Abstract 1293: Gender-specific And Testosterone-dependent Hypertension In Soluble Guanylate Cyclase α1-deficient Mice.
Introduction. The clinical relevance of gender differences in cardiovascular pathology and the underlying molecular mechanisms are increasingly recognized, prompting scientists and clinicians to consider gender-specific treatment for cardiovascular diseases. Nitric oxide (NO) plays a major role in regulating vascular tone and myocardial function and appears to have a gender-specific modulatory role on blood pressure (BP) regulation. However, the downstream signaling pathways remain incompletely elucidated. Soluble guanylate cyclase (sGC) is a major target of NO. We generated sGCα1 knockout (sGCα1−/−) mice in order to investigate the function of sGCα1β1, the predominant isoform in the cardiovascular system, in the regulation of blood pressure and cardiac function.
Methods. Cardiovascular parameters were studied in male and female wild-type (WT) and sGCα1−/− mice using non-invasive (Visitech tail-cuff device) and invasive (Millar pressure volume catheter) methods. BP was measured in male sGCα1−/− mice before and after orchiectomy or treatment with the testosterone receptor antagonist flutamide (40 mg/kg, sc, daily, for 5 weeks) and in female sGCα1−/− mice before and after ovariectomy.
Results. sGCα1-deficiency was associated with impaired ventricular relaxation as demonstrated by a prolonged time constant of isovolumic relaxation (τ, 4.6±0.1 vs 5.2±0.1 and 4.5±0.1 vs 4.8±0.1 in WT and sGCα1−/−, male and female mice respectively, P<0.05 for both) and with increased cardiac contractility as shown by an increased end-systolic pressure/ volume ratio (Ees, 15±2 vs 56±3 and 12±1 vs 39±6 in WT and sGCα1−/−, male and female mice respectively, P<0.05 for both). Male sGCα1−/− mice developed hypertension (157±3 mmHg vs 121±2 in WT, P<0.05), whereas female sGCα1−/− mice did not. Orchiectomy or administration of flutamide prevented hypertension in male sGCα1−/− mice (120±7 and 124±11, respectively), but ovariectomy did not influence BP in female sGCα1−/− mice.
Conclusions. We suggest that NO-cGMP signaling has a gender-specific and testosterone-dependent impact on cardiovascular function. sGC activators, under development for the treatment of hypertension and other cardiovascular diseases, may have differing efficacy in males and females.