الفهرس 
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Abstract
Myocardial ischemia/ reperfusion (I/R) injury is at the center of the pathology of the most common cardiovascular diseases. Myocardial I/R injury is a complex phenomenon including many pathological changes and impacts, such as systolic dysfunction, arrhythmias and rapidly proceeding to irreversible cell death by apoptosis with eventual heart failure.
There is a great interest to the new combination drug therapy “angiotensin receptor neprilysin (NEP) inhibitors “(ARNI) that plays a promising role in myocardial I/R through alleviating the effects of the activated renin angiotensin aldosterone system (RAAS) and prevention of destruction of natriuretic peptides by NEP enzyme thus augmenting their beneficial effects on the heart.
Nitroglycerin (NTG) and carvedilol (CAR) are among the most documented drugs for control of myocardial ischemic injury through decreasing infarct size and improving cardiac hemodynamic.
In this study, we designed a combination therapy that is similar to the first approved ARNI therapy (sacubitril/valsartan), instead using irbesartan (ARB)/thiorphan (NEPi). We evaluated the possible beneficial effect of pretreatment of combined ARB/NEPi therapy in comparison to each nitroglycerin and carvedilol on cardiac hemodynamics, ventricular arrhythmias, oxidative stress, myocardial enzymatic activity, Na+/K+ATPase pump activity, mitochondrial functions, and myocardial apoptosis following induction of I/R.
In the current experiment, male Wistar rats that were randomly allocated into two main groups: Sham group (10 rats) and I/R group (60 rats) which underwent ischemia for 35 minutes through ligation of left anterior descending (LAD) coronary artery, and then reperfusion for 60 minutes by releasing the ligation and before scarification. I/R group was divided into six subgroups (10 rats each): untreated I/R subgroup; TH/IRB+IR (0.1/5mg/kg, 0.1/10mg/kg & 0.1/15mg/kg) subgroups receiving TH and IRB each by intraperitoneal injection; Nitroglycerin+IR subgroup (receiving NTG 0.2 mg/kg/3-5 min by repeated intra-arterial bolus injection for four times only); Carvedilol+IR subgroup (receiving CAR 10mg/kg by intraperitoneal injection). All drugs were administered 15min before induction of I/R.
The following parameters were measured:
• Cardiac hemodynamics: Mean arterial blood pressure (MBP), Left ventricular end diastolic pressure (LVEDP) and (LV dP/dtmax).
• Electrocardiography (ECG): ECG parameters (Heart rate, QRS duration, ST segment height, and QTc interval) and arrhythmia evaluation (incidence, duration, and score).
• Biochemical parameters: Measurement of cardiac superoxide dismutase (SOD) and malondialdehyde (MDA) to evaluate oxidative stress. Measurement of cardiac endothelin- 1 (ET-1) and creatine kinase–MB (CK-MB) to detect tissue injury. Measurement of cardiac ATP content and Na+/K+ATPase pump activity. Evaluation of mitochondrial functions by measuring cardiac mitochondrial complexes (I, II, III and IV) activities.
• Histopathological examination with Hematoxylin and eosin stain and Masson’s trichome stain to detect the pathological changes of myocardial tissues.
• Electron microscopy imaging of cardiac tissues.
• Immunohistochemistry examination for the expression of Bcl-2 and Bax proteins.
The results of the present work could be summarized as follow:
1. TH/IRB (0.1/5mg/kg, 0.1/10 mg/kg and 0.1/15 mg/kg), Nitroglycerin and Carvedilol administration conserved cardiac hemodynamics (↓LVEDP and ↑ LV dP/dtmax) and improved arrhythmia incidence, duration and score compared to untreated I/R subgroup. They also mitigated oxidative stress (↓ MDA and ↑ SOD), cardiac damage (↓ CK-MB), ↓ ET-1 levels, prevented apoptosis (↑Bcl2/Bax ratio) except for CAR. Moreover, they preserved cardiac ATP content and Na+/K+ATPase pump activity and improved mitochondria complexes activities, along with apparent improvement in histopathological changes and electron microscopy examination of left ventricle compared to untreated I/R subgroup except for CAR.
2. TH/IRB in a dose of (0.1/10 mg/kg) showed significant improvement in cardiac hemodynamics ,biochemical parameters, histopathological changes and electron microscopy examination compared to TH/IRB+IR (0.1/5 mg/kg and 0.1/15 mg/kg) and carvedilol+IR subgroups.
3. TH/IRB in a dose of (0.1/10 mg/kg) showed significant improvement only in mitochondrial complexes activity I and II compared to nitroglycerin+IR subgroup.
Conclusion:
Thiorphan/Irbesartan combination therapy conserved cardiac functions, decreased arrhythmia severity and cardiac injury following I/R in this Wistar rat model. These could be explained by the reported ability to decrease oxidative stress, decrease levels of CK-MB and ET-1, preserve mitochondria complexes activities, prevent apoptosis, increase cardiac ATP content, and cardiac Na+/K+ ATPase pump activity. TH/IRB (0.1/10 mg/kg) showed comparable effect to nitroglycerin in reducing I/R injury consequences with superior effect in preserving mitochondrial complexes I and II activities.
Moreover, the same combination dose showed a comparable effect to carvedilol regarding MBP, LVEDP, arrhythmia incidence, score, and duration, with superior effect regarding myocardial injury mediators. Therefore, the ARNI combination (thiorphan/irbesartan) could be a promising combination in reducing I/R injury and its associated arrhythmia, which requires further clinical assessment.