Guanylyl cyclase-A, an underestimated player in aldosterone downregulation?

Exogenous natriuretic peptides (NPs) were shown to inhibit adrenal aldosterone release, suggesting the presence of a cardiomyocyte-adrenal zona glomerulosa (ZG) endocrine communication. However, the exact link between natriuretic peptides (NPs) and aldosterone downregulation is yet unknown. To dissect whether ANP/BNP regulates aldosterone release in vivo, we generated mice with ZG-restricted GC-A deletion (KO), i.e., disrupting the suggested aldosterone inhibitory signaling pathway, and analyzed in the high-salt diet 4% (HSD) model. Animals were fed a normal salt diet (basal level, NSD) and then HSD for 2 weeks. Arterial blood pressure was measured by tail cuff in awake mice. At a baseline (NSD), both systolic and diastolic BP did not differ between the genotypes, while HSD was associated with a significant BP increase, being more pronounced in the KOs. After 2 weeks of HSD, terminal pressure-volume loop analysis confirmed the observed differences and indicated increased cardiac output and stroke volume in KOs under HSD. Further PAS-stained left ventricle section morphometry revealed the cardiomyocyte hypertrophy trend in the KOs. Adrenal weights did not differ between the genotypes, however aldosterone synthase mRNA expression tended to be lower in KOs. Nevertheless, in ZG GC-A KO, a significantly higher plasma aldosterone level was observed, indicating an important role of GC-A in aldosterone release downregulation. Our results suggest endogenous NPs mediate an endocrine cardiomyocyte communication to the adrenal ZG cells, ultimately moderating aldosterone release. This axis could contribute to the physiological maintenance of intravascular volume and arterial blood pressure, protecting the heart from pathological inflammation and remodeling.