Early Sacubitril/Valsartan Treatment Attenuates Time-of-Day Blood Pressure Variation and Neurohumoral Alterations in DOCA-Salt Hypertensive Rats

Abstract

BACKGROUND. Diurnal blood pressure (BP) variation is strongly associated with cardiovascular morbidity, endothelial dysfunction, and target-organ damage in hypertension. The renin–angiotensin–aldosterone system (RAAS), endothelin-1 (ET-1), and melatonin are important regulators of both vascular tone and circadian hemodynamic rhythms. This study investigated the effects of early sacubitril/valsartan treatment on time-of-day BP variation and neurohumoral alterations in DOCA-salt hypertensive rats. OBJECTIVES. To evaluate the preventive and therapeutic impacts of sacubitril/valsartan on blood pressure fluctuations and related serum biomarkers at specific diurnal time points. METHODS. Forty male rats were randomly divided into four groups (n=10/group): control, DOCA-salt hypertensive, therapeutic sacubitril/valsartan treatment after hypertension induction, and early sacubitril/valsartan treatment initiated simultaneously with hypertension induction. Hypertension was induced by intraperitoneal administration of deoxycorticosterone acetate (DOCA; 25 mg/kg) combined with 1% NaCl and 0.2% KCl in drinking water for 4 weeks. Sacubitril/valsartan was administered orally at 30 mg/kg/day. Systolic BP (SBP), diastolic BP (DBP), and heart rate (HR) were assessed weekly and at three specific time points (09:00, 15:00, and 21:00). Serum levels of ET-1, angiotensin II (Ang II), and melatonin were determined using ELISA. RESULTS. DOCA-salt hypertension significantly increased SBP, DBP, and HR compared with controls (p-values determined via post hoc analysis; p<0.001), accompanied by marked elevations in ET-1 and Ang II levels and reduced melatonin concentrations. Untreated hypertensive rats exhibited significant alterations in time-of-day BP values, with a loss of the normal fluctuations seen in controls. Therapeutic administration of sacubitril/valsartan restored near-normal BP values (SBP: 123.2±10 mmHg; DBP: 59.2±5 mmHg), normalized circadian hemodynamic fluctuations, reduced ET-1 and Ang II concentrations, and restored melatonin levels. Early initiation of treatment exerted an even more pronounced protective effect, preventing the development of hypertension, minimizing diurnal BP variability, and attenuating cardiovascular dysfunction. CONCLUSIONS. Early initiation of sacubitril/valsartan effectively prevents the development of DOCA-salt hypertension, modifies time-of-day hemodynamic variations at the measured points, and regulates serum endothelin-1, melatonin, and angiotensin II profiles. These findings suggest that early neurohumoral modulation with sacubitril/valsartan may confer significant cardioprotective benefits beyond conventional BP reduction, particularly by preserving circadian cardiovascular regulation.