Potentiation of the effect of thiazide derivatives by carbonic anhydrase inhibitors: molecular mechanisms and potential clinical implications.

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  • Author(s): Zahedi K;Zahedi K; Barone S; Xu J; Soleimani M
  • Source:
    PloS one [PLoS One] 2013 Nov 18; Vol. 8 (11), pp. e79327. Date of Electronic Publication: 2013 Nov 18 (Print Publication: 2013).
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Carbonic Anhydrase Inhibitors/*pharmacology ; Diuretics/*pharmacology ; Kidney/*drug effects ; Kidney/*metabolism ; Thiazides/*pharmacology; Acetazolamide/pharmacology ; Animals ; Chloride-Bicarbonate Antiporters/metabolism ; Nephrons/drug effects ; Rats ; Rats, Sprague-Dawley ; Sodium Chloride Symporters/metabolism ; Sulfate Transporters
    • Abstract:
      Background: Carbonic anhydrase inhibitors (CAI) are mild diuretics, hence not widely used in fluid overloaded states. They are however the treatment of choice for certain non-kidney conditions. Thiazides, specific inhibitors of Na-Cl cotransport (NCC), are mild agents and the most widely used diuretics in the world for control of mild hypertension.
      Hypothesis: In addition to inhibiting the salt reabsorption in the proximal tubule, CAIs down-regulate pendrin, therefore leaving NCC as the major salt absorbing transporter in the distal nephron, and hence allowing for massive diuresis by the inhibitors of NCC in the setting of increased delivery of salt from the proximal tubule.
      Experimental Protocols and Results: Daily treatment of rats with acetazolamide (ACTZ), a known CAI, for 10 days caused mild diuresis whereas daily treatment with hydrochlorothiazide (HCTZ) for 4 days caused hardly any diuresis. However, treatment of rats that were pretreated with ACTZ for 6 days with a combination of ACTZ plus HCTZ for 4 additional days increased the urine output by greater than 2 fold (p<0.001, n = 5) compared to ACTZ-treated animals. Sodium excretion increased by 80% in the ACTZ plus HCTZ group and animals developed significant volume depletion, metabolic alkalosis and pre-renal failure. Molecular studies demonstrated ∼75% reduction in pendrin expression by ACTZ. The increased urine output in ACTZ/HCTZ treated rats was associated with a significant reduction in urine osmolality and reduced membrane localization of AQP-2 (aquaporin2).
      Conclusions: These results indicate that ACTZ down-regulates pendrin expression and leaves NCC as the major salt absorbing transporter in the distal nephron in the setting of increased delivery of salt from the proximal tubule. Despite being considered mild agents individually, we propose that the combination of ACTZ and HCTZ is a powerful diuretic regimen.
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    • Grant Information:
      R56 DK062809 United States DK NIDDK NIH HHS; R56DK62809 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (Carbonic Anhydrase Inhibitors)
      0 (Chloride-Bicarbonate Antiporters)
      0 (Diuretics)
      0 (Slc26A4 protein, rat)
      0 (Sodium Chloride Symporters)
      0 (Sulfate Transporters)
      0 (Thiazides)
      O3FX965V0I (Acetazolamide)
    • Publication Date:
      Date Created: 20131122 Date Completed: 20140711 Latest Revision: 20211021
    • Publication Date:
      20221213
    • Accession Number:
      PMC3832474
    • Accession Number:
      10.1371/journal.pone.0079327
    • Accession Number:
      24260196