Decreased vasopressin-mediated renal water reabsorption in rats with compensated liver cirrhosis.
Experiments were performed to investigate vasopressin type 2 receptor (V2)-mediated renal water reabsorption and the renal expression of the vasopressin-regulated water channel aquaporin-2 (AQP-2) in cirrhotic rats with sodium retention but without ascites. In addition, the expression of the furosemide-sensitive type 1 Na-K-2Cl cotransporter (BSC-1) and the natriuretic response to an intravenous test dose furosemide (7.5 mg/kg) during acute V2-receptor blockade was measured. Acute V2-receptor blockade with the selective nonpeptide antagonist OPC-31260 (800 microg . kg-1 . h-1) was performed during conditions in which volume depletion was prevented by computer-driven, servo-controlled intravenous volume replacement with 150 mM glucose. OPC-31260 produced a significantly smaller increase in urine flow rate (-26%) and free water clearance (-18%) in cirrhotic rats than in control rats. The natriuretic response to an intravenous test dose furosemide (7.5 mg/kg) was significantly increased in cirrhotic rats (+52%), but pretreatment with OPC-31260 did not affect the natriuretic response to furosemide in neither cirrhotic nor in control rats. Semiquantitative immunoblotting showed a significant downregulation of AQP-2 in the renal cortex (-72%) and in the outer medulla (-44%). The relative expression of BSC-1 in the outer medulla was unchanged in cirrhotic rats. The corticopapillary gradient of Na was significantly increased in cirrhotic rats. Since daily urine flow rate was similar in cirrhotic and sham-operated rats, we suggest that non-vasopressin-mediated water reabsorption is increased in cirrhotic rats probably as a result of an increased corticomedullary gradient due to exaggerated NaCl reabsorption in the thick ascending limb of Henle's loop.
Department of Pharmacology, the Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
T E
TE
Jonassen
S
S
Nielsen
S
S
Christensen
J S
JS
Petersen
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D001552:Benzazepines / Q000494:pharmacology*; D001663:Bilirubin / Q000097:blood; D001834:Body Water / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis; D002951:Citrates / Q000493:pharmacokinetics / Q000652:urine; D004231:Diuresis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007473:Ion Channels / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D008106:Liver Cirrhosis, Experimental / Q000503:physiopathology*; D009318:Natriuresis; D011188:Potassium / Q000097:blood / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000097:blood / Q000378:metabolism / Q000652:urine; D028021:Sodium-Potassium-Chloride Symporters; D014667:Vasopressins / Q000097:blood / Q000502:physiology*
D065092:Antidiuretic Hormone Receptor Antagonists; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D001552:Benzazepines; D002352:Carrier Proteins; D002951:Citrates; D007473:Ion Channels; D028021:Sodium-Potassium-Chloride Symporters; D014667:Vasopressins; C076251:mozavaptan; C070669:lithium citrate; D005665:Furosemide; D012964:Sodium; D000410:Alanine Transaminase; D001663:Bilirubin; D011188:Potassium