Gender-specific hypertension and responsiveness to nitric oxide in sGCα1 knockout mice
Gender-specific hypertension and responsiveness to nitric oxide in sGCα1 knockout mice
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DOI：
10.1093/cvr/cvn068
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发表时间：
2008-07-01
影响因子：
10.8
通讯作者：
Brouckaert, Peter
中科院分区：
文献类型：
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作者：
Buys, Emmanuel S.;Sips, Patrick;Brouckaert, Peter
目的可溶性鸟苷酸环化酶（sGC）α（1）β（1）亚型合成环鸟苷酸（cGMP）是一氧化氮（NO）在心血管系统中发挥作用的部分机制。因为现有的sGC抑制剂既不是酶特异性的，也不是亚型特异性的，我们产生了α 1亚基的敲除小鼠。（sGC α（-/-）（1）小鼠），以研究sGC α（1）β（1）在血压和心脏功能调节中的功能。方法和结果使用非侵入性和侵入性血流动力学技术评估血压，在完整和性腺切除的雄性和雌性sGC α（-/-）（1）和野生型（WT）小鼠中。在雄性和雌性sGC α（-/-）（1）和WT小鼠的左心室插入电导导管，评估心脏功能。雄性sGC alpha（-/-）（1）小鼠出现高血压（147 +/- 2 mmHg），而雌性sGC alpha（-/-）（1）小鼠未出现高血压（115 +/- 2 mmHg）。睾丸切除术和雄激素受体拮抗剂治疗可预防高血压，而卵巢切除术不影响表型。长期睾酮治疗增加了卵巢切除sGC α（-/-）（1）小鼠的血压，但在WT小鼠中没有。NO合成酶抑制剂N-ω-硝基-L-精氨酸甲酯盐酸盐在雄性和雌性WT和sGC alpha（-/-）小鼠中升高血压的作用相似（1）。与WT小鼠相比，sGC alpha（-/-）（1）雄性和雌性小鼠中NO供体化合物降低血压的能力略有减弱。直接sGC刺激剂BAY 41-2272仅在WT小鼠中降低血压。结论sGC α（1）β（1）源性cGMP信号具有性别特异性和睾酮依赖性心血管效应，NO对体循环血压的影响不依赖于sGC α（1）β（1）。
Aim The effects of nitric oxide (NO) in the cardiovascular system are attributed in part to cGMP synthesis by the alpha(1)beta(1) isoform of soluble guanylate cyclase (sGC). Because available sGC inhibitors are neither enzyme-nor isoform-specific, we generated knockout mice for the alpha(1) subunit (sGC alpha(-/-)(1) mice) in order to investigate the function of sGC alpha(1)beta(1) in the regulation of blood pressure and cardiac function.Methods and results Blood pressure was evaluated, using both non-invasive and invasive haemodynamic techniques, in intact and gonadectomized male and female sGC alpha(-/-)(1) and wild-type (WT) mice. Cardiac function was assessed with a conductance catheter inserted in the left ventricle of male and female sGC alpha(-/-)(1) and WT mice. Male sGC alpha(-/-)(1) mice developed hypertension (147 +/- 2 mmHg), whereas female sGC alpha(-/-)(1) mice did not (115 +/- 2 mmHg). Orchidectomy and treatment with an androgen receptor antagonist prevented hypertension, while ovariectomy did not influence the phenotype. Chronic testosterone treatment increased blood pressure in ovariectomized sGC alpha(-/-)(1) mice but not in WT mice. The NO synthase inhibitor N-omega-nitro-L-arginine methyl ester hydrochloride raised blood pressure similarly in male and female WT and sGC alpha(-/-)(1) mice. The ability of NO donor compounds to reduce blood pressure was slightly attenuated in sGC alpha(-/-)(1) male and female mice as compared to WT mice. The direct sGC stimulator BAY 41-2272 reduced blood pressure only in WT mice. Increased cardiac contractility and arterial elastance as well as impaired ventricular relaxation were observed in both male and female sGC alpha(-/-)(1) mice.Conclusion These findings demonstrate that sGC alpha(1)beta(1)-derived cGMP signalling has gender- specific and testosterone-dependent cardiovascular effects and reveal that the effects of NO on systemic blood pressure do not require sGC alpha(1)beta(1).