title: Potent cardioprotective effect of the 4-anilinoquinazoline derivative PD153035: involvement of mitochondrial K(ATP) channel activation.
abstract: BACKGROUND
  The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function.
  
  
  RESULTS
  Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation.
  
  
  CONCLUSIONS
  We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.
authors.affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Renata A
authors.initials: RA
authors.lastname: Cavalheiro
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Marin
authors.forename: Silvana A
authors.initials: SA
authors.lastname: Rocco
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Cerqueira
authors.forename: Camille C Caldeira
authors.initials: CC
authors.lastname: da Silva
authors.forename: Roberto
authors.initials: R
authors.lastname: Rittner
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.forename: Anibal E
authors.initials: AE
authors.lastname: Vercesi
authors.forename: Kleber G
authors.initials: KG
authors.lastname: Franchini
authors.forename: Roger F
authors.initials: RF
authors.lastname: Castilho
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D003486:Cyanides / Q000633:toxicity; D006334:Heart Function Tests; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002316:Cardiotonic Agents; D003486:Cyanides; D015221:Potassium Channels; D011799:Quinazolines; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D011188:Potassium; D002118:Calcium; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline