Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 13, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn068
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Gender-specific hypertension and responsiveness to nitric oxide in sGC
1 knockout mice
a Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), Technologiepark 927, B-9052 Ghent, Belgium
b Department of Molecular Biology, Ghent University, B-9052 Ghent Belgium
c Centre for Transgene Technology and Gene Therapy, University of Leuven and VIB, Herestraat 49, B-3000 Leuven, Belgium
d Cardiovascular Research Center, Massachusetts General Hospital, 149, 13th street, Charlestown, MA 02129
e Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 50, Blossom Street, Boston, MA 02114
To whom correspondence should be addressed: E-mail: Peter.Brouckaert{at}dmbr.Ugent.be Tel: +32 9 33 13 710; Fax: +32 9 33 13 609 Technologiepark 927, B-9052 Ghent, Belgium
Aim: The effects of nitric oxide (NO) in the cardiovascular system are attributed in part to cGMP synthesis by the 
1β1 isoform of soluble guanylate cyclase (sGC). Because available sGC inhibitors are neither enzyme- nor isoform-specific, we generated knockout mice for the 1 subunit (sGC1–/- mice) in order to investigate the function of sGC1β1 in the regulation of blood pressure and cardiac function.
Methods: Blood pressure was evaluated, using both non-invasive and invasive hemodynamic techniques, in intact and gonadectomized male and female sGC1–/- and wild-type (WT) mice. Cardiac function was assessed with a conductance catheter inserted in the left ventricle of male and female sGC1–/- and WT mice.
Results: Male sGC1–/- mice developed hypertension (147±2 mmHg), while female sGC1–/- 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 sGC1–/- mice but not in WT mice. The NO synthase inhibitor N
-nitro-L-arginine methyl ester hydrochloride raised blood pressure similarly in male and female WT and sGC1–/- mice. The ability of NO donor compounds to reduce blood pressure was slightly attenuated in sGC1–/- 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 sGC1–/- mice.
Conclusions: These findings demonstrate that sGC1β1-derived cGMP signaling has gender-specific and testosterone-dependent cardiovascular effects and reveal that the effects of NO on systemic blood pressure do not require sGC1β1.
KEYWORDS nitric oxide; gender; hypertension; blood pressure; ventricular function
Time for primary review: 23 days
* These authors contributed equally to this work.
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