Comparative Study BetweenNebivolol And Lisinopril In Experimentally Induced
Myocardial InfarctionIn Rats
Mohamed El. Mansour, Mahmoud M. Elfouly, Omaima M. Abd Allah and Abeer A.Eldeeb
Department of Pharmacology & Therapeutics, Benha Faculty of Medicine, Benha University.
Abstract
Myocardial infarction (MI) is an irreversible injury or subsequent necrosis of myocardial
cells due to interruption of blood supply to a part of the heart.The present study was designed to
compare the benificial therapeutic effects of nebivolol and lisinopril on the progression of
myocardial infarction in a rat model of isoprenaline induced acute myocardial infarction. Animals
were classified intonormal control group (received normal saline), Myocardial infarcted group (s.c
injection ofisoprenaline at a dose of 150mg/kg/day diluted in 2ml of saline on two consecutive days
with an interval of 24 hours between application, Nebivolol treated infarcted group(0.5mg/kg p.o.)
once daily for 4 weeks after induction of MI, Lisinopril treated infarcted group (20mg/kg p.o.) once
daily for 4 weeks after induction of MI. The obtained results in the current work revealed that
induction of myocardial infarction by isoprenaline resulted in significant increase heart rate,
decrease mean arterial blood pressure and increase T-wave voltageat the end of the study, while
administration of nebivolol and lisinopril to myocardial infarcted rats for 4 weeks resulted in
decrease of heart rate, decrease mean arterial blood pressure, decrease in T-wave voltageand
improved histopathological changes of heart as compared to infarcted untreated rats.
Conclusively:Administration of Nebivolol and lisinopril immediately afteroccurance of acute
myocardial infarction prevent progression of the disease and improve pathological changes
occurred in the heart.
INTRODUCTION:
Cardiovascular diseases cause 12 million deaths throughout the world each year,
according to the third monitoring report of the World Health Organization (Gharacholou et al.,
2011). Risk factors for CAD include smoking, hypertension, dyslipidemia, diabetes mellitus, obesity,
mental stress and depression.The major cause of acute myocardial infarction is coronary
atherosclerosis with superimposed luminal thrombus, which accounts for more than 80 percent of
all infarcts. Myocardial infarctions resulting from non atherosclerotic diseases of the coronary
arteries are rare (Ohtani et al., 2006). Disruption of plaques is considered to underlie most acute
coronary syndrome (Boersma et al, 2003). Nebivolol has been shown to have protective effects in
experimental models of experimental ischemia and reperfusion injury (Vandeplassche et al., 1991).
In humans, it was shown that administration of nebivolol, as compared with atenolol, more
effectively improves exercise tolerance and time to onset of angina during exercise test (Van Bortel
et al., 1992). Nebivolol and carvedilol have been shown to increase coronary flow reserve in
patients with ischemic heart disease and non ischemic dilated cardiomyopathy more consistently
than other β-blockers,which is expected to be associated with a clinically relevant reduction in
ischemic threshold (Galderisi et al., 2008).It has been suggested that early beta-blocker treatment
decreases myocardial oxygen consumption, favorably influences coronary blood flow, reduces
infarct size and improvements in ejection fraction (Halkin et al., 2004). Studies with nebivolol have
showed that cardio-protective effects were not only mediated by their adrenergic receptor blocker
activity, but also by other mechanisms such as antioxidant activity and anti-neutrophil effects (Yang
et al., 2003 and Celik et al., 2006).The mechanism by which lisinopril improves the outcome
following an acute MI involves reduced peripheral vascular resistance, improved perfusion and a
direct action on the myocardium. Addition of an ACE inhibitor within the initial 24 hour period
after an acute MI, attenuates LV dilatation, improves perfusion and inhibition of angiotensin II
production reduces the workload on the heart, and inhibits collagen production (Maki Urushihara
and Hiroyuki Kobori, 2011).ACE inhibitors reduce ischaemic events, mortality and hospital
admissions (heart failure or further MI) in this group of patients. There is good evidence to suggest
that they should be started early (Pedrazzini et al., 2008).
