A Novel Paradigm for Sacubitril/Valsartan: Beta-Endorphin Elevation As a Contributor to Exercise Tolerance Improvement in Rats with Preexisting Heart Failure Induced by Pressure Overload

Background: Simultaneous angiotensin receptor (AT(1)) blockade and neprilysin inhibition with the use of sacubitril/valsartan has been recently approved to treat patients with heart failure (HF). Therapeutic benefits of this therapy have been attributed to natriuretic peptide elevation and AT(1) receptor blockade. However, that pharmacologic picture may not be complete. The aims of this study were to investigate the pharmacology of sacubitril/valsartan compared with sacubitril and valsartan alone and to examine their impact on peptides up-regulated by neprilysin inhibition, such as beta-endorphin. Methods and Results: An HF model was induced by pressure overload via constriction of the suprarenal abdominal aorta in rats. Sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg), or placebo was administered by daily oral gavage (starting 4 weeks after pressure overload onset and continued for 4 additional weeks; n = 8 in each group). Exercise tolerance testing was conducted using a rodent treadmill and hemodynamic assessments were conducted under anesthesia with the use of Millar left ventricular (LV) conductance technology. Pressure overload led to exercise intolerance by 4 weeks and to hypertension and LV dysfunction and remodeling by 8 weeks. Both sacubitril/valsartan and sacubitril elevated betaendorphin levels, by 40% and 54%, respectively, and improved exercise tolerance, by 93% and 112%, whereas valsartan did not. Indices of LV dysfunction persisted with the use of sacubitril/valsartan and valsartan therapies and even deteriorated in sacubitril group. Conclusions: When added to valsartan, sacubitril increases beta-endorphin concentrations and improves exercise tolerance. These data suggest beta-endorphin elevation as a potential mechanism of action leading to improvement in exercise tolerance that is seen with sacubitril/valsartan. This therapeutic benefit is potentially independent from LV function.