title: Increased endothelin-1 production in diabetic patients after cardioplegic arrest and reperfusion impairs coronary vascular reactivity: reversal by means of endothelin antagonism.
abstract: OBJECTIVE
  Evidence has accrued to suggest that diabetic patients face an increased risk of ischemic events and low output syndrome and might mount an inordinate response to ischemia and reperfusion. Because hyperglycemia is a potent stimulus for endothelin-1 production, we hypothesized that increased production, action, or both of endothelin-1 in diabetes might represent an important mediator of endothelial dysfunction in patients with that disease. To this aim, we compared the effects of cardioplegic arrest and reperfusion on coronary sinus effluent endothelin-1 levels and atrial arteriolar vascular responses in diabetic and case-matched nondiabetic patients undergoing coronary artery bypass grafting.
  
  
  METHODS
  In study 1 coronary sinus effluent endothelin-1 levels were assessed at baseline and at 1 and 10 minutes after reperfusion in 13 diabetic and 12 nondiabetic patients matched for age, ejection fraction, Parsonnet score, and crossclamp time. In study 2 vascular responses of atrial arterioles subjected to perioperative ischemia-reperfusion were evaluated with videomicroscopy. Atrial microvessels (from appendages) were obtained before and after removal of the aortic crossclamp, and vascular responses to exogenously administered endothelin-1 (10(-10) mol/L) and substance P (10(-8) mol/L) were studied in the presence or absence of BQ-123, an endothelin A receptor antagonist.
  
  
  RESULTS
  Diabetic patients elaborated more endothelin-1 at 1 and 10 minutes after reperfusion (P =.01). Endothelin-1-mediated vasoconstriction was similar in diabetic and nondiabetic atrial microvessels before cardioplegic arrest and cardiopulmonary bypass. After cardiopulmonary bypass and reperfusion, endothelin-1-mediated vasoconstriction was enhanced in both groups; however, this response was greater in microvessels from diabetic patients (P =.02). BQ-123, the endothelin A antagonist, attenuated the effects of bypass and reperfusion on endothelin-1-mediated vasoconstriction in both groups (P =.01). Substance P-mediated vasodilatation was similar in diabetic and nondiabetic atrial microvessels before bypass. After bypass and reperfusion, substance P-mediated vasodilatation was diminished in both groups; however, this response was more pronounced in the diabetic group (P =.003). BQ-123 coincubation restored substance P-mediated vasodilatation in both groups.
  
  
  CONCLUSIONS
  We determined the following: (1) the coronary effluent release of endothelin-1 is higher in diabetic than in nondiabetic patients after cardiopulmonary bypass and reperfusion; (2) diabetic coronary microvessels respond to bypass and reperfusion with greater endothelin-1-mediated vasoconstriction and diminished nitric oxide-mediated vasodilatation; and (3) these effects are attenuated by endothelin antagonism. Endothelin-1 might be an important mediator of ischemia-reperfusion injury in patients with diabetes. Furthermore, use of endothelin receptor antagonists might be a novel strategy for improving 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: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
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: D000368:Aged; D001026:Coronary Artery Bypass; D003331:Coronary Vessels / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006324:Heart Arrest, Induced; D006801:Humans; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000494:pharmacology; D011184:Postoperative Period
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)