In
heart failure, the renal responsiveness to exogenous and endogenous
atrial natriuretic peptide (
ANP) is blunted. The mechanisms of renal hyporesponsiveness to
ANP are complex, but one potential mechanism is decreased expression of
natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that
glucocorticoids could produce potent diuresis and natriuresis in patients with
heart failure, but the precise mechanism is unclear. In the present study, we found
dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat
ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the
ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated
heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal
sodium excretion. It is noteworthy that Dex dramatically lowered plasma
ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were
glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (
RU486). Collectively,
glucocorticoids could improve renal responsiveness to
ANP by up-regulating NPR-A expression in the IMCD and induce a potent
diuretic action in rats with decompensated
heart failure.