Role of angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis in the hypotensive effect of azilsartan
Role of angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis in the hypotensive effect of azilsartan
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DOI：
10.1038/hr.2014.49
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发表时间：
2014-07-01
影响因子：
5.4
通讯作者：
Horiuchi, Masatsugu
中科院分区：
文献类型：
--
作者：
Iwanami, Jun;Mogi, Masaki;Horiuchi, Masatsugu
血管紧张素（Ang）转换酶（ACE） 2/Ang-(1-7)/Mas轴对ACE/Ang II/Ang II型1 （AT(1)）受体轴在血压控制中的可能的抵消作用已有报道。我们研究了这一途径可能参与新开发的AT(1)受体阻滞剂（ARB）阿兹沙坦的降压作用，并将阿兹沙坦与另一种ARB奥美沙坦的作用进行了比较。将携带人肾素和血管紧张素原基因（hRN/hANG-Tg）的转基因小鼠给予阿齐沙坦或奥美沙坦。通过无线电遥测测定，hRN/hANG-Tg小鼠的收缩压和舒张压明显高于野生型（WT）小鼠。阿齐沙坦或奥美沙坦治疗（1或5 mg kg(-1) / d）可显著降低收缩压和舒张压，且阿齐沙坦的降压作用比奥美沙坦更显著。hRN/hANG-Tg小鼠尿钠浓度呈年龄依赖性下降。阿兹沙坦或奥美沙坦使尿钠浓度升高，但这种作用在奥美沙坦组弱于阿兹沙坦组。阿兹沙坦降低肾脏中enact - α mRNA的表达，降低心重比。奥美沙坦也有类似的效果，但效果不那么明显。hRN/hANG-Tg小鼠肾脏和心脏中ACE2 mRNA的表达低于WT小鼠。阿齐沙坦能减弱ACE2 mRNA表达的减少，但奥美沙坦不能。这些结果表明阿齐沙坦的降压和抗肥厚作用可能与激活ACE2/Ang-(1-7)/Mas轴并阻断AT(1)受体有关。
The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/Mas axis against the ACE/Ang II/Ang II type 1 (AT(1)) receptor axis in blood pressure control has been previously described. We examined the possibility that this pathway might be involved in the anti-hypertensive effect of a newly developed AT(1) receptor blocker (ARB), azilsartan, and compared azilsartan's effects with those of another ARB, olmesartan. Transgenic mice carrying the human renin and angiotensinogen genes (hRN/hANG-Tg) were given azilsartan or olmesartan. Systolic and diastolic blood pressure, as determined by radiotelemetry, were significantly higher in hRN/hANG-Tg mice than in wild-type (WT) mice. Treatment with azilsartan or olmesartan (1 or 5 mg kg(-1) per day) significantly decreased systolic and diastolic blood pressure, and the blood pressure-lowering effect of azilsartan was more marked than that of olmesartan. The urinary Na concentration decreased in an age-dependent manner in hRN/hANG-Tg mice. Administration of azilsartan or olmesartan increased urinary Na concentration, and this effect was weaker with olmesartan than with azilsartan. Azilsartan decreased ENaC-alpha mRNA expression in the kidney and decreased the ratio of heart to body weight. Olmesartan had a similar but less-marked effect. ACE2 mRNA expression was lower in the kidneys and hearts of hRN/hANG-Tg mice than in WT mice. This decrease in ACE2 mRNA expression was attenuated by azilsartan, but not by olmesartan. These results suggest that the hypotensive and anti-hypertrophic effects of azilsartan may involve activation of the ACE2/Ang-(1-7)/Mas axis with AT(1) receptor blockade.