Selective V2-receptor vasopressin antagonism decreases urinary aquaporin-2 excretion in patients with chronic heart failure.
Aquaporin-2 (AQP-2), a water channel located on the apical membrane of collecting duct cells, regulates water reabsorption under the control of vasopressin (AVP). Using an antibody directed to human AQP-2, a quantitative Western blot analysis was performed to determine the collecting duct responsiveness to an oral, nonpeptide, V2 receptor antagonist (VPA-985) in patients with chronic NYHA II and III heart failure. Standards were derived by conjugating the immunizing peptide to maleimide-activated bovine serum albumin and a standard curve was generated for each blot. Quantification of baseline steady-state AQP-2 excretion was done by collecting urine on the day before study drug administration. The next day patients received either placebo or VPA-985 at one of four different doses and urine was collected every 2 h. Thereafter, urinary AQP-2 excretion was calculated as a ratio of the urine flow and was expressed in pmol/h. During baseline, steady-state excretion did not change significantly (T0-T2, 458 +/- 44; T2-T4, 443 +/- 35; T4-T6, 422 +/- 35; T6-T8, 401 +/- 30). Compared to placebo, urinary AQP-2 excretion decreased significantly and in all groups in a dose-dependent manner during VPA-985 administration. The most impressive decrease was observed in the 250-mg group (T0-T2, 89 +/- 5; T2-T4, 50 +/- 18; T4-T6, 43 +/- 22; T6-T8, 42 +/- 23; P < 0.001 during each period compared with baseline and placebo results). VPA-985 significantly increased solute-free water clearance and urine output and significantly decreased urinary osmolality. Urinary AQP-2 excretion correlated best with solute-free water clearance during T0-T2 and T2-T4 collection, but a correlation with urinary osmolality and urinary output was also found during these periods. In conclusion, AQP-2 urinary excretion, as measured by quantitative Western analysis, is a sensitive biologic marker to assess the short-term responsiveness of the collecting duct to a V2 receptor AVP antagonist in chronic heart failure.
Martin
P Y
PY
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Abraham
W T
WT
Lieming
X
X
Olson
B R
BR
Oren
R M
RM
Ohara
M
M
Schrier
R W
RW
D000284:Administration, Oral; D000368:Aged; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000187:drug effects / Q000652:urine*; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D015415:Biomarkers / Q000652:urine; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D011758:Pyrroles; D012016:Reference Values; D012680:Sensitivity and Specificity; D001569:Benzodiazepines
D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D001127:Arginine Vasopressin; D001381:Azepines; D001549:Benzamides; D015415:Biomarkers; D011758:Pyrroles; C496023:AQP2 protein, human; C409452:lixivaptan; D001569:Benzodiazepines