title: Hyperglycemia exaggerates ischemia-reperfusion-induced cardiomyocyte injury: reversal with endothelin antagonism.
abstract: OBJECTIVE
  We have previously demonstrated an importance of endothelin-1 in diabetic patients undergoing bypass surgery. Recent evidence suggests that cardiomyocytes might also produce endothelin-1, which might directly impair myocyte contractility by increasing intracellular calcium levels. Because hyperglycemia is a potent stimulus of endothelin-1 production, we hypothesized that increased production, action, or both of endothelin-1 might be a mediator of direct cardiomyocyte injury in diabetes. Therefore we studied the effects of endothelin receptor blockers (BQ-123 and bosentan) on hyperglycemia-induced endothelin-1 production and cellular injury after ischemia-reperfusion.
  
  
  METHODS
  Using a human ventricular heart cell model of simulated ischemia-reperfusion, we studied the effects of normoglycemia (5 mmol/L, 48 hours) and hyperglycemia (25 mmol/L, 48 hours) on cellular injury and endothelin-1 production. Furthermore, the effects of selective endothelin-A and mixed endothelin-A/B receptor antagonism (with BQ-123 and bosentan, respectively) were evaluated.
  
  
  RESULTS
  Cellular injury, as assessed by means of trypan blue uptake, was higher in human ventricular heart cells subjected to hyperglycemia and simulated ischemia-reperfusion injury (P =.01); this effect was prevented with both BQ-123 and bosentan (P =.01). In addition, heart cells from the hyperglycemic group elaborated more endothelin-1 after ischemia-reperfusion (P =.02).
  
  
  CONCLUSIONS
  Endothelin-1 production and cellular injury were greater in human ventricular heart cells subjected to hyperglycemic conditions and simulated ischemia-reperfusion. These effects are mediated by endothelin-A receptors because both BQ-123 and bosentan exerted similar degrees of protection. Endothelin receptor blockade is a novel strategy to improve the resistance of the diabetic heart to cardioplegic arrest and reperfusion.
authors.affiliation: Division of Cardiac Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.forename: Andrew
authors.initials: A
authors.lastname: Maitland
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Neil C
authors.initials: NC
authors.lastname: Pomroy
authors.forename: Donald A G
authors.initials: DA
authors.lastname: Mickle
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Lawrence
authors.initials: L
authors.lastname: Ko
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
mesh_terms: D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood*; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D013449:Sulfonamides; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)