Hyperglycemia exaggerates ischemia-reperfusion-induced cardiomyocyte injury: reversal with endothelin antagonism.
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.
Verma
Subodh
S
Division of Cardiac Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Maitland
Andrew
A
Weisel
Richard D
RD
Li
Shu-Hong
SH
Fedak
Paul W M
PW
Pomroy
Neil C
NC
Mickle
Donald A G
DA
Li
Ren-Ke
RK
Ko
Lawrence
L
Rao
Vivek
V
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*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D013449:Sulfonamides; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)