrations of these
markers at the time of infarction. In addition, Mg
2+
pre-treatment
prior to ISO or treatment with Mg
2+
alone did not alter the
concentrations of these markers.
Discussion
Despite theadvances inmodernmedical therapy, themortality rate
due to MI remains high. In this study, we used a catecholamine-
induced MI model and found that Mg
2+
prophylaxis did not alter
the infarct size, as quantified by TTC staining. Mg
2+
also had no
effect on the ISO-induced ventricular hypotension or disruption
of electrophysiological signals. Therefore, while Mg
2+
did not
worsen MI, the preconditions for its therapeutic indications
remain unclear.
Several animal models have been developed to mimic human
MI
in vivo
, but the lack of reliability, reproducibility or survival
remains a problem. Surgical methods such as ligation and
cauterisation of coronary arteries produce well-demarcated
infarcts compared to the more global infarcts due to ISO (Fig.
1). However, surgical techniques are invasive and associated
with post-operative mortality rates as high as 40–50% within 24
hours, and the infarct sizes also vary.
39
Pharmacological methods such as ISO-induced MI are
non-invasive and the drug doses can be adjusted to minimise
mortality. However, the methods produce diffuse global infarcts
of variable sizes. The ISO-induced MI disease model mimics
cardiovascular stress disorders that not only produce infarction,
but in which intracellular Mg
2+
deficiency may play a role.
31,32
Nevertheless, in our study, Mg
2+
pre-treatment did not alter
infarct size, suggesting a lack of Mg
2+
cardioprotection, as also
reported in other studies,
13,14
and at the same time, contradicting
the results of some previous studies.
7-11
The moderate dose of ISO used in our study was optimal to
induce infarcts and to minimise mortality in our rats. However,
the relatively smaller infarcts induced (~15% of the whole
ventricular tissue), compared to coronary ligation models (~50%
of the localised region at risk),
7,8,11
may have made it more difficult
to identify any mild effects of Mg
2+
, especially with the presence
of baseline infarcts that are attributable to tissue handling.
The protective effects of Mg
2+
may depend on the dose,
bioavailability, and the timing of administration as well as on the
type of experimental protocol used. In the experimental studies
showing Mg
2+
protection, Mg
2+
was given during reperfusion,
7-11
which is a different protocol from the one used in our study. In
some studies, Mg
2+
was protective only when administered early
during reperfusion.
8,9
By contrast, Mg
2+
may have preconditioned
the myocardium through the activation of ATP-dependent K
+
channels,
22
and also protected it in a cellular model of ischaemia
alone without reperfusion.
25
In our study, serum Mg
2+
was not measured, making it
uncertain whether adequate prophylaxis may have been achieved
at the onset of MI. However, a similar dose of Mg
2+
used in
other studies in rats achieved neuroprotection,
35,40
and lower
doses used in guinea pigs provided cardioprotection.
41
In studies
where repeated doses of Mg
2+
were used, it was re-administered
only after four hours,
40
a longer period than when ISO was given
in our study. Furthermore, in guinea pigs, Mg
2+
cardioprotection
occurred even if the insult was given at a time when Mg
2+
levels
in the plasma and heart tissue were no longer significantly
elevated,
41
indicating that the downstream cellular effects from
the adequate initial exposure to Mg
2+
may outlast the real
elevation of Mg
2+
in the tissue or plasma.
The low-voltage ECG induced by ISO administration was
possibly due to the infarct-related loss of tissue, whereas the
presence of pathological Q waves are indicative of an evolving
MI.
38
We however did not observe an elevation of the ST segment,
in contrast towhat would be expected in acute infarction, andwhat
has been reported by others.
42
The ST segment in rats is difficult
to assess because the end of the QRS complex merges with the
T wave (Fig. 2), thereby overshadowing the isoelectric portion.
43
Therefore, the decreases in the S- and T-wave amplitudes by ISO
and Mg
2+
in our study may in fact reflect ST-segment modulation.
Overall, Mg
2+
pre-treatment did not reverse the electrical changes,
in keeping with the unaltered infarct size.
Table 2. Summary data on the effects of chemical treatments on ECG parameters
ECG parameter
Treatment groups
Control
(
n
=
8)
ISO
(
n
=
9)
ISO + Mg
2+
(
n
=
10)
Mg
2+
(
n
=
8)
Heart rate (bpm) 406.9
±
9.5 416.6
±
14.2
418.4
±
7.2
405.8
±
15.4
P amplitude (mV) 0.184
±
0.010 0.165
±
0.009
0.167
±
0.014
0.162
±
0.013
Q amplitude (mV) –0.024
±
0.008 –0.111
±
0.020** –0.107
±
0.021* –0.025
±
0.008
R amplitude (mV) 0.590
±
0.056 0.193
±
0.030*** 0.216
±
0.031*** 0.619
±
0.044
S amplitude (mV) –0.300
±
0.073 –0.129
±
0.060 –0.050
±
0.022* –0.248
±
0.054
T amplitude (mV) 0.123
±
0.010 0.087
±
0.009* 0.023
±
0.018*** 0.134
±
0.008
ST height (mV)
0.054
±
0.032 0.081
±
0.008
0.061
±
0.007
0.109
±
0.014
P duration (s)
0.184
±
0.010 0.164
±
0.009
0.166
±
0.015
0.161
±
0.013
PR interval (s)
0.046
±
0.003 0.050
±
0.003
0.046
±
0.002
0.050
±
0.002
QRS interval (s) 0.014
±
0.001 0.014
±
0.001
0.013
±
0.001
0.015
±
0.001
QT interval (s)
0.061
±
0.003 0.046
±
0.005
0.056
±
0.007
0.054
±
0.002
QTc (s)
0.157
±
0.009 0.123
±
0.016
0.148
±
0.017
0.140
±
0.004
T
peak-
T
end
(s)
0.040
±
0.003 0.025
±
0.003* 0.024
±
0.003* 0.030
±
0.001
ECG parameters were sampled from lead II recordings. QTc was calculated using
Bazett’s formula. Values are mean
±
SEM; *
p
<
0.05; **
p
<
0.01 and ***
p
<
0.001 (treat-
ment vs control).