Single intravenous injection of CoQ<sub>10</sub> reduces infarct size in a rat model of ischemia and reperfusion injury

doi:10.4236/wjcd.2013.35A001

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World Journal of Cardiovascular Diseases, 2013, 3, 1-7 WJCD

http://dx.doi.org/10.4236/wjcd.2013.35A001 Published Online August 2013 (http://www.scirp.org/journal/wjcd/)

Single intravenous injection of CoQ10 reduces infarct size

in a rat model of ischemia and reperfusion injury*

Alexander Ivanov1#, Evgenia Gorodetskaya1,2, Elena Kalenikova1,2, Oleg Medvedev1,2

1Department of Pharmacology, Faculty of Basic Medicine, M.V. Lomonosov Moscow State University, Moscow, Russia

2Russian Cardiology Research and Production Complex, Moscow, Russia

Email: #[email protected]

Received 7 June 2013; revised 7 July 2013; accepted 22 July 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Maintenance of mitochondrial activity and antioxi-

dant features of coenzyme Q10 (CoQ10) could be an

effective background for treatment of acute myocar-

dial ischemia. Dietary uptake of CoQ10 is limited to

only a few percent. In urgent cases, parenteral admi-

nistration of CoQ10 could provide fast increase of its

plasma and myocardial levels. The aim was to evalu-

ate whether a single intravenous (i.v.) injection of so-

lubilized CoQ10 before ischemia/reperfusion (IR) could

lead to replenishment of its myocardial levels and li-

mits subsequent myocardial IR injury. Methods: 30

min prior to coronary artery occlusion rats received

i.v. solubilized CoQ10 (30 mg/kg) or saline (1 ml/kg).

After 30 min of ischemia and 120 min of reperfusion,

infarct zone of left ventricle (LV) and quantity of

CoQ10 in LV were determined. Cardiac rhythm was

monitored through the whole experiment. Results: At

the beginning of reperfusion, arrhythmias were recor-

ded in 8 (from 9) in saline and 2 (from 9) in CoQ10-

treated rats. Arrhythmias in CoQ10-treated rats arose

later (40 ± 8 sec) and had less duration (26 ± 14 sec);

14 ± 13 sec and 52 ± 17 sec in saline treated rats re-

spectively. At the end of reperfusion CoQ10 treated

rats revealed: 2 fold higher CoQ10 content in LV (p <

0.01), limitation of infarct zone by 35% (p < 0.01).

Higher levels of CoQ10 were accompanied by less in-

farct size (r = −0.77, p < 0.001). Conclusion: Single i.v.

injection of CoQ10 effectively increased its myocardial

levels and protected heart against IR injury by dimi-

nishing the size of the irreversibly damaged myocar-

dium, decreasing frequency and duration of arrhyth-

mias. The infarct zone inversely correlated with the

quantity of CoQ10 in LV.

Keywords: Coenzyme Q10; Intravenous Injection;

Myocardial Ischemia; Reperfusion Injury

1. INTRODUCTION

Myocardial infarct leads to irreversible loss of cardimyo-

cytes accompanied by deterioration of contractile func-

tion and arrhythmias. Restoration of coronary blood flow

limits necrosis of ischemic myocardium, but from the

other hand reperfusion by itself results in myocardium

damage [1]. Reperfusion initiates generation of free ra-

dicals, intracellular Ca2+-overload, fast pH changes [2].

Excessive formation of free radicals results in cell death.

Free radicals trigger inflammatory mediators such nu-

clear factor-kB sensitive to reduction/oxidative balance,

interleukin-1b, tumor necrosis factor α [3,4]. It is well

known that endogenous antioxidants such as glutathione

peroxidase, superoxide dismutase and catalase are natu-

ral defense attenuating the ischemia/reperfusion (IR) in-

jury [5]. Preservation of viable myocardium is possible

with help of cardioprotectors.