MATERIALS AND METHODS:
Myocardial infarction was induced in rats by subcutaneous injection of isoprenaline at a dose of
150mg/kg/day diluted in 2ml of saline on two consecutive days with an interval of 24 hours between
application.
Animal groups: each group contained 6 rats.
Group (I): Normal control group (given saline only). Group (II): Myocardial infarction group.
Myocardial infarction induced by subcutaneous injection of Isoprenaline at a dose of 150mg/kg/day
diluted in 2ml of saline on two consecutive days with an interval of 24 hours between application
(Lobo Filho et al., 2011).Group (III):Nebivolol treated infracted group: The rats of this group
given nebivolol at a dose of 0.5 mg/kg p.o. once daily for 4 weeks after 2 days of administration of
isoprenaline (Mercanoğlu et al., 2010).Group (IV):Lisinopril treated infracted group: The rats of
this group given Lisinopril at a dose of 20 mg/kg p.o. once daily for 4 weeks after 2 days of
administration of isoprenaline(Christian et al., 1996).
STATISTICAL ANALYSIS
All values were expressed as mean ± S.D. Data were statistically analyzed using one way ANOVA
followed by Tukey's multiple comparison tests. The p value of less than 0.05 was considered to be
statistically significant.
RESULTS:
Effect of nebivolol versus lisinopril on myocardial infarction parameters in rats after 4 weeks.
Data in table (1) show that untreated infarcted group resulted in significant increase (489.3± 13.5)
in HR in comparison to control group while nebivolol and lisinopril treated group show significant
decrease (408.8±10.8and 424.6± 12.2) in HR in comparison to infracted untreated group.
Table 1: Effects of nebivolol and lisinopril on heart ratein isoprnaline-induced myocardial
infarction in rats at the end of study (after 4 weeks).
group
parameter
Heart rate
Control
Untreatedinfarcted
Nebivolol treatedLisinopril treated
group
group
group
a
b
405.5± 15.2
489.3± 13.5
408.8±10.8
424.6± 12.2b
Data represented as Mean ± SEM (n = 6).
a: Significant difference from control group at p<0.05.
b: Significant difference from infarcted group at p<0.05.
Data in table (2) show that untreated infarcted group resulted in significant decrease in MBP
(99.46± 1.6) while nebivolol and lisinopril treated group resulted in significant decrease (81.55±
0.98 and 88.6± 2.7) in MBP in comparison to untreated infracted group.
Table 2: Effects of nebivolol and lisinopril on mean arterial blood pressure in isoprnalineinduced myocardial infarction in rats at the end of study (after 4 weeks).
group
Control
parameter
Mean arterial
blood pressure
(MBP)
109.88± 10.7
untreated
Nebivolol treated Lisinopril treated
Infarcted group
group
group
99.46± 1.6a
81.55± 0.98a,b
88.6± 2.7a,b
Data represented as Mean ± SEM (n = 6).
a: Significant difference from control group at p<0.05.
b: Significant difference from infarcted group at p<0.05.
Data in table (3) show that untreated infarcted group resulted in significant increase (1.15±0.04) in
T-wave voltage while nebivolol and lisinopril treated group resulted in significant decrease (0.42 ±
0.02and 0.71± 0.04) in T-wave voltage in comparison to untreated infarcted group.
Table 3: Effects of nebivolol and lisinopril on T-wave voltage in isoprnaline-induced myocardial
infarction in rats at the end of study (after 4 weeks).
group
Control
parameter
T-wave voltage
0.00
UntreatedInfarctedNebivolol treatedLisinopril treated
group
group
group
1.15±0.04a
0.42 ± 0.02a,b
0.71± 0.04a,b,c
Data represented as Mean ± SEM (n = 6).
a: Significant difference from control group at p<0.05.
b: Significant difference from infarcted group at p<0.05.
c: Significant difference from nebivolol-treated group at p<0.05 .
