Gender-specific hypertension and responsiveness to nitric oxide in sGCalpha1 knockout mice.
OBJECTIVE
The effects of nitric oxide (NO) in the cardiovascular system are attributed in part to cGMP synthesis by the alpha1beta1 isoform of soluble guanylate cyclase (sGC). Because available sGC inhibitors are neither enzyme- nor isoform-specific, we generated knockout mice for the alpha1 subunit (sGCalpha1(-/-) mice) in order to investigate the function of sGCalpha1beta1 in the regulation of blood pressure and cardiac function.


RESULTS
Blood pressure was evaluated, using both non-invasive and invasive haemodynamic techniques, in intact and gonadectomized male and female sGCalpha1(-/-) and wild-type (WT) mice. Cardiac function was assessed with a conductance catheter inserted in the left ventricle of male and female sGCalpha1(-/-) and WT mice. Male sGCalpha1(-/-) mice developed hypertension (147 +/- 2 mmHg), whereas female sGCalpha1(-/-) 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 sGCalpha1(-/-) mice but not in WT mice. The NO synthase inhibitor Nomega-nitro-L-arginine methyl ester hydrochloride raised blood pressure similarly in male and female WT and sGCalpha1(-/-) mice. The ability of NO donor compounds to reduce blood pressure was slightly attenuated in sGCalpha1(-/-) 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 sGCalpha1(-/-) mice.


CONCLUSIONS
These findings demonstrate that sGCalpha1beta1-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 sGCalpha1beta1.
Buys
Emmanuel S
ES
Department for Molecular Biomedical Research, Flanders Institute for Biotechnology , Technologiepark 927, B-9052 Ghent, Belgium.
Sips
Patrick
P
Vermeersch
Pieter
P
Raher
Michael J
MJ
Rogge
Elke
E
Ichinose
Fumito
F
Dewerchin
Mieke
M
Bloch
Kenneth D
KD
Janssens
Stefan
S
Brouckaert
Peter
P
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007527:Isoenzymes; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D009919:Orchiectomy; D010052:Ovariectomy; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013739:Testosterone / Q000378:metabolism; D014655:Vascular Resistance / Q000502:physiology
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D007527:Isoenzymes; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D013739:Testosterone; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP