title: In-vivo administration of CLC-K kidney chloride channels inhibitors increases water diuresis in rats:  a new drug target for hypertension?
abstract: OBJECTIVE
  The human kidney-specific chloride channels ClC-Ka (rodent ClC-K1) and ClC-Kb (rodent ClC-K2) are important determinants of renal function, participating to urine concentration and blood pressure regulation mechanisms. Here we tested the hypothesis that these chloride channels could represent new drug targets for inducing diuretic and antihypertensive effects.
  
  
  METHODS
  To this purpose, the CLC-K blockers benzofuran derivatives MT-189 and RT-93 (10, 50, 100 mg/kg), were acutely administered by gavage in Wistar rats, and pharmacodynamic and pharmacokinetic parameters determined by functional, bioanalytical, biochemical and molecular biology assays.
  
  
  RESULTS
  Plasma concentration values for MT-189 and RT-93 were indicative of good bioavailability. Both MT-189 and RT-93 dose-dependently increased urine volume without affecting electrolyte balance. A comparable reduction of SBP was observed in rats after MT-189, RT-93 or furosemide administration. Benzofuran derivatives treatment did not affect kidney CLC-K mRNA level or inner medulla osmolality, whereas a significant vasopressin-independent down-regulation of aquaporin water channel type 2 was observed at protein and transcriptional levels. In rats treated with benzofuran derivatives, the observed polyuria was mainly water diuresis; this finding indirectly supports a cross-talk between chloride and water transport in nephron. Moreover, preliminary in-vitro evaluation of the drugs capability to cross the blood-inner ear barrier suggests that these compounds have a limited ability to induce potential auditory side effects.
  
  
  CONCLUSIONS
  CLC-K blockers may represent a new class of drugs for the treatment of conditions associated with expanded extracellular volume, with a hopeful high therapeutic potential for hypertensive patients carrying ClC-K gain-of-function polymorphisms.
authors.affiliation: Section of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, Bari, Italy. aliantonio@farmbiol.uniba.it
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gramegna
authors.forename: Giulia M
authors.initials: GM
authors.lastname: Camerino
authors.forename: Maria M
authors.initials: MM
authors.lastname: Dinardo
authors.forename: Antonia
authors.initials: A
authors.lastname: Scaramuzzi
authors.forename: Maria A
authors.initials: MA
authors.lastname: Potenza
authors.forename: Monica
authors.initials: M
authors.lastname: Montagnani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Procino
authors.forename: Domenica R
authors.initials: DR
authors.lastname: Lasorsa
authors.forename: Lisa
authors.initials: L
authors.lastname: Mastrofrancesco
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
authors.forename: Maria G
authors.initials: MG
authors.lastname: Perrone
authors.forename: Angela
authors.initials: A
authors.lastname: Lopedota
authors.forename: Salvatore
authors.initials: S
authors.lastname: Conte
authors.forename: Rosa
authors.initials: R
authors.lastname: Penza
authors.forename: Giovanna
authors.initials: G
authors.lastname: Valenti
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.forename: Diana Conte
authors.initials: DC
authors.lastname: Camerino
mesh_terms: D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D004231:Diuresis; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D014867:Water
chemical_list: D018118:Chloride Channels; D014867:Water