Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects
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- Yahiro Eiji
- Department of Cardiology, Fukuoka University School of Medicine
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- Miura Shin-ichiro
- Department of Cardiology, Fukuoka University School of Medicine Department of Molecular Cardiovascular Therapeutics, Fukuoka University School of Medicine
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- Suematsu Yasunori
- Department of Cardiology, Fukuoka University School of Medicine
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- Matsuo Yoshino
- Department of Cardiology, Fukuoka University School of Medicine
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- Arimura Tadaaki
- Department of Cardiology, Fukuoka University School of Medicine
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- Kuwano Takashi
- Department of Cardiology, Fukuoka University School of Medicine
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- Imaizumi Satoshi
- Department of Cardiology, Fukuoka University School of Medicine
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- Iwata Atsushi
- Department of Cardiology, Fukuoka University School of Medicine
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- Uehara Yoshinari
- Department of Cardiology, Fukuoka University School of Medicine Department of Molecular Cardiovascular Therapeutics, Fukuoka University School of Medicine
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- Saku Keijiro
- Department of Cardiology, Fukuoka University School of Medicine Department of Molecular Cardiovascular Therapeutics, Fukuoka University School of Medicine
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抄録
While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.<br>We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.<br>An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.
収録刊行物
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- International Heart Journal
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International Heart Journal 56 (6), 656-660, 2015
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