Abstract 5079: Hypertension in Soluble Guanylate Cyclase α1- Deficient Mice is Associated With Hyperaldosteronism
Introduction. Hypertension is an important modifiable risk factor for cardiovascular disease. Altered activity of both the renin-angiotensin system (RAS) and the nitric oxide (NO)-cGMP signaling pathway have been associated with hypertension. However, the interaction of the RAS and the NO-cGMP signaling pathway remains incompletely characterized. We previously reported that male mice deficient in the α1 subunit of soluble guanylate cyclase (sGCα1−/− mice), an important NO receptor, develop hypertension. Here, we hypothesized that increased activity of the RAS underlies the hypertension associated with sGCα1-deficiency.
Methods. Plasma renin activity and aldosterone were measured in the plasma of anesthetized (100 mg/kg ketamine, 5 mg/kg xylazine) 12–14 weeks old male wild-type (WT) and sGCα1−/− mice by radioimmunoassay. Na+ and K+ were analyzed using Spotchem blood chemistry. Blood pressure was measured invasively (Millar pressure volume catheter) in male WT and sGCα1−/− mice, treated with vehicle or the aldosterone receptor antagonist, Spironolactone (100 mg/kg/day, sc for 7 days).
Results. PRA was higher in sGCα1−/− than in WT mice (0.29±0.01 vs 0.23±0.03 μg/ml/hr, respectively, P<0.05). Plasma levels of aldosterone were elevated in sGCα1−/− mice as compared to WT mice (0.47±0.03 vs 0.34±0.03 ng/ml, respectively, P<0.05). Correlating with the hyperaldosteronism seen in sGCα1−/− mice, plasma K+ levels were higher (5.4±0.2 vs 4.4±0.2 mEq/L, respectively, P<0.05), and plasma Na+ levels were lower (144±0 vs 146±1 mEq/L, respectively, P<0.05) in sGCα1−/− mice than in WT mice. Mean arterial pressure (MAP) was the same in WT mice treated with Spironolactone or vehicle (131±5 vs 137±3 mmHg, respectively), but MAP was less in sGCα1−/− mice after treatment with Spironolactone than after treatment with vehicle (125±8 vs 173±14 mmHg, respectively, P<0.01).
Conclusions. Together, these data suggest that altered RAS activity and, more specifically, increased aldosterone signaling, contribute to the hypertension associated with sGCα1-deficiency. These findings highlight the importance of sGC in the regulation of the RAS and suggest that sGC may be a therapeutic target in renin-dependent hypertension.