In heart failure, the renal response 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 the 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 increase the expression of NPR-A in the IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 hours and peaked after 48 hours. The cultured IMCD cells were, then, stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cyclic guanosine monophosphate (cGMP, the second messenger for the ANP) generation in the 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. Of note, Dex dramatically lowered plasma ANP, cGMP levels and left ventricular end diastolic pressure. These favourable effects induced by Dex were glucocorticoid receptor (GR) mediated and were abolished by the GR antagonist RU486. Collectively, glucocorticoids could improve renal response to ANP by upregulating NPR-A expression in the IMCD and induce a potent diuretic action in decompensated heart failure rats.
- Received June 6, 2011.
- Revision received July 1, 2011.
- Accepted July 5, 2011.
- The American Society for Pharmacology and Experimental Therapeutics