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J Thorac Cardiovasc Surg 2002;123:1120-1124
© 2002 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology (CSP) |
From the Division of Cardiac Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada,a and the Division of Cardiac Surgery, Foothills Hospital, University of Calgary, Calgary, Alberta, Canada.b
Supported by the Heart and Stroke Foundation of Ontario (R.D.W.), Canadian Diabetes Association (R.D.W., V.R., S.V.), and Physicians Services Incorporated (S.V., R.D.W.). S.V. is a Fellow of the Medical Research Council of Canada. P.W.M. is a Research Fellow of the Heart and Stroke Foundation of Canada. S.V. was the C. Walton Lillehei Forum Finalist.
Read at the Eighty-first Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 6-9, 2001.
Received for publication Sept 7, 2001. Revisions requested Oct 22, 2001; revisions received Nov 12, 2001. Accepted for publication Nov 13, 2001. Address for reprints: Richard D. Weisel, MD, FRCSC, Professor and Chairman, Division of Cardiac Surgery, The Toronto General Hospital, EN 14-215, 200 Elizabeth St, Toronto, Ontario, M5G 2C4 Canada (E-mail: richard.weisel{at}uhn.on.ca).
Objectives: 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.
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J. Thorac. Cardiovasc. Surg. 2002 123: 1031-1034.
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