Coenzyme Q10 (CoQ10) is the endogenous compound,

essential for mitochondrial function, possesses antioxi-

dant and free radical scavenger features [6]. Long per os

administration CoQ10 is recommended for prevention and

treatment of coronary artery disease, arterial hyperten-

sion, heart failure, hyperlipidemia [7]. However, dietary

uptake of CoQ10 is limited to only a few percent [8] and

elevation of CoQ10 levels for cardioprotection requires

long preventive treatment [9]. Replenishment of CoQ10

by cells could be effective during heart surgeries (pre-

ventive administration before procedures) or as inhibi-

tion of IR injury (restoration of coronary flow after myo-

cardial infarction). Fast increase in plasma CoQ10 levels

and subsequent uptake by myocardium could be reached

with intravenous (i.v.) injection.

*The research was supported by grants 11-04-00894-a, 12-04-01246-а

(Russian Foundation of Basic Research).

#Corresponding author.

The aim of the study is to investigate the effects of

single i.v. pretreatment of solubilized CoQ10 on its myo-

OPEN ACCESS

A. Ivanov et al. / World Journal of Cardiovascular Diseases 3 (2013) 1-7

cardial level and IR injury.

2. METHODS

2.1. Animals

Animal-handling procedures followed the Guide for the

Care and Use of Laboratory Animals [10] and with prior

approval by the Bioethics committee of Lomonosov Mo-

scow State University. Healthy male Wistar rats were

housed separately in cages under a 12:12 hour light/dark

cycle at 22˚C with free access to tap water and food.

2.2. Assessment of CoQ10 Levels in Myocardium

30 min after Its Single I.V. Injection

Anesthetized rats (sodium pentobarbital, 45 mg/kg, intra-

peritoneally) with venous catheters were used. Rats re-

ceived i.v. a bolus of CoQ10 (30 mg/kg, solubilized

CoQ10 in Kudesan solution, “Akvion”, Russia)—

“CoQ10” group (n = 5) or saline (1 ml/kg, 0.9% NaCl)—

“Control” group (n = 7). 30 min after injection rats were

euthanized with 3 M KCl i.v., left ventricle (LV) samples

were collected, frozen and stored at −20˚C for further

analysis. Quantitative analysis of myocardial CoQ10 le-

vels was performed by reversed-phase HPLC with elec-

trochemical detection as described previously [9].

2.3. Assessment of Cardioprotective Effects of

Single I.V. Injection of CoQ10

Surgical preparation. Rats anesthetized as described

above were placed on a heated pad (body temperature

37.5˚C ± 0.5˚C). Continuous infusion of pentobarbitallum

sodium as maintaining narcosis (20 mg/ml, 200 μl/h) was

performed via plastic catheter in femoral vein (“KD Scien-

tific 210”, USA). To monitor blood pressure femoral ar-

tery catheter was connected to measurement equipment

“Macintosh—MacLab” (“ADInstruments”, Australia).

Cardiac rhythm was monitored with a standard lead-1

electrocardiogram (ECG) (“MacLab”, “ADInstruments”,

Australia).

Model of myocardial IR. After intubation (Inspira

Advanced Safety Ventilator, Volume Controlled 55 -

7058, Harvard Apparatus) left thoracotomy with fourth

rib removing was performed on the rat in supine position

and the ligature with an atraumatic needle was placed

around the left anterior descending coronary artery. Then

a rat was allowed to recover for 30 min. A small plastic

snare was threaded through the ligature and placed in

contact with the heart. 30 min prior to occlusion rats

received i.v. of 1 ml/kg 0.9% NaCl (group “Saline + IR”,

n = 11) or 30 mg/kg of solubilized CoQ10 (group “CoQ10

+ IR”, n = 10). The artery was occluded by applying

tension to the ligature for 30 min and reperfusion was

achieved by releasing the tension for 120 min. The sham-

operated rats (group “Saline + Sham”, n = 9) received

saline bolus after thread placement and underwent the

same study procedures except coronary artery occlusion.

