Angiotensin II receptor-neprilysin inhibitor sacubitril/valsartan improves endothelial dysfunction in spontaneously hypertensive rats

Takunori Seki, Kenichi Goto, Yasuo Kansui, Toshio Ohtsubo, Kiyoshi Matsumura, Takanari Kitazono

研究成果: ジャーナルへの寄稿記事

13 引用 (Scopus)

抄録

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 (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. Agematched, 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.

元の言語英語
記事番号e006617
ジャーナルJournal of the American Heart Association
6
発行部数10
DOI
出版物ステータス出版済み - 10 1 2017

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Valsartan
Neprilysin
Angiotensin Receptors
Inbred SHR Rats
Endothelium
Cromakalim
Inbred WKY Rats
Renin-Angiotensin System
Acetylcholine
Adenosine Triphosphate
Hypertension
Angiotensin II Type 1 Receptor Blockers
LCZ 696
Mesenteric Arteries
Superior Mesenteric Artery
Nitric Oxide Donors
Nitroprusside
Vasodilation
Membrane Potentials
Antihypertensive Agents

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

Angiotensin II receptor-neprilysin inhibitor sacubitril/valsartan improves endothelial dysfunction in spontaneously hypertensive rats. / Seki, Takunori; Goto, Kenichi; Kansui, Yasuo; Ohtsubo, Toshio; Matsumura, Kiyoshi; Kitazono, Takanari.

:: Journal of the American Heart Association, 巻 6, 番号 10, e006617, 01.10.2017.

研究成果: ジャーナルへの寄稿記事

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abstract = "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 (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. Agematched, 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.",
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T1 - Angiotensin II receptor-neprilysin inhibitor sacubitril/valsartan improves endothelial dysfunction in spontaneously hypertensive rats

AU - Seki, Takunori

AU - Goto, Kenichi

AU - Kansui, Yasuo

AU - Ohtsubo, Toshio

AU - Matsumura, Kiyoshi

AU - Kitazono, Takanari

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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 (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. Agematched, 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.

AB - 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 (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. Agematched, 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.

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