Gender-specific hypertension and responsiveness to nitric oxide in sGCa1 knockout mice
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Raher, Michael J.
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CitationBuys, Emmanuel S., Patrick Sips, Pieter Vermeersch, Michael J. Raher, Elke Rogge, Fumito Ichinose, Mieke Dewerchin, Kenneth D. Bloch, Stefan Janssens, and Peter Brouckaert. 2008. “Gender-Specific Hypertension and Responsiveness to Nitric Oxide in sGCa1 Knockout Mice.” Cardiovascular Research 79 (1) (March 13): 179–186. doi:10.1093/cvr/cvn068.
AbstractAim: The effects of nitric oxide (NO) in the cardiovascular system are attributed in part to cGMP synthesis by the α1β1 isoform of soluble guanylate cyclase (sGC). Because available sGC inhibitors are neither enzyme- nor isoform-specific, we generated knockout mice for the α1 subunit (sGCα1−/− mice) in order to investigate the function of sGCα1β1 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 sGCα1−/− and wild-type (WT) mice. Cardiac function was assessed with a conductance catheter inserted in the left ventricle of male and female sGCα1−/− and WT mice. Male sGCα1−/− mice developed hypertension (147 ± 2 mmHg), whereas female sGCα1−/− 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 sGCα1−/− mice but not in WT mice. The NO synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride raised blood pressure similarly in male and female WT and sGCα1−/− mice. The ability of NO donor compounds to reduce blood pressure was slightly attenuated in sGCα1−/− 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 sGCα1−/− mice. Conclusion: These findings demonstrate that sGCα1β1-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 sGCα1β1.
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