Endothelin ETA Receptor Blockade With Darusentan Increases Sodium and Potassium Excretion in Aging Rats

Abstract

This study investigated whether intrarenal endothelin-1(ET-1) contributes to sodium excretion in aged rats. Metabolic function studies were performed in male Wistar rats (3 and 24 months) treated with placebo or the orally active ET(A) receptor antagonist darusentan (20 mg/kg/d) for 4 weeks. Mean arterial pressure was measured using an intra-arterial catheter. Electrolytes, aldosterone levels, renin activity, and angiotensin converting enzyme activity were determined in plasma, and mRNA expression of epithelial sodium channel (ENaC) and Na(+), K(+)-ATPase subunits was measured in the renal cortex and medulla. Aging was associated with a marked decrease in urinary excretion of sodium, chloride, and potassium (all P < 0.001) as well as renin activity (P < 0.05), but had no significant effect on gene expression of ENaC or Na(+), K(+)-ATPase subunits. In aged rats, darusentan treatment increased ion excretion (P < 0.05), reduced cortical gene expression of alphaENaC and alpha(1)-Na(+), K(+)-ATPase (both P < 0.05), and increased plasma aldosterone levels (P < 0.01). These data demonstrate a decrease of sodium and potassium excretion in aged rats, changes that are partly sensitive to ETA receptor blockade. Treatment with darusentan also reduced cortical expression of alphaENaC and alpha(1)-Na(+), K(+)-ATPase and increased plasma aldosterone levels independently of blood pressure, electrolytes, renin activity, or angiotensin converting enzyme activity. These findings may provide new pathogenetic links between aging and sodium sensitivity.