This study investigated whether sacubitril/valsartan and ivabradine are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in a rat experimental model of spontaneous hypertension (spontaneously hypertensive rats, SHRs) and whether this potential protection is associated with RAAS alterations. Five groups of three-month-old male Wistar rats and SHRs were treated for six weeks as follows: untreated Wistar controls, Wistar plus sacubitril/valsartan, SHR, SHR plus sacubitril/valsartan, and SHR plus ivabradine. The SHRs developed a systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, and LV systolic and diastolic dysfunction. However, no changes in serum RAAS were observed in SHRs compared with the controls. Elevated SBP in SHRs was decreased by sacubitril/valsartan but not by ivabradine, and only sacubitril/valsartan attenuated LV hypertrophy. Both sacubitril/valsartan and ivabradine reduced LV collagen content and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7, and aldosterone, while ivabradine did not affect the RAAS. We conclude that the SHR is a normal-to-low serum RAAS model of experimental hypertension. While the protection of the hypertensive heart in SHRs by sacubitril/valsartan may be related to an Ang II blockade and the protective Ang 1-7, the benefits of ivabradine were not associated with RAAS modulation.

3rd Department of Internal Medicine Faculty of Medicine Comenius University 83305 Bratislava Slovakia

Attoquant Diagnostics 1110 Vienna Austria

Department of Physiology Faculty of Medicine in Hradec Kralove Charles University 50003 Hradec Kralove Czech Republic

Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences 84505 Bratislava Slovakia

Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences 81371 Bratislava Slovakia

Institute of Pathophysiology Faculty of Medicine Comenius University 81108 Bratislava Slovakia

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