Angiotensin II Receptor–Neprilysin Inhibitor Sacubitril/Valsartan Improves Endothelial Dysfunction in Spontaneously Hypertensive Rats

Abstract

BackgroundWe have previously demonstrated that antihypertensive treatment with renin‐angiotensin system inhibitors restores the impaired endothelium‐dependent hyperpolarization (EDH)–mediated responses in spontaneously hypertensive rats (SHRs). Herein, we investigated whether the angiotensin II receptor–neprilysin inhibitor sacubitril/valsartan (LCZ696) would improve reduced EDH‐mediated responses and whether LCZ696 would exert additional effects on endothelium‐dependent and endothelium‐independent vasorelaxation compared with an angiotensin II type 1 receptor blocker alone during hypertension.Methods and Results SHRs were treated for 3 months with either LCZ696 or valsartan, from the age of 8 to 11 months. Age‐matched, untreated SHRs and Wistar‐Kyoto rats served as controls. Membrane potentials and contractile responses were recorded from the isolated superior mesenteric arteries. Acetylcholine‐induced, EDH‐mediated responses were impaired in untreated SHRs compared with Wistar‐Kyoto rats. EDH‐mediated responses were similarly improved in the LCZ696‐ and valsartan‐treated SHRs. No difference was observed in acetylcholine‐induced, nitric oxide‐mediated relaxations among the 4 groups. Endothelium‐independent relaxations in response to a nitric oxide donor, sodium nitroprusside, and those to levcromakalim, an ATP‐sensitive K+‐channel opener, were similar among the 4 groups; however, the sensitivities to levcromakalim were significantly higher in both LCZ696‐ and valsartan‐treated SHRs.Conclusions LCZ696 appears to be as effective as valsartan in improving the impaired EDH‐mediated responses during hypertension. LCZ696 and valsartan exert similar beneficial effects on endothelium‐independent relaxation via enhanced sensitivity of the ATP‐sensitive K+ channel. However, the dual blockade of renin‐angiotensin system and neutral endopeptidase with LCZ696 does not appear to provide additional benefit over valsartan alone on vasomotor function in mesenteric arteries of SHRs.

Microarray Profiling of Circular RNA Identifies hsa_circ_0126991 as a Potential Risk Factor for Essential Hypertension

“…Studies have shown that circRNA-Cdr1as is downregulated and sponges miR-135a in bladder cancer tissues, and proliferation, invasion, and migration of bladder cancer cells in vitro is inhibited by overexpressed Cdr1as [Seki et al, 2017]. In our study, circ_0126991 was predicted to interact with miR-10a-5p in a circRNA microarray using MiRanda.…”

Dual Angiotensin Receptor and Neprilysin Inhibitor Ameliorates Portal Hypertension in Portal Hypertensive Rats

“…In a study comparing the effect of LCZ696 to valsartan monotherapy, LCZ696 significantly ameliorated the impairment of acetylcholine-induced vascular relaxation, while it was not exerted by valsartan [23]. However, another study showed that LCZ696 was as effective as valsartan in improving the impaired endothelium-dependent hyperpolarization-mediated responses during hypertension, while no difference was observed in acetylcholine-induced, nitric oxide-mediated relaxations [24]. Indeed, the ARNI-induced hepatic ET-1 and eNOS downregulation in portal hypertensive rats has not been reported in the previous literature, and the ET-1 downregulation may play a dominant role in the LCZ696-induced portal hypotensive effect according to our data.…”

Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats

“…It is therefore possible that neprilysin inhibitor treatment contributes to cardioprotection by inhibiting bradykinin metabolism. Seki et al [26] reported that inhibition of neprilysin with LCZ696 does not appear to have an additional benefit over valsartan alone for the endothelial functions of arteries in spontaneously hypertensive rats. Their study suggests that vasoactive peptides, such as C-type natriuretic peptide, bradykinin, and substance P, which can accumulate because of neprilysin inhibition, may not play a crucial role in the improvement of endothelial functions.…”

“…The difference in target organs between their study and this one may have contributed to the favorable effects of LCZ696 compared with valsartan alone in the present study. Seki et al [26] focused on endothelial functions, whereas here the study focused on cardiac tissue including cardiomyocytes and fibroblasts. Another explanation is the difference in animal model.…”