Abstract 5079: Hypertension in Soluble Guanylate Cyclase α 1 - Deficient Mice is Associated With Hyperaldosteronism

Abstract

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 α 1 subunit of soluble guanylate cyclase (sGC α 1 −/− mice), an important NO receptor, develop hypertension. Here, we hypothesized that increased activity of the RAS underlies the hypertension associated with sGC α 1 -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 sGC α 1 −/− 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 sGC α 1 −/− mice, treated with vehicle or the aldosterone receptor antagonist, Spironolactone (100 mg/kg/day, sc for 7 days). Results . PRA was higher in sGC α 1 −/− than in WT mice (0.29±0.01 vs 0.23±0.03 μ g/ml/hr, respectively, P<0.05). Plasma levels of aldosterone were elevated in sGC α 1 −/− 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 sGC α 1 −/− 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 sGC α 1 −/− 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 sGC α 1 −/− 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 sGC α 1 -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.