Background: Hypertension is a major cause of death and morbidity worldwide and is increasing in prevalence. The Renin–angiotensin system (RAS) is the most common mechanism involved in the pathophysiology of hypertension. Understanding the mechanism of the pathophysiologic processes will help direct potential therapeutic strategies to treat hypertension and improve cardiac function. Recently, a novel drug LCZ696 containing both an angiotensin receptor blocker valsartan and a neprilysin inhibitor (AHU377) has shown a promising effect on the treatment of hypertension. However, the effects of LCZ696 on the expression of main components of RAS, namely, angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin II type 1 receptor (AT1 R), angiotensin II type 2 receptor (AT2 R), and angiotensin (1-7) receptor/Mas receptor (MasR) remain unclear. The aim of the present study was to evaluate the effects of LCZ696 on the protective arms of RAS in the cardiac tissue when compared with valsartan under the equal inhibition of AT1 R. We hypothesized that the superior effects of LCZ696 may contribute to its greater effect on the RAS than valsartan. Materials and Methods: Sixteen-week-old female spontaneously hypertensive rats (SHRs) were used in this study. Wistar-Kyoto (WKY) rats were used as controls. All rats were randomly divided into LCZ696 (n = 10), valsartan (n = 10), SHR (n = 10), and WKY (n = 10) groups under a 12-hour dark and 12-hour light cycle and provided with regular chow diet and water. The tail-cuff method was performed to measure blood pressure. Cardiac function was assessed by echocardiography. Results: The blood pressure value was lower in LCZ696 than valsartan in SHR after 12 weeks of treatment. Further, LCZ696 inhibits the ACE and AT1 R protein expression in the cardiac of SHR and significantly upregulate the protective axis of RAS components, including ACE2, MasR, and AT2 R. Left ventricular AT2 R messenger RNA (mRNA) expression was higher in the LCZ696+SHR group compared with valsartan. In addition, real-time polymerase chain reaction analysis revealed that LCZ696 enhanced the mRNA expression of antihypertensive components AT2 R, ACE2, and MasR and decreased the expression of AT1 R. However, only AT2 R and ACE2 mRNA expressions have a statistical difference between the LCZ696 and valsartan groups. No difference was observed in the mRNA expression of ACE and MasR. The stronger positive signal of transforming growth factor β in the left ventricle was inhibited in each administrated group compared with SHR groups. Conclusions: LCZ696 ameliorates the vasoconstrictor axis of the RAS AT1 R and stimulate the protective arm effectors, ACE2 and AT2 R, as well as reverses the compensatory upregulation of neuronal nitric oxide synthase and endothelial nitric oxide synthase in SHR. These findings suggest the mechanistic insight of the cardiac-protective and greater hypotensive effects of LCZ696.
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