Data in table (4) show that untreated infarcted group resulted in significant increase (41.81±2.7%)
in Percent area of degenerativechanges (%) while nebivolol and lisinopril treated group resulted in
significant decrease (33.16±2.02%and 34.66±2.23%) inPercent area of degenerativechanges (%) in
comparison to untreated infarcted group.
Table 4: Effects of nebivolol and lisinopril onpercent area of degenerativechanges (%) in
isoprnaline-induced myocardial infarction in rats at the end of study (after 4 weeks).
group
parameter
Percent area of
degenerative
changes (%)
Control
0.00%
UntreatedInfarctedNebivolol treatedLisinopril treated
group
group
group
41.81±2.7%a
33.16±2.02%a,b 34.66±2.23%a,b
Data represented as Mean ± SEM (n = 6).
a: Significant difference from control group at p<0.05.
b: Significant difference from infarcted group at p<0.05.
Histopthological Examination: Sections were serially cut from the apex to the base at 1-mm
intervals, deparaffinized and stained with hematoxylin-eosin (HE). Control group showed clear
integrity of myocardial membrane, normal cardiac fibers without any infraction or infiltration of
inflammatory cells (Figure 1).Myocardial infarcted group showed significant increase of area of
degenerative changes in the form of cardiac muscle necrosis with congested blood vessels,
interstitial edema and inflammatory cells infiltration (Figure 2). While nebivololand lisinopril
treated group showed decrease of this pathological changes (figure 3 and 4).
Figure (1): A photomicrograph of a cut section in the heart of a control rat (group I)Showing
interlacing (a) bundles of cardiomyocytes with (b) spindle shaped nucleus with abundant
eosinophilic cytoplasm (H&Ex40).
Figure (2): A photomicrograph of a cut section in the heart of infarcted rat (group II)Showing (A)
Cardiac muscle necrosis. (B) Congested blood vessels. (C) Interstitial edema.
(D)
Inflammatory cells infiltration. (H&Ex40).
Figure (3): A photomicrograph of a cut section in the heart of infarcted rat (group II)Showing (A)
Cardiac muscle necrosis. (D) Inflammatory cells infilteration. (H&Ex40).
Figure (4): A photomicrograph of a cut section in the heart of lisinopril treated infarcted rat (group
IV)Showing (A) Decrease cardiac muscle necrosis. (B) Decrease congested blood vessels
(H&Ex40).
DISCUSSION
Myocardial infarction (MI) is defined as irreversible injury or subsequent necrosis of
myocardial cells due to interruption of blood supply to a part of the heart (Patel et al., 2010 and
Upaganlawar et al., 2010).
Current pharmacological treatment of MI is to control the neurohormonal activation
with angiotensin converting enzyme (ACE) inhibitors and beta blockers has been shown to decrease
mortality and morbidity by reducing remodeling (Rahko, 2005).
The present study was designed to explore the benificial therapeutic effects of nebivolol
and lisinopril on the progression of experimentally induced myocardial infraction in rats model
with isoprenaline regarding to their effects on heart rate, T-wave voltage changes, mean arterial
blood pressure and percent area of degenerative changes of the heart (histopathological changes of
the heart).
The obtained results in the current work revealed that induction of myocardial infarction
by isoprenaline resulted in significant increase heart rate, decrease mean arterial blood pressure,
increase T-wave voltage at the end of the study (after 4 weeks) in untreated infarcted group.
These results are in agreement with Thippeswamy et al., (2009); Goyal et al., (2010)
and Upaganlawar et al., (2010), who observed that ISO injected rats showed MI which is evident
by significant fall in systolic, diastolic and mean blood pressure and increase in heart rate.
In the present study it was found that administration of nebivolol and lisinopril to
myocardial infarcted rats for 4 weeks resulted in decrease of heart rate, decrease mean arterial
blood pressure, decrease in T-wave voltage.
