Effect of Sacubitril/Valsartan Combination on Circadian Rhythm of Hemodynamic Parameters, Inflammatory Biomarkers and Melatonin Synthesis in Experimental Arterial Hypertension

The circadian rhythm of blood pressure (BP) has been getting more attention since a rise in nocturnal BP and an increase in morning BP have been found to be independent risk factors for cardio-cerebrovascular disorders. The renin-angiotensin-aldosterone system (RAAS) is implicated in BP circadian rhythm, and RAAS inhibitors play an important role in BP circadian rhythm management. Experiments were carried out on male rats weighing 200,0-250,0 g. Animals were randomly divided into the following groups: I – control group; II – DOCA-salt hypertensive group; III – S/V oral dose of 30 mg/kg per day after 28-day intake of DOCA and salt solutions administration. IV - sacubitril / valsartan (S/V) oral dose 30 mg/kg per day with DOCA and salt solutions as drinking water for 4 weeks; In II group of rats with DOCA-salt arterial hypertension (AH) the mean values of systolic blood pressure (SBP) – 153,6 ± 5,4 mmHg, diastolic blood pressure DBP – 67,9 ± 2,8 mmHg and heart rate (HR) – 394 ± 12/min were significantly higher in comparison with control group of animals (123,0 ± 5,2 mmHg, P<0.001), (55,6 ± 3,0 mmHg, p<0.05) and (361 ± 24/min, p<0.001), respectively. As for III group of animals, treatment with the S/V combination proved to be beneficial and the SBP and DBP, as well as the HR returned to normal values. In IV – experimental group S/V revealed preventive action regarding hemodynamic changes during development of AH by decreasing values of SBP ( -50 ± 11,8 mmHg, p<0,001), DBP (-16 ± 6,0 mmHg, p<0,001), and HB (­- 67 ± 15,6 beat/min, p<0,001). In hypertensive rats, the level of inflammatory markers increased significantly, namely IL-1 was 8.6 pg/ml and TNF-alpha was 46.8 pg/ml. Both values returned to normal range after the use of S/V in experimental groups III and IV. In a group of rats with DOCA-induced hypertension, melatonin levels were significantly decreased compared to the control group (-6 pg/ml) and increased again after prevention and treatment of hypertension with S/V. Respectively, an improvement in the disturbed circadian rhythm of hemodynamic parameters was revealed in the same experimental groups of animals. Contrary to melatonin, levels of angiotensin II were increased in hypertensive rats and decreased after blood pressure normalization with S/V combination. We hypothesize that during arterial hypertension, elevated circulating angiotensin II crosses the blood-brain barrier and acts on the melatonin-synthesizing enzyme tryptophan hydroxylase causing its downregulation, which is followed by a decrease in melatonin levels. This in turn causes increase in the inflammatory mediators IL1 and TNF. Based on the data obtained as a result of our study, we can conclude that the S/V combination has a multiple mechanism of action that is likely to have significant positive effects on the long-term outcomes of hypertension and patient survival.