Glucocorticoids Reverse Diluted Hyponatremia Through Inhibiting Arginine Vasopressin Pathway in Heart Failure Rats.

Background Arginine vasopressin dependent antidiuresis plays a key role in water-sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result in hyponatremia, all of which can be reversed by glucocorticoid supplement. Methods and Results Heart failure was induced by coronary artery ligation for 8 weeks. A total of 32 rats were randomly assigned to 4 groups (n=8/group): sham surgery group, congestive heart failure group, dexamethasone group, and dexamethasone in combination with glucocorticoid receptor antagonist RU486 group. An acute water loading test was administered 6 hours after drug administration. Left ventricular function was measured by a pressure-volume catheter. Protein expressions were determined by immunohistochemistry and immunoblotting. The pressure-volume loop analysis showed that dexamethasone improves cardiac function in rats with heart failure. Western blotting confirmed that dexamethasone remarkably reduces the expressions of V2R, aquaporin 2, and aquaporin 3 in the renal-collecting ducts. As a result of V2R downregulation, the expressions of glucocorticoid regulated kinase 1, apical epithelial sodium channels, and the furosemide-sensitive Na-K-2Cl cotransporter were also downregulated. These favorable effects induced by dexamethasone were mostly abolished by the glucocorticoid receptor inhibitor RU486, indicating that the aforementioned effects are glucocorticoid receptor mediated. Conclusions Glucocorticoids can reverse diluted hyponatremia via inhibiting the vasopressin receptor pathway in rats with heart failure.

Endothelin production in the rabbit collecting ducts of acute renal failure models. An immunohistochemical study.

Endothelin 1 (ET-1) production was examined in the rabbit nephron in acute renal failure (ARF) induced by uranyl acetate administration or by clamping the renal artery. Uranyl acetate dissolved in saline was injected intravenously at a dose of 0.8 mg/kg (n = 12). In the ischemic kidney experiment, 60 min of left renal artery clamping was carried out 1 week after removing the right kidney (n = 8). Plasma and urine concentrations of ET-1 were measured 0, 24, and 48 h after treatment, and immunohistochemical studies of renal tissues obtained 48 h after the experiments were carried out using ET-1 monoclonal antibody. The fractional excretion of ET-1 increased from 10 to 89% at 48 h in the uranyl acetate treated group and from 6 to 15% at 24 h in the renal artery clamping group, suggesting the existence of ET-1 secretion from the nephron in both types of ARF. By immunohistochemical examination, strong ET-1 expression was noted only in the collecting ducts. No staining was observed in other parts of the nephron in both types of ARF. The present study indicates that the increased expression of ET-1 probably reflects production by the collecting ducts in both rabbit ARF models.

Compensatory hypertrophy and adaptation in the cortical collecting duct.

The cortical collecting duct (CCD) undergoes hypertrophy and functional adaptation following reduction of renal mass. The nature and mechanisms of these changes have been investigated using microperfusion of isolated CCD from rabbit remnant kidneys. By 1 week after reduction of renal mass, tubule hypertrophy and increased sodium transport are fully developed. The transport adaptations are specific or selective, since bicarbonate transport in these CCD is unchanged. Mineralocorticoids may play an important role in the hypertrophy and increased sodium transport, since plasma aldosterone increases early after reduction of renal mass. Also, adrenalectomy abolishes the changes in size and sodium transport, even with supplementation of aldosterone to unstressed physiologic levels. Epidermal growth factor also has immediate effects on CCD sodium transport; however, the direction of the effect is opposite--an inhibition of transport.