These results are in agreement with Savsani et al., (2014), showed that ISO injected rats
significantly decreased in DBP and MBP along with significantly increased in heart rate as
compared to normal control rats. But nebivolol treatment significantly increased in MBP along
with significantly decreased in heart rate as compared to ISO injected rats. Mercanoğlu et al.,
(2010), observed that treatment of MI in a rat with ischemia-reperfusion model with nebivolol
significantly decrease heart rate and mean blood pressure. Rosei et al., (2003) showed that
nebivolol was slightly more effective, in comparison with lisinopril, in terms of reduction in DBP.
This greater efficacy was obtained without any increase in adverse effects, since both treatments
were equally well tolerated.
Wollert et al., (1994), observed that treatment of infarcted rats with lisinopril showed
decrease of both heart rate and blood pressure. And these results is in line with Veeravalli et al.,
(2003), who observed that treatment of infarcted rat model of acute ischemia and perfusion with
lisinopril alone or in combination with apstatin decreased blood pressure and heart rate. But
Ahmad et al., (2008) showed that administration of lisinopril for 4 weeks after MI produced minor
effect in MBP and significant decrease HR. One study in patients with heart failure and angina
indicated that ACEI treatment may worsen ischemia, because of the hypotension that compromises
myocardial perfusion (Cleland et al., 1991).
Regarding ECG changes, the results of the present study revealed that, infarcted
untreated group showed significant increase in T-wave voltage.
These results are in agreement with those of Surawicz (1974) who reported that the "T"
wave was elevated in rats after coronary ischemia.
The ECG tracing showed sinus tachycardia in addition to the injury current in form of
highly peaked T-wave. These results were in agreement with the observation of El-Hawary et al.
(1988).
These results are in agreement with Björck et al. (2010), who showed that use of aspirin,
beta-blockers, ACE inhibitors, or statins before hospital admission in patients with a first acute MI
is associated with substantially less risk of presenting with ST elevation myocardial infarction
(STEMI).
Savsani et al., (2014), showed that nebivolol treatment in isoproterenol treated rats
prevented the altered ECG pattern towards normal suggesting the cell membrane stabilizing
potential of nebivolol which might be due to its potent antioxidant property.
The mechanism of benefit from beta-blocker therapy in STEMI (ST-elevation myocardial
infraction) is still unclear. It has been suggested that early beta-blocker treatment decreases
myocardial oxygen consumption, favorably influences coronary blood flow, reduces infarct size and
improvements in ejection fraction (Halkin et al., 2004).
Renin-angiotensin-aldosterone system modulation with ACEIs reduces early and late
mortality in STEMI patients even in the absence of a reperfusion strategy (Marc Cohen et al.,
2010).
As regard to histopathological changes in the heart it was found that treatment of
infarcted rats with nebivolol and lisinopril showed improvement these changes.
Savsani et al., (2014), who showed that treatment of infarcted rats with nebivolol induce
improvement in histopathological changes of the heart produced in infracted untreated group in the
form of decrease infiltration of inflammatory cells and the morphology of cardiac muscle fibers was
relatively well preserved with decrease of necrosis.
Connelly et al., (2013), showed that histologic analysis demonstrated increased
extracellular matrix deposition in the noninfarct, subendocardial region of all MI groups when
compared with sham operated animals. ACEi significantly reduced matrix deposition.
cardiomyocyte size was increased in MI animals and significantly decrease with ACEi therapy.
In post-myocardial infarction and congestive heart failure studies, the benefit from beta1 blockade arises from decreased work of the heart (via reduced HR and blood pressure), reduced
ventricular fibrillation risk, and a reduction in catecholamine-induced (beta-1) cardiac necrosis
and apoptosis; thus, intrinsic sympathomimetic activity reduces efficacy (Podbregar and Voga,
2002).
