title: Potentiation of the effect of thiazide derivatives by carbonic anhydrase inhibitors: molecular mechanisms and potential clinical implications.
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.
  
  
  OBJECTIVE
  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.
  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.
authors.affiliation: Center on Genetics of Transport and the Department of Medicine, University of Cincinnati, Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio.
authors.forename: Kamyar
authors.initials: K
authors.lastname: Zahedi
authors.forename: Sharon
authors.initials: S
authors.lastname: Barone
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D009399:Nephrons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D049992:Sodium Chloride Symporters / Q000378:metabolism; D000076988:Sulfate Transporters; D049971:Thiazides / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D027963:Chloride-Bicarbonate Antiporters; D004232:Diuretics; C494615:Slc26A4 protein, rat; D049992:Sodium Chloride Symporters; D000076988:Sulfate Transporters; D049971:Thiazides; D000086:Acetazolamide