Protection against isoproterenol-induced cardiac injury by sacubitril/valsartan is associated with upregulation of the alternative renin-angiotensin-aldosterone system pathway.

Long-term stimulation of myocardial beta-receptors by isoproterenol is a well-established model of heart damage and failure. This study investigated the potential interactions of isoproterenol administration with the renin-angiotensin-aldosterone system (RAAS) and whether sacubitril/valsartan (ARNI) protection against left ventricular (LV) remodeling and dysfunction was associated with the modulation of the RAAS. Four groups of three-month-old male Wistar rats were treated for six weeks as follows: controls, sacubitril/valsartan (ARNI, 68 mg/kg/day orally), isoproterenol (5 mg/kg the first day and 1 mg for next six days + four weeks recovery), isoproterenol (as above) + ARNI (one week pre-treatment followed by 5 weeks treatment during ISO-treatment and recovery period). Systolic blood pressure (SBP) was markedly reduced only in the first week of both ISO-treated groups. Isoproterenol induced pathological remodeling of the LV, as well as deterioration of its function as determined by echocardiography. Yet, no changes in serum renin-angiotensin-aldosterone levels were observed. ARNI lowered SBP, alleviated LV remodeling, improved LV systolic and diastolic dysfunction and also raised the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 and aldosterone. We conclude that isoproterenol treatment for one week followed by a four-week recovery induced a normal-to-low serum renin-angiotensin-aldosterone model of left ventricular damage. Protection by ARNI against pathological remodeling and LV dysfunction was related to Ang II blockade and upregulation of the alternative pathway of the renin-angiotensin-aldosterone system.