Sacubitril/Valsartan Combination Partially Improves Cardiac Systolic Function through β1-/β2-AR Responsiveness but Not Diastolic Function in a Rat Model of Type 2 Diabetes

Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Increased renin-angiotensin-aldosterone system activity and decreased β-adrenergic receptor (β-AR) responsiveness contribute to diabetic cardiac dysfunction. We evaluated the effect of sacubitril/valsartan (neprilysin inhibitor plus angiotensin receptor antagonist combination), and valsartan treatments on the diabetic cardiac function through β-AR responsiveness, and on protein expression of diastolic components. 6-week-old male Sprague-Dawley rats were divided into control, diabetic, sacubitril/valsartan (68 mg/kg), and valsartan treated (31 mg/kg) diabetic groups. Diabetes was induced by high fat diet plus low dose streptozotocin (30 mg/kg, intraperitoneal). After 10 weeks of diabetes, rats were treated for 4 weeks. Systolic/diastolic function was assessed by in vivo echocardiography and pressure-volume loop analysis. β-AR mediated responsiveness was assessed by in vitro papillary muscle and Langendorff heart experiments. Protein expression of sarcoplasmic reticulum calcium ATPase2a, phospholamban, and phosphorylated phospholamban was determined by Western blot. Sacubitril/valsartan improved ejection fraction and fractional shortening to a similar extent as valsartan alone. None of the treatments affected in vivo diastolic parameters or expression of related proteins. β1-/β2-AR mediated responsiveness was partially restored in treated animals. β3-AR mediated relaxation responses were comparable among groups. The beneficial effect of sacubitril/valsartan on systolic function may be attributed to improved β1-/β2-AR responsiveness.