DOCA/Salt: much more than a model of hypertension.

Mineralocorticoid excess produces inflammation, hypertrophy, and fibrosis independently of its effects on sodium balance and blood pressure. Mineralocorticoids act through the mineralocorticoid receptor (MR) which mediates transcriptional and rapid non-genomic effects in non-epithelial cells including cardiomyocytes, vascular endothelial and smooth muscle cells, macrophages and T-cells, and neurons. DOCA, an inactive pro-drug, is converted to DOC with variable efficiency in different cells types. The affinities of DOC and aldo for the MR are similar; the affinity of DOC for the glucocorticoid receptor (GR) is greater than that of aldosterone. As DOC is rapidly inactivated in the kidney, doses of DOCA required to increase renal sodium and water resorption produce relatively greater non-renal effects and concentrations of DOC that activate both MR and GR. Thus the DOCA excess is not equivalent to endogenous aldosterone excess. Nonetheless, the mechanisms of both steroids that produce cardiovascular inflammation and remodeling are direct and independent of hypertension, as well as indirect, through increased blood pressure.