CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 6, November/December 2011
AFRICA
319
The effect of mebudipine on cardiac function and
activity of the myocardial nitric oxide system in
ischaemia–reperfusion injury in rats
R GHYASI, M MOHAMMADI, R BADALZADEH, B RASHIDI, G SEPEHRI
Abstract
Objectives:
Previous studies have suggested that failure of the
synthesis of nitric oxide is involved in the pathophysiology of
myocardial ischaemia–reperfusion injury. In this study, we
investigated the effect of mebudipine, a new dihydropyridine
calcium channel blocker, on cardiac function and activity of
the myocardial nitric oxide system in ischaemia–reperfusion
injury in isolated rat hearts.
Methods:
Forty male Wistar rats (250–300 g) were divided
into four groups (
n
=
10): sham, control, vehicle and drug
groups. The animals were anesthetised with sodium pento-
barbital (6 mg/kg intraperitoneal). The hearts were quickly
removed, mounted on a Longendorff apparatus and perfused
with Krebs-Henseleit solution under constant pressure at
37°C. After 20 min stabilisation period, the ischaemic groups
received 30 min global ischaemia and 120 min reperfu-
sion. For the drug and vehicle groups, before ischaemia
the hearts were perfused with mebudipine (10
-3
µ
M) or
ethanol-enriched solution (0.01%) for 25 min, respectively.
Myocardial function, and creatine kinase, lactate dehydog-
enase and total nitric oxide metabolite (nitrite and nitrate)
levels were analysed.
Results:
Cardiac functions had recovered significantly in
the mebudipine group (
p
<
0.01). Furthermore, mebudi-
pine remarkably reduced the levels of lactate dehydogenase
and creatine kinase in the coronary effluent and increased
myocardial nitric oxide metabolite levels compared with the
control group.
Conclusion:
Our results indicate that mebudipine reduced
the intensity of myocardial ischaemia–reperfusion injury,
and that activation of the myocardial nitric oxide system
played an important role in this regard.
Keywords:
ischaemia, nitric oxide, reperfusion, mebudipine,
isolated heart
Submitted 16/1/10, accepted 31/8/10
Cardiovasc J Afr
2011;
22
: 319–323
DOI: 10.5830/CVJA-2010-078
Early reperfusion is an absolute prerequisite for the survival of
ischaemic myocardium. However, reperfusion has been consid-
ered a double-edged sword because reperfusion itself may lead to
additional accelerated myocardial injury beyond that generated
by ischaemia alone. This results in a spectrum of reperfusion-
associated pathologies, collectively called reperfusion injury.
1
The underlying pathophysiological mechanisms of ischaemia–
reperfusion have not been fully elucidated. It has been suggested
that an overproduction of oxygen-derived free radicals
2
and
intracellular calcium overload during the first minutes of reflow
might be involved.
3
However, oxygen-derived free radicals
and hypercontracture due to calcium overload are not the only
candidates responsible for reperfusion injury. Other factors of
importance in the pathogenesis of reperfusion injury include
platelet- and neutrophil-mediated injury, the renin–angiotensin
system and the complement activation.
2
It is known that nitric oxide (NO) is involved in the regulation
of myocardial contractility and contributes to myocardial protec-
tion in ischaemic pre- and postconditioning.
4
NO plays multiple
roles in the cardiovascular system, mediating a number of physio-
logical and pathophysiological processes. In smooth muscle
cells, NO activates guanylate cyclase by a hem-dependent
mechanism, resulting in an increased concentration of guanosine
3
′
,5
′
-cyclic monophosphate (cGMP), which leads to a decreased
intracellular concentration of Ca
2+
and subsequent relaxation of
the vessels.
5
Reduced basal availability of NO and impairment of endothe-
lial NO-dependent mechanisms due to dysfunction of the
normally protective endothelium may be involved in the patho-
genesis of several cardiovascular diseases, including atheroscle-
rosis, hypertension, heart failure, coronary heart disease, arterial
thrombotic disorders and stroke.
6
In cardiomyocytes, the NO/
cGMP pathway is involved in the inhibition of Ca
2+
influx by
cGMP-dependent phosphorylation of L-type Ca
2+
channels,
7
antagonism of the effects of
b
-adrenergic stimulation, and
decrease in myocardial contractility and heart rate, as well as in
reduction in myocardial oxygen consumption and opening of the
sarcolemmal K
ATP
channels. Reduced Ca
2+
current may alleviate
Ca
2+
overload associated with acute myocardial ischaemia as one
of the major mechanisms of ischaemic injury.
5
Ca
2+
channel antagonists are used for a variety of diseases,
including heart and coronary disease and have become one of the
standard first choices of drugs for essential hypertension. They
Physiology and Neuroscience Research Centre, Faculty of
Medicine, Kerman University of Medical Sciences, Kerman,
Iran
R GHYASI, MSc
G SEPEHRI, PhD
Department of Physiology, Drug Applied Research Centre,
Faculty of Medicine, Tabriz University of Medical Sciences,
Iran
M MOHAMMADI, PhD,
R BADALZADEH, PhD,
The Young Researchers Club of Tabriz, Islamic Azad
University, Tabriz, Iran
R BADALZADEH, PhD
Department of Anatomy, Faculty of Medicine, Isfahan
University of Medical Sciences, Isfahan, Iran
B RASHIDI, PhD
