The potential effect of Neprilysin Inhibitor- Angiotensin Receptor Blocker (Thiorphan-Irbesartan) in A Rat Model of Myocardial Ischemic Reperfusion Injury: A Comparative study with each; Nitrate and Carvedilol

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.