Through each experiment blood pressure (BP) was mea-

sured as BPm = (BPs + 2xBPd)/3, where BPm—mean

arterial blood pressure, BPs—systolic blood pressure,

BPd—diastolic blood pressure.

Arrhythmia analysis was performed accordingly to

Lambeth Conventions [11]: 1) number of rats with pre-

sence of any ventricle tachyarrhythmia (VTA); 2) num-

ber of VTA episodes per one rat; 3) time to development

of the first VTA episode; 4) total duration of VRA epi-

sodes per one rat; 5) number of rats with lethal VTA.

Assessment of myocardial damage. At the end of re-

perfusion ligature around coronary artery was tighten

again and Evans-Blue stain (5%, 0.5 ml) was infused i.v.

to mark the risk zone (the non-stained tissue). Rats were

euthanized with 3 M KCl i.v. Heart and liver were quick-

ly removed. LV was separated, irrigated with cold water,

frozen and stored at −20˚C for further analysis. To dis-

tinguish living myocardium within risk zone frozen LV

was cut into 2 mm transverse slices, which were incu-

bated in 2% triphenyl tetrazolium chloride (TTC) in pH

7.4 buffer at 37˚C for 15 min (Figure 1). On the slices

the risk zone (ischemic area) was determined as ratio of

not-stained with Evans-Blue myocardium to total myo-

cardium area. The volume of infarct zone was calculated

as ratio of not stained with TTC myocardium (necrotic

tissue) to ischemic area.

Coenzyme Q10 assay in rat liver and LV was perform-

ed with HPLC [9]. LV myocardial level was estimated

after assessment of myocardial damage.

2.4. Data Analysis

Values are presented as mean ± SD. Statistical analysis

was performed with Statistica 8.0 (Stat Soft, Inc.). The

differences in the means between the groups were tested

using one-way ANOVA, followed by post hoc analysis

for multiple comparisons (Student-Newman-Keuls me-

thod) to test for statistical significance (p < 0.05). Cate-

gorical values were compared using Fisher test (p <

0.05).

3. RESULTS

Single i.v. bolus of solubilized CoQ10 led in 30 min to

enhanced myocardial levels by 18.5% (p < 0.05) versus

control rats. 30 rats were used in experiments for as-

sessment of single i.v. injection of CoQ10 for cardiopro-

tection. 2 rats died in “Saline + IR” group and 1 rat in

“CoQ10 + IR” group during ischemia.

Baseline values of blood pressure were similar in all

experimental groups indicating equal initial conditions

(Figure 2). Ischemia and reperfusion led to continuous

A. Ivanov et al. / World Journal of Cardiovascular Diseases 3 (2013) 1-7

5 mm

(d)

(c)

(a)

(b)

CoQ

+ Ischemia (30 min)/Reperfusion (120 min)

Saline + Ischemia (30 min)/Reperfusion (120 min)

Figure 1. Slices of LV after 30 min of ischemia, caused by coronary artery

occlusion, and subsequent 120 min of reperfusion, staining with Evans Blue

and triphenyltetrazolium: infarct rats treated i.v. with saline (a) or CoQ10 (c).

b and d—the same slices with differentiation of areas: blue stained area—

not-ischemic myocardium, red stained area—ischemic not-infarcted myo-

cardium, white stained area—necrose zone. I.v. injection of CoQ10 (30

mg/kg) 30 min prior to coronary occlusion resulted in limitation of portion

of irreversibly damaged myocardium.

Figure 2. Values of mean blood pressure measured in femoral artery of sham-operated (Saline + Sham)

and CoQ10 (CoQ10 + IR) or saline (Saline + IR) treated infarct rats. *p < 0.05 vs baseline, #p < 0.05 vs

sham-operated rats.

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A. Ivanov et al. / World Journal of Cardiovascular Diseases 3 (2013) 1-7

decrease of BPm. CoQ10-treated rats had the same profile

of BPm curve as saline treated infarct rats. Sham-oper-

ated rats had slight decrease of BPm during the whole

experiment, but without statistical significance within

group, which possibly could be related with continuous

infusion of anesthetic.

