title: In vitro and in vivo characterization of a new organic nitrate hybrid drug covalently bound to pioglitazone.
abstract: OBJECTIVE
  Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. The new compound CLC-3000 is an aminoethyl nitrate (AEN) derivative of pioglitazone, a thiazolidinedione antidiabetic agent combining the peroxisome proliferator-activated receptor γ agonist activity of pioglitazone with the NO-donating activity of the nitrate moiety.
  
  
  METHODS
  In vitro and in vivo characterization was performed by isometric tension recording, platelet function, bleeding time and detection of oxidative stress.
  
  
  RESULTS
  In vitro, CLC-3000 displayed more potent vasodilation than pioglitazone alone or classical nitrates. In vitro, some effects on oxidative stress parameters were observed. Authentic AEN or the AEN-containing linker CLC-1275 displayed antiaggregatory effects. In vivo treatment with CLC-3000 for 7 days did neither induce endothelial dysfunction nor nitrate tolerance nor oxidative stress. Acute or chronic administration of AEN increased the tail vein bleeding time in mice.
  
  
  CONCLUSIONS
  In summary, the results of these studies demonstrate that CLC-3000 contains a vasodilative and antithrombotic activity that is not evident with pioglitazone alone, and that 7 days of exposure in vivo showed no typical signs of nitrate tolerance, endothelial dysfunction or other safety concerns in Wistar rats.
authors.affiliation: Molekulare Kardiologie, II. Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg-Universität Mainz, Mainz, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Amanda
authors.initials: A
authors.lastname: Pfeffer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Jurk
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansen
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwierczek
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: Karl
authors.initials: K
authors.lastname: Burgin
authors.forename: Dirk
authors.initials: D
authors.lastname: Sartor
authors.forename: Armin
authors.initials: A
authors.lastname: Scherhag
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology*; D000077205:Pioglitazone; D010974:Platelet Aggregation / Q000187:drug effects; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D007004:Hypoglycemic Agents; D009566:Nitrates; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077205:Pioglitazone