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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado.
Correspondence to Dr. Robert W. Schrier, Department of Medicine, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262. Phone: 303-315-7765; Fax: 303-315-7702; E-mail: Robert.Schrier{at}UCHSC.edu
Abstract. 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.
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