During ischemia 10 rats of 11 in group “Saline + IR”

had episodes of arrhythmias. Pretreatment with CoQ10 had

no impact on arrhythmias characteristics during ischemia

(Table 1). However, at the beginning of reperfusion ar-

rhythmias occurred in 8 of 9 animals in the “Saline + IR”

and in 2 of 9 animals in “CoQ10 + IR”. In “CoQ10 + IR”

group reperfusion arrhythmias appeared later and had

shorter duration (Table 1).

At the end of reperfusion infarct size of saline treated

infarct rats was 47% ± 6%. Single i.v. CoQ10 injection

prior to coronary occlusion limited irreversible myocar-

dial cell injury to 31 ± 7%. These groups had no statistical

significance in the volume of area at risk that pointed to

equal baseline ischemia conditions (Figures 1 and 3).

Figure 3. Myocardial infarct size quantification presented as

the percentage of the area at risk. Assessment was performed

after pre-treatment with i.v. injection of CoQ10 (“CoQ + IR”) or

saline (“Saline + IR”) 30 min prior to a regional myocardial

ischemia (30 min) and reperfusion (120 min). I.v. injection of

CoQ10 prior to coronary occlusion resulted in reduced portion

of irreversibly damaged myocardium by 35% in comparison

with saline-treated rats (p < 0.01).

I.v. injection of CoQ10 led to enhance levels of CoQ10

in myocardium and liver: 180 min after administration of

CoQ10 its level was increased in LV by 210% (p < 0.01),

in liver by 2081% (p < 0.01) in comparison with sham-

operated rats (Figure 4). There was no difference in

CoQ10 tissue levels between saline-treated infarct rats

and sham-operated rats. The relationship between infarct

size and myocardial content of CoQ10 in LV of both in-

farct groups was revealed: the higher levels of CoQ10

were accompanied by less quantity of damaged myocar-

dium (r = −0,77, p < 0.001; Figure 5).

Figure 4. Myocardial and liver CoQ10 levels measured 180 min

after single i.v. injection of CoQ10 (CoQ10 + IR) or saline (Sa-

line + IR) and following ischemia-reperfusion (IR) relatively to

sham-operated animals (Saline + Sham). Increased content of

CoQ10 after its single i.v. injection 30 min prior to coronary

artery occlusion were observed in LV and liver. *p < 0.05 vs

“Saline + Sham”, #p < 0.05 vs “Saline + IR”. Percentages were

calculated relatively to sham-operated animals.

Table 1. Cardiac rhythm alterations in rats underwent myocardial ischemia/reperfusion.

Ischemia Reperfusion

Saline + IR CoQ10 + IR Saline + IR CoQ10 + IR

Rats used, n 11 10 9 9

Rats with lethal VTA* (n) 2 1 0 0

Rats with presence of any VTA (n) 8 8 8 2

Number of VTA episodes per one rat 6.7 ± 1.4 6.5 ± 2.2 5.1 ± 1.7 6.5 ± 3.5

Time to development of the first VTA episode from the

start of ischemia or reperfusion, sec 364 ± 55 374 ± 62 14 ± 13 40 ± 8

Total duration of VTA episodes per one rat, sec 103 ± 41 92 ± 58 52 ± 17 26 ± 14

*VTA—ventricle tachyarrhythmia.

A. Ivanov et al. / World Journal of Cardiovascular Diseases 3 (2013) 1-7 5

Figure 5. Correlation between CoQ10 levels in LV of infarct

rats and LV infarct size (r = −0.77, p < 0.0001) was calculated.

CoQ10 or saline was injected 30 min prior to coronary artery

occlusion and following regional myocardial ischemia (30 min)

and reperfusion (120 min).