Studies with nebivolol have showed that cardio-protective effects were not only mediated
by their adrenergic receptor blocker activity, but also by other mechanisms such as antioxidant
activity and anti-neutrophil effects (Yang et al., 2003). Favorable effects of nebivolol on ventricular
function in patients with chronic heart failure have been reported (Edes et al., 2005 and
Kurlianskaya et al., 2005).
The mechanism by which lisinopril improves the outcome following an acute MI involves
reduced peripheral vascular resistance, improved perfusion and a direct action on the myocardium.
Addition of an ACE inhibitor within the initial 24 hour period after an acute MI, attenuates LV
dilatation, improves perfusion and inhibition of angiotensin II production reduces the workload on
the heart, and inhibits collagen production (Maki Urushihara and Hiroyuki Kobori, 2011).
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‫دراسة مقارنة بين كال من النبيفولول والليسينوبريل فى احتشاء عضلة القلب المحدث تجريبيا فى فئ ارن التجارب‬
‫محمد المتولى منصور ومحمود محمد الفولى وأميمة محمد عبدهللا وعبير على الديب‬
‫قسم األدوية والعالج كلية طب بنها‪ -‬جامعة بنها‬
‫يعتبر احتشاء عضلة القلب هو ضرر ال رجعة فيها او نخر الحق بخاليا عضلة القلب بسبب انقطاع وصول الدم‬
‫الى جزء من القلب‪ .‬وقد تم تصميم هذه الدراسة لمقارنة األثار العالجية لكالم من عقار النبيفلول والليسينوبريل على‬
‫تطور احتشاء عضلة القلب المحدث معمليا للفئران بااليزوبرينالين‪ .‬المجموعة األولى "الضابطة" تم اعطاء الفئران‬
‫محلول ملح ‪ .%9‬المجموعة الثانية تم احداث احتشاء بعضلة القلب باستخدام االيزوبرينالين "‪051‬مجم‪/‬كجم‪/‬يوم"‬
‫ويخفف فى ‪2‬سم محلول ملح ‪ %1.9‬على مدار يومين بفرق ‪22‬ساعة بين الجرعتين‪ .‬المجموعة الثالثة اخذت‬
‫النبيفلول "‪ 1.5‬مجم‪/‬كجم" مرة واحدة يوميا بالفم لمدة ‪2‬اسابيع بعد احداث احتشاء بعضلة القلب‪ .‬المجموعة الرابعة‬
‫أخذت الليسينوبريل "‪21‬مجم‪/‬كجم" مرة واحدة بالفم يوميا لمدة ‪2‬اسابيع بعد احداث احتشاء بعضلة القلب‪ .‬وكشفت‬
‫النتائج التي تم الحصول عليها في الدراسة ان حقن األيزوبرينالين "‪051‬مجم‪/‬كجم‪/‬يوم" مخففة فى ‪2‬سم محلول ملح‬
‫فى يومين متتاليين مع فاصل ‪ 22‬ساعة بين الجرعتين أدى إلى احتشاء عضلة القلب من خالل زيادة عدد ضربات‬
‫القلب مع تغيرات فى شكل موجات (ت) بالزيادة وانخفاض ضغط الدم واحداث تغيرات نسيجية بالقلب بالمقارنة مع‬
‫المجم وعة الضابطة‪ .‬أما إعطاء النبيفلول بعد إحداث احتشاء بعضلة القلب أدى إلى إنخفاض فى معدل ضربات‬
‫القلب وضغط الدم وانخفاض الزيادة فى موجات (ت) وتحسين التغيرات النسيجية بالمقارنة مع المجموعة المصابة‬
‫التى اخذت األيزوبرينالين بدون عالج‪ .‬أما إعطاء الليسينوبريل بعد احداث احتشاء بعضلة القلب أدى إلى انخفاض‬
‫فى ضربات القلب وانخفاض ضغط الدم وانخفاض الزيادة فى موجات (ت) وتحسين التغيرات النسيجية بالمقارنة مع‬
‫المجموعة التى اخذت االيزوبرينالين بدون عالج‪.‬‬