Sex-Specific Influence of Angiotensin Type 2 Receptor Stimulation on Renal Function A Novel Therapeutic Target for Hypertension
Sex-Specific Influence of Angiotensin Type 2 Receptor Stimulation on Renal Function A Novel Therapeutic Target for Hypertension
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DOI：
10.1161/hypertensionaha.111.184986
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发表时间：
2012-02-01
期刊：
影响因子：
8.3
通讯作者：
Denton, Kate M.
中科院分区：
文献类型：
--
作者：
Hilliard, Lucinda M.;Jones, Emma S.;Denton, Kate M.
肾素-血管紧张素系统是动脉压和体液容量的强大调节器。越来越多的证据表明，血管紧张素2型受体（AT（2）R），介导血管紧张素肽的血管舒张和利钠作用，在女性中增强，因此，可能是一个创新的治疗靶点。我们研究了直接刺激AT（2）R对11- 12周龄麻醉雄性和雌性Sprague-Dawley大鼠肾功能的治疗潜力。在存在和不存在AT（2）R阻断（PD 123319; 1 mg/kg/h）的情况下，对高选择性非肽类AT（2）R激动剂化合物21（100、200和300 ng/kg/min）的分级输注反应进行肾血流量检查。直接AT（2）R刺激显著增加雄性和雌性动物的肾血流量，而不影响动脉压。这仅在雌性中是剂量依赖性的，并且在施用最高剂量的化合物21时在雌性中更大程度地发生（雄性：13.1 +/-2.4%相对于雌性：在300 ng/kg/min相对于基线时肾血流量变化23.0 +/-3.2%; P < 0.01）。此外，AT（2）R刺激显著增加了雄性和雌性的钠和水排泄，程度相似（P组= 0.05和0.005）。然而，两种性别的肾小球滤过率均无显著变化，提示肾小管功能改变可能是AT（2）R诱导的尿钠排泄而非血流动力学效应的原因。综上所述，本研究提供了直接刺激AT（2）R在男性和女性肾脏中产生血管舒张和利钠作用的证据。因此，AT（2）R可能是治疗男性和女性肾脏和心血管疾病的有价值的治疗靶点。（高血压。2012; 59[第2部分]：409-414。
The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT(2)R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT(2)R stimulation on renal function in 11- to 12-week-old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT(2)R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT(2)R blockade (PD123319; 1 mg/kg per hour). Direct AT(2)R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1 +/- 2.4% versus females: 23.0 +/- 3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; P < 0.01). In addition, AT(2)R stimulation significantly increased sodium and water excretion to a similar extent in males and females (P-Group = 0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT(2)R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT(2)R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT(2)R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women. (Hypertension. 2012; 59[part 2]: 409-414.)