期刊
CARDIOVASCULAR RESEARCH
卷 79, 期 1, 页码 179-186出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvn068
关键词
nitric oxide; gender; hypertension; blood pressure; ventricular function
资金
- NHLBI NIH HHS [HL070896] Funding Source: Medline
- NIGMS NIH HHS [GM079360] Funding Source: Medline
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).
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