Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, 126 University Pl, University of Glasgow, Glasgow G12 8TA, UK.
Hypertension. 2012 Feb;59(2):300-7. doi: 10.1161/HYPERTENSIONAHA.111.177485. Epub 2011 Dec 19.
The renin-angiotensin system regulates cardiovascular physiology via angiotensin II engaging the angiotensin type 1 or type 2 receptors. Classic actions are type 1 receptor mediated, whereas the type 2 receptor may counteract type 1 receptor activity. Angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7) and angiotensin I to angiotensin-(1-9). Angiotensin-(1-7) antagonizes angiotensin II actions via the receptor Mas. Angiotensin-(1-9) was shown recently to block cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Here, we investigated in vivo effects of angiotensin-(1-9) via the angiotensin type 2 receptor. Angiotensin-(1-9) (100 ng/kg per minute) with or without the angiotensin type 2 receptor antagonist PD123 319 (100 ng/kg per minute) or PD123 319 alone was infused via osmotic minipump for 4 weeks into stroke-prone spontaneously hypertensive rats. We measured blood pressure by radiotelemetry and cardiac structure and function by echocardiography. Angiotensin-(1-9) did not affect blood pressure or left ventricular mass index but reduced cardiac fibrosis by 50% (P<0.01) through modulating collagen I expression, reversed by PD123 319 coinfusion. In addition, angiotensin-(1-9) inhibited fibroblast proliferation in vitro in a PD123 319-sensitive manner. Aortic myography revealed that angiotensin-(1-9) significantly increased contraction to phenylephrine compared with controls after N-nitro-l-arginine methyl ester treatment, an effect abolished by PD123 319 coinfusion (area under the curve: angiotensin-(1-9) N-nitro-l-arginine methyl ester=98.9±11.8%; control+N-nitro-l-arginine methyl ester=74.0±10.4%; P<0.01), suggesting that angiotensin-(1-9) improved basal NO bioavailability in an angiotensin type 2 receptor-sensitive manner. In summary, angiotensin-(1-9) reduced cardiac fibrosis and altered aortic contraction via the angiotensin type 2 receptor supporting a direct role for angiotensin-(1-9) in the renin-angiotensin system.
肾素-血管紧张素系统通过血管紧张素 II 与血管紧张素 1 型或 2 型受体结合来调节心血管生理学。经典作用是由 1 型受体介导的，而 2 型受体可能拮抗 1 型受体的活性。血管紧张素转换酶 2 将血管紧张素 II 代谢为血管紧张素-(1-7)和血管紧张素 I 为血管紧张素-(1-9)。血管紧张素-(1-7)通过受体 Mas 拮抗血管紧张素 II 的作用。最近的研究表明，血管紧张素-(1-9)通过血管紧张素 2 型受体阻断心肌细胞肥大。在这里，我们通过血管紧张素 2 型受体研究了血管紧张素-(1-9)的体内作用。通过渗透微型泵以 100ng/kg/分钟的速度输注血管紧张素-(1-9)(或同时输注血管紧张素 2 型受体拮抗剂 PD123319100ng/kg/分钟)或单独输注 PD123319，共 4 周，用于易发生中风的自发性高血压大鼠。我们通过无线电遥测测量血压，通过超声心动图测量心脏结构和功能。血管紧张素-(1-9)不影响血压或左心室质量指数，但通过调节胶原蛋白 I 的表达将心脏纤维化减少 50%(P<0.01)，这一作用可被 PD123319 共输注所逆转。此外，血管紧张素-(1-9)在体外以 PD123319 敏感的方式抑制成纤维细胞增殖。主动脉血管张力研究显示，与对照组相比，血管紧张素-(1-9)在 N-硝基-L-精氨酸甲酯处理后显著增加了对苯肾上腺素的收缩反应，这一作用被 PD123319 共输注所消除(曲线下面积：血管紧张素-(1-9)+N-硝基-L-精氨酸甲酯=98.9±11.8%；对照+N-硝基-L-精氨酸甲酯=74.0±10.4%；P<0.01)，这表明血管紧张素-(1-9)以血管紧张素 2 型受体敏感的方式改善了基础 NO 的生物利用度。总之，血管紧张素-(1-9)通过血管紧张素 2 型受体减少心脏纤维化和改变主动脉收缩，支持血管紧张素-(1-9)在肾素-血管紧张素系统中发挥直接作用。
