This study of seven healthy young subjects was designed both to establish whether endothelin-1 (ET-1) is involved in the homeostasis of blood volume and to clarify the relationship between plasma and urinary ET-1. Acute volume expansion (+17%) caused increases in venous blood pressure (+4.4 mmHg) and the plasma concentration of ET-1 (+129%) and a decrease (-99%) in the urinary excretion of ET-1. Volume depletion (-8.5%) provoked an increase in the plasma concentration of ET-1 without altering the urinary excretion of ET-1. Passive elevation of an arm resulting in a local decrease of venous blood pressure (-17 mmHg) elicited an increase of the local formation of ET-1, with a 10-fold increase in the venous-arterial gradient compared with the opposite arm, which lay at the level of the heart. The increased local formation of ET-1 was blunted by volume expansion. The results indicate that 1) plasma ET-1 and urinary ET-1 represent two different endothelin-generating systems, both of which are involved in the regulation of blood volume, and 2) plasma ET-1 appears to be an important mechanism for the long-lasting adaptations of venous wall tension to changes in blood volume.

. Increased renal endothelin formation is associated with sodium retention and increased free water clearance. Am. J. Physiol. 275 (Heart Circ. Physiol. 44): H1070-H1077, 1998.-To investigate whether renal endothelin (ET)-1 participates in water and sodium handling, we investigated the influence of different sodium intakes on renal production of ET-1 in eight healthy subjects. The functional relationship with the reninangiotensin system was also studied. Renal ET-1 formation is affected by sodium intake, because 1 wk of high sodium decreased urinary ET-1 excretion (Ϫ34%, P Ͻ 0.05), whereas a low-sodium diet increased ET-1 excretion (66%, P Ͻ 0.05) and mRNA expression for preproendothelin-1 in epithelial cells of medullary collecting ducts and endothelial cells of the peritubular capillary network. Increased ET-1 renal synthesis was associated with sodium retention and increased free water clearance. Urinary ET-1 excretion changes from normal to low-sodium diet were negatively related to contemporary changes in sodium excretion (r ϭ 0.97, P Ͻ 0.05) and were positively correlated with free water clearance (r ϭ 0.97, P Ͻ 0.05). These correlations were maintained during angiotensin-converting enzyme inhibition, which only partially reduced ET-1 renal excretion. These results indicate that renal ET-1 production is indeed modulated by varying sodium intakes and may exert a role in sodium and water handling. sodium balance; renal function; urine; angiotensin II ABUNDANT EXPRESSION of endothelin (ET)-1 peptide and mRNA for its precursor, preproendothelin-1 (prepro-ET-1), have been found in the vascular endothelium of the renal vascular bed, including glomerular capillaries, arterioles, and peritubular capillaries (15,24). Subsequent studies have demonstrated that ET-1 is present in high concentrations in the inner medulla of the kidney (24), where ET-1 receptors are also located (5), and that ET-1 secretion is not limited to vascular endothelium, because primary epithelial cell cultures derived from the renal tubule secrete abundant amounts of ET-1 (10). ET-1 secretion in the renal medulla is highly compartmentalized in tubules with the following secretion hierarchy: inner medullary collecting ducts (IMCD) Ͼ medullary thick ascending limb Ͼ cortical collecting ducts Ͼ proximal tubule (11,29).The physiological activities of ET-1 on renal sodium and water handling still remain to be clarified (11). Convincing evidence exists that ET-1 may inhibit arginine vasopressin (AVP)-stimulated water reabsorption in the collecting ducts. Several studies have demonstrated that ET-1 binding to the ET B receptor subtype reduces Na ϩ -K ϩ -ATPase activity in the IMCD (34) and inhibits vasopressin-stimulated cAMP accumulation and water transport on isolated cortical collecting ducts from rats (23, 30). These and other studies (11,29) indicate that ET-1 might regulate water reabsorption independently of its effects on Na ϩ reabsorption or renal hemodynamics.Studies investigating the activity of ET-1 on sodium reabsorption have given confl...

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