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1 Department of Pharmacology, the Panum Institute, University of Copenhagen, DK-2200 Copenhagen; and 2 Department of Cell Biology, Institute of Anatomy, University of Århus, DK-8000 Århus, Denmark
Previous studies have suggested that
mineralocorticoids are needed for a normal action of vasopressin on
collecting duct osmotic water permeability. However, the mechanisms
behind this are unknown. To investigate if aldosterone-receptor
blockade influences vasopressin type 2 receptor
(V2)-mediated renal water
reabsorption and the renal expression of the vasopressin-regulated
water channel aquaporin-2 (AQP2), rats were treated with the
aldosterone-receptor antagonist canrenoate (20 mg/day iv) for 4 wk.
Daily urine flow was increased significantly by 44%, and urine
osmolality was decreased by 27% in canrenoate-treated rats. Acute
V2-receptor blockade (OPC-31260, 800 µg · kg
1 · h1)
was performed under conditions in which volume depletion was prevented.
In control rats, OPC-31260 induced a significant increase in urine flow
rate (V, +25%) and free water clearance
(CH2O,
29%). In canrenoate-treated rats, the effect of OPC-31260 was
significantly reduced, and semiquantiative immunoblotting demonstrated
a significant reduction (45%) in AQP2 expression. Because rats with
common bile duct ligation (CBL) have a reduced vasopressin-mediated
water reabsorption compared with normal rats (V: 24%;
CH2O:
28%, and 86% downregulation of AQP2), the effect of canrenoate
combined with OPC-31260 was tested. Canrenoate treatment of CBL rats
significantly increased daily urine flow, decreased urine osmolality,
and impaired the aquaretic response to OPC-31260 (V: 23%;
CH2O:
31%) with maintained suppression of the renal AQP2 expression.
Thus canrenoate treatment of normal and CBL rats showed
1) increased urine production, 2) reduced aquaretic effect of acute
V2-receptor blockade, and 3) a marked reduction in AQP2
expression. This strongly supports the view that aldosterone plays a
significant role for vasopressin-mediated water reabsorption.
aquaporin-2; V2-receptor; OPC-31260; collecting ducts; canrenoate; cirrhosis
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