Gender-specific hypertension and responsiveness to nitric oxide in sGCα1 knockout mice

Abstract

Aim: The effects of nitric oxide (NO) in the cardiovascular system are attributed in part to cGMP synthesis by the α1β 1 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 sGCα 1-/- 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 sGCα1β 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 sGCα1β 1. © The Author 2008.