Atrial natriuretic peptide (ANP) provides a potent defense mechanism against volume overload in mammals. Its primary receptor, natriuretic peptide receptor-A (NPR-A), is localized mostly in the kidney, but also is found in hypothalamic areas involved in body fluid volume regulation. Acute glucocorticoid administration produces potent diuresis and natriuresis, possibly by acting in the renal natriuretic peptide system. However, chronic glucocorticoid administration attenuates renal water and sodium excretion. The precise mechanism underlying this paradoxical phenomenon is unclear. We assume that chronic glucocorticoid administration may activate natriuretic peptide system in hypothalamus, and cause volume depletion by inhibiting dehydration-induced water intake. Volume depletion, in turn, compromises renal water excretion. To test this postulation, we determined the effect of dexamethasone on dehydration-induced water intake and assessed the expression of NPR-A in the hypothalamus. The rats were deprived of water for 24 hours to have dehydrated status. Prior to free access to water, the water-deprived rats were pretreated with dexamethasone or vehicle. Urinary volume and water intake were monitored. We found that dexamethasone pretreatment not only produced potent diuresis, but dramatically inhibited the dehydration-induced water intake. Western blotting analysis showed the expression of NPR-A in the hypothalamus was dramatically upregulated by dexamethasone. Consequently, cyclic guanosine monophosphate (the second messenger for the ANP) content in the hypothalamus was remarkably increased. The inhibitory effect of dexamethasone on water intake presented in a time- and dose-dependent manner, which emerged at least after 18-hour dexamethasone pretreatment. This effect was glucocorticoid receptor (GR) mediated and was abolished by GR antagonist RU486. These results indicated a possible physiologic role for glucocorticoids in the hypothalamic control of water intake and revealed that the glucocorticoids can act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume.

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 17␤-hydroxy-11␤-[4-dimethylamino phenyl]-17␣-[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.

The present study demonstrated that prednisone can rapidly eliminate volume overload and improve clinical status and renal function in CHF patients with diuretic resistance. Further prospective randomized clinical studies are warranted to confirm its clinical efficacy.

This pilot study showed that prednisone had potent potentiating diuretic effects in patients with heart failure and might improve renal function in the same time. Further prospective randomized clinical studies are warranted to determine the preferable dose and its efficacy in decompensated congestive heart failure.