Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats
Left ventricular (LV) diastolic dysfunction is increasingly common in heart failure with preserved ejection fraction (HFpEF), and new drug therapy is desired. We recently reported that dantrolene (DAN) attenuates pressure-overload induced hypertrophic signaling through stabilization of tetrameric st...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580823000304 |
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| author | Junya Nawata Takeshi Yamamoto Shinji Tanaka Yasutake Yano Tomoyuki Uchida Shohei Fujii Yoshihide Nakamura Takeshi Suetomi Hitoshi Uchinoumi Tetsuro Oda Shigeki Kobayashi Masafumi Yano |
| author_facet | Junya Nawata Takeshi Yamamoto Shinji Tanaka Yasutake Yano Tomoyuki Uchida Shohei Fujii Yoshihide Nakamura Takeshi Suetomi Hitoshi Uchinoumi Tetsuro Oda Shigeki Kobayashi Masafumi Yano |
| author_sort | Junya Nawata |
| collection | DOAJ |
| description | Left ventricular (LV) diastolic dysfunction is increasingly common in heart failure with preserved ejection fraction (HFpEF), and new drug therapy is desired. We recently reported that dantrolene (DAN) attenuates pressure-overload induced hypertrophic signaling through stabilization of tetrameric structure of cardiac ryanodine receptor (RyR2). Because cardiac hypertrophy substantially affects LV diastolic properties, we investigated the effect of DAN on LV diastolic properties in mineralocorticoid-salt–induced hypertensive rat model exhibiting the HFpEF phenotype.Male Sprague-Dawley (SD) rats (8 weeks old) received an uninephrectomy (UNX), subcutaneous implantation of a 200 mg pellet of deoxycorticosterone acetate (DOCA), and 0.9% NaCl water (UNX + DOCA-salt). UNX, a control pellet, and water without NaCl served as controls (UNX control). The effect of oral administration of 100 mg/kg/d DAN was examined in UNX control and UNX + DOCA-salt groups (UNX + DAN and UNX + DOCA-salt + DAN).UNX + DOCA-salt treatment resulted in mild hypertension. Chronic administration of DAN to UNX + DOCA-salt rats (UNX + DOCA-salt + DAN) did not affect blood pressure. DAN treatment increased the mitral annular early relaxation velocity in the UNX + DOCA-salt group. The size of cardiomyocytes increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. LV fibrotic area was significantly smaller in the UNX + DOCA-salt + DAN group than in the UNX + DOCA-salt group (2.0 ± 0.2% vs 4.0 ± 0.4%). The LV chamber stiffness significantly increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. DAN treatment normalized the CaM-RyR2 interaction and inhibited aberrant Ca2+ release.DAN improved left ventricular diastolic properties with respect to both myocardial relaxation and chamber stiffness. DAN may be a new treatment option for HFpEF. |
| first_indexed | 2024-03-13T07:57:06Z |
| format | Article |
| id | doaj.art-723330659f784a2bb2ad94d9faad46aa |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-03-13T07:57:06Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-723330659f784a2bb2ad94d9faad46aa2023-06-02T04:23:22ZengElsevierBiochemistry and Biophysics Reports2405-58082023-07-0134101449Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive ratsJunya Nawata0Takeshi Yamamoto1Shinji Tanaka2Yasutake Yano3Tomoyuki Uchida4Shohei Fujii5Yoshihide Nakamura6Takeshi Suetomi7Hitoshi Uchinoumi8Tetsuro Oda9Shigeki Kobayashi10Masafumi Yano11Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanCorresponding author. Department of Laboratory Medicine, Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, 1Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.; Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanDepartment of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, JapanLeft ventricular (LV) diastolic dysfunction is increasingly common in heart failure with preserved ejection fraction (HFpEF), and new drug therapy is desired. We recently reported that dantrolene (DAN) attenuates pressure-overload induced hypertrophic signaling through stabilization of tetrameric structure of cardiac ryanodine receptor (RyR2). Because cardiac hypertrophy substantially affects LV diastolic properties, we investigated the effect of DAN on LV diastolic properties in mineralocorticoid-salt–induced hypertensive rat model exhibiting the HFpEF phenotype.Male Sprague-Dawley (SD) rats (8 weeks old) received an uninephrectomy (UNX), subcutaneous implantation of a 200 mg pellet of deoxycorticosterone acetate (DOCA), and 0.9% NaCl water (UNX + DOCA-salt). UNX, a control pellet, and water without NaCl served as controls (UNX control). The effect of oral administration of 100 mg/kg/d DAN was examined in UNX control and UNX + DOCA-salt groups (UNX + DAN and UNX + DOCA-salt + DAN).UNX + DOCA-salt treatment resulted in mild hypertension. Chronic administration of DAN to UNX + DOCA-salt rats (UNX + DOCA-salt + DAN) did not affect blood pressure. DAN treatment increased the mitral annular early relaxation velocity in the UNX + DOCA-salt group. The size of cardiomyocytes increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. LV fibrotic area was significantly smaller in the UNX + DOCA-salt + DAN group than in the UNX + DOCA-salt group (2.0 ± 0.2% vs 4.0 ± 0.4%). The LV chamber stiffness significantly increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. DAN treatment normalized the CaM-RyR2 interaction and inhibited aberrant Ca2+ release.DAN improved left ventricular diastolic properties with respect to both myocardial relaxation and chamber stiffness. DAN may be a new treatment option for HFpEF.http://www.sciencedirect.com/science/article/pii/S2405580823000304DantroleneCalmodulinHypertrophyHFpEF |
| spellingShingle | Junya Nawata Takeshi Yamamoto Shinji Tanaka Yasutake Yano Tomoyuki Uchida Shohei Fujii Yoshihide Nakamura Takeshi Suetomi Hitoshi Uchinoumi Tetsuro Oda Shigeki Kobayashi Masafumi Yano Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats Biochemistry and Biophysics Reports Dantrolene Calmodulin Hypertrophy HFpEF |
| title | Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats |
| title_full | Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats |
| title_fullStr | Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats |
| title_full_unstemmed | Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats |
| title_short | Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats |
| title_sort | dantrolene improves left ventricular diastolic property in mineralcorticoid salt induced hypertensive rats |
| topic | Dantrolene Calmodulin Hypertrophy HFpEF |
| url | http://www.sciencedirect.com/science/article/pii/S2405580823000304 |
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