4. DISCUSSION

The most effective way to limit the portion of irreversi-

bly damaged cardiomyocytes is rapid and complete res-

toration of coronary blood flow. However, reperfusion

itself contributes to myocardial injury. The presented re-

sults demonstrated that single i.v. injection of CoQ10 re-

sulted in replenishment of its levels in myocardium, which

was accompanied by limitation of IR injury.

Tissue preservation can be achieved if the restoration

of blood flow is accompanied by additional treatment as

it is presented in our study by preventive i.v. administra-

tion of CoQ10.

Previously, on the rat model of MI induced by coro-

nary artery ligation, it was shown the limitation of infarct

size by 40% and limitation of myocardial hypertrophy as

a result of long preventive (3 weeks) and post-infarct (3

weeks) per os administration of CoQ10. In that study,

treatment of CoQ10 during 6 weeks led to elevation of its

myocardial levels by 20% - 30%. [9] In the present study

single i.v. CoQ10 injection resulted in a similar increase

of its levels in myocardium 30 min after administration.

Therefore, this time was chosen for CoQ10 injection on

the model of myocardial IR.

Free radicals are generated in postischemic myocar-

dium and when exceeding the ability of the cellular na-

tive free radical scavenging features it lead to cardio-

myocytes dysfunction and death. CoQ10 protects myo-

cardium from IR injury due to bioenergetics and anti-

oxidant properties [6]. CoQ10 neutralizes the excessive

formation of reactive oxygen species by suppression of

NADPH oxidase expression [12]; scavenges lipid perox-

ides [13]; prevents nitrative stress by inhibition of excess

NO production [14]. Inhibition of opening mitochondrial

permeability transition pore, induced by reactive oxygen

species, is one of the possible mechanisms of cardiopro-

tective effect of CoQ10 [15-18]. Protective mechanism of

CoQ10 can be associated with multiple anti-inflammatory

effects by influencing the expression of NFkB1-depen-

dent genes [19] and non-specific restoration of damaged

membranes [20].

CoQ10 is recommended for long-term adjunctive ther-

apy for various cardiovascular disorders, as hypotensive

and cardioprotective agent [21]. Correlation between tis-

sue levels of CoQ10 and severity of cardiovascular patho-

logy is found in man [7,21-23]. Low levels of CoQ10 are

observed in 70% - 75% of patients with heart disease and

strong correlation is estimated between reduced levels of

CoQ10 and mortality in patients with congestive heart fai-

lure [24].

However, CoQ10 bioavailability after per os admini-

stration is extremely low [8]. In urgent cases, it is neces-

sary to increase myocardial CoQ10 content rapidly, which

could be reached via i.v. injection. Few experimental stu-

dies explored that intracoronary or i.v. administration of

CoQ10-loaded liposomes increased its myocardial levels,

limited zone of IR injury and maintained heart function

[20,25-27]. Cardioprotective effects of i.v. CoQ10-loaded

liposomes administration before ischemia/reperfusion

were evaluated mostly on isolated hearts [25-27] and a

few in vivo studies were conducted [20]. In that studies it

was shown that CoQ10 administration improved recovery

of function (diastolic pressure), aerobic efficiency and

creatine kinase activity after reperfusion [26]; protected

endothelial-dependent and endothelial-independent vaso-

dilation after IR [25]; improved recovery of diastolic

pressure and mytochondrial function at the end of IR

[27]; limited infarct size [20].

In our in vivo study, it was shown at the first time that

i.v. injection of solubilized CoQ10 protected myocardium

against subsequent IR as effective as liposome forms. I.v.

injection of solubilized CoQ10 provided quickly elevation

of its plasma levels and tissue uptake. Liver had a high

capacity to uptake CoQ10 and could contribute signifi-

cantly to maintenance of plasma and myocardial CoQ10

concentrations for a long period. CoQ10 myocardial lev-

els inversely correlated to the infarct size. Antiarrhyth-

mic effect of CoQ10 revealed in the present study was

also reported in previous studies [21,28].

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