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J Thorac Cardiovasc Surg 2002;124:1113-1121
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Myocyte and endothelial effects of preconditioning the jeopardized heart by inhibiting Na⁺/H⁺ exchange

From the Department of Surgery, Division of Cardiothoracic Surgery,^a and the Department of Physiology,^b University of California, Los Angeles, School of Medicine, Los Angeles, Calif.

Received for publication Dec 18, 2001. Revisions requested Jan 22, 2002; revisions received March 29, 2002. Accepted for publication April 8, 2002. Address for reprints: Gerald D. Buckberg, MD, Division of Cardiothoracic Surgery, 62-258 Center for the Health Sciences, Los Angeles, CA 90095-1701 (E-mail: gbuckberg{at}mednet.ucla.edu).

Objectives: The preconditioning effects of the adjunctive, cardiac-specific sodium-hydrogen ion exchange inhibitor cariporide (cariporide mesilate, HOE 642) were studied in hearts subjected to 30 minutes of normothermic ischemia and reperfusion to assess myocardial and endothelial changes.
Methods: Sixteen Yorkshire-Duroc pigs (27-34 kg) receiving cardiopulmonary bypass underwent either cardiopulmonary bypass alone (control, n = 4) or 30 minutes of normothermic ischemia, followed by 30 minutes of blood reperfusion (n = 12). Six hearts were treated with 5 mg/kg cariporide administered intravenously 15 minutes before ischemia.
Results: Cardiopulmonary bypass alone caused no changes. Conversely, 30 minutes of global normothermic ischemia caused 33% mortality and, in survivors, depression of left ventricular function to 22% ± 6% of baseline preload recruitable stroke work and increased creatine kinase MB by 406% (88 ± 13 U/L), conjugated dienes by 17% (161 ± 0.2 AU/mL), and myeloperoxidase activity by 297% (0.036 ± 0.005 U/g). Myocardial edema developed (3.5% water gain). Coronary sinus endothelin 1 increased by 111% (2.05 ± 0.38 pg/mL), and nitric oxide production decreased by 10%. These adverse effects were limited by pretreatment with cariporide, which allowed complete survival and restored preload recruitable stroke work to 78% ± 11%. Measurements of creatine kinase MB, conjugated dienes, myeloperoxidase, water, and endothelin 1 returned to baseline values, and nitric oxide production was accentuated 3-fold.
Conclusions: These observations show that adjunctive pretreatment with cariporide delays myocardial and endothelial injury during ischemia and reperfusion, limits oxygen-derived radical injury, restores function, reduces edema, and preserves endothelin and nitric oxide balance at normal values. The myeloperoxidase changes show that less white blood cell adherence supports reduced reperfusion endothelial damage.

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