Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme
Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme
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DOI：
10.1291/hypres.29.865
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发表时间：
2006-11-01
影响因子：
5.4
通讯作者：
Shimamoto, Kazuaki
中科院分区：
文献类型：
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作者：
Agata, Jun;Ura, Nobuyuki;Shimamoto, Kazuaki
血管紧张素 II 受体阻滞剂 (ARB) 广泛用于治疗高血压。据信，由于缺乏肾素活性的负反馈，ARB 治疗会增加血浆血管紧张素 II (Ang II) 的水平。然而，Ichikawa (Hypertens Res 2001；24：641-646)报道，高血压患者长期用奥美沙坦治疗导致血浆Ang II水平降低，但机制尚未确定。据报道，血管紧张素 1-7 (Ang-(1-7)) 可增强缓激肽的作用，并可作为血管紧张素转换酶 (ACE) 抑制剂。已知ACE2是2000年发现的一种新型ACE相关羧肽酶，可将Ang I水解为Ang-(1-9)，也将Ang II水解为Ang-(1-7)。最近有报道称，奥美沙坦通过增加心肌梗死大鼠的ACE2表达来增加血浆Ang-(1-7)。我们推测ACE2的过度表达可能与Ang II水平的降低和奥美沙坦的心脏保护作用有关。与给予媒介物的 SHRSP 相比，向 12 周龄易发生中风的自发性高血压大鼠 (SHRSP) 施用 0.5 mg/kg/天的奥美沙坦 4 周可显着降低血压和左心室重量。奥美沙坦和 (D-Ala (7))-Ang-(1-7)（一种选择性 Ang-(1-7) 拮抗剂）的共同给药可部分抑制奥美沙坦对血压和左心室重量的影响。有趣的是，与单独奥美沙坦相比(D-Ala(7))-Ang-(1-7)与奥美沙坦的共同给药显着增加血浆Ang II水平(453.2+/-113.8pg/ml)(144.9+/-27.0pg/ml，p<0.05)。此外，与用媒介物治疗的Wistar京都大鼠和SHRSP大鼠相比，奥美沙坦显着增加了心脏ACE2表达水平。奥美沙坦显着改善心血管重塑和心脏亚硝酸盐/硝酸盐含量，但奥美沙坦和(D-Ala(7))-Ang-(1-7)的共同给药部分逆转了这种抗重塑作用和亚硝酸盐/硝酸盐的增加。这些发现表明，除了 Ang II 受体阻断作用外，奥美沙坦还可能表现出 ACE 抑制作用，防止 Ang II 水平升高，并通过 ACE2 过度表达增加心脏一氧化氮生成和内源性 Ang-(1-7) 来保护心血管重塑。
Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala (7))-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration Of (D-Ala(7))-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2 +/- 113.8 pg/ml) compared to olmesartan alone (144.9 +/- 27.0 pg/ml, p < 0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/nitrate content, but co-administration of olmesartan and (D-Ala(7))-Ang-(1-7) partially reversed this antiremodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.