Open AccessAngiotensin II Receptor–Neprilysin Inhibitor Sacubitril/Valsartan Improves Endothelial Dysfunction in Spontaneously Hypertensive Rats
Author(s) -
Seki Takunori,
Goto Kenichi,
Kansui Yasuo,
Ohtsubo Toshio,
Matsumura Kiyoshi,
Kitazono Takanari
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.006617
Subject(s) - valsartan , medicine , sacubitril, valsartan , endocrinology , sodium nitroprusside , nitric oxide , angiotensin ii , angiotensin receptor , neprilysin , endothelium , endothelial dysfunction , mesenteric arteries , sacubitril , renin–angiotensin system , acetylcholine , pharmacology , receptor , blood pressure , artery , chemistry , biochemistry , enzyme
Background We have previously demonstrated that antihypertensive treatment with renin‐angiotensin system inhibitors restores the impaired endothelium‐dependent hyperpolarization ( EDH )–mediated responses in spontaneously hypertensive rats ( SHR s). Herein, we investigated whether the angiotensin II receptor–neprilysin inhibitor sacubitril/valsartan ( LCZ 696) would improve reduced EDH ‐mediated responses and whether LCZ 696 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 SHR s were treated for 3 months with either LCZ 696 or valsartan, from the age of 8 to 11 months. Age‐matched, untreated SHR s 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 SHR s compared with Wistar‐Kyoto rats. EDH ‐mediated responses were similarly improved in the LCZ 696‐ and valsartan‐treated SHR s. 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 LCZ 696‐ and valsartan‐treated SHR s. Conclusions LCZ 696 appears to be as effective as valsartan in improving the impaired EDH ‐mediated responses during hypertension. LCZ 696 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 LCZ 696 does not appear to provide additional benefit over valsartan alone on vasomotor function in mesenteric arteries of SHR s.