Preservation of mitochondrial structure and function after cardioplegic arrest in the neonate using a selective mitochondrial KATP channel opener

• Published in: The Annals of thoracic surgery Vol. 81; no. 5; pp. 1817 - 1823
• Main Authors: LIXING WANG, KINNEAR, Caroline, HAMMEL, James M, WEI ZHU, ZHONGDONG HUA, WENYU MI, CALDARONE, Christopher A
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Science 01.05.2006
• Subjects: Adenosine Triphosphate - analysis; Animals; Animals, Newborn; Apoptosis - physiology; Biological and medical sciences; Cytochromes c - metabolism; Diazoxide - pharmacology; Heart Arrest, Induced; Hemodynamics; Medical sciences; Mitochondria, Heart - physiology; Mitochondria, Heart - ultrastructure; Oxygen Consumption; Potassium Channels; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the respiratory system; Swine; Translocation, Genetic; Vasodilator Agents - pharmacology; Human; Mitochondria; Organ preservation; Newborn; Treatment; Preservation; Respiratory disease; Surgery; Ionic channel; Thorax; Structure
• ISSN: 0003-4975; 1552-6259
• DOI: 10.1016/j.athoracsur.2005.11.029

Mitochondrial dysfunction may contribute to early postoperative neonatal heart dysfunction. Diazoxide, a mitochondrial-selective adenosine triphosphate-sensitive potassium-channel opener, is associated with mitochondrial preservation after cardioplegic arrest. We evaluated the mitochondrial-protective effect of diazoxide in terms of mitochondrial structure and function after neonatal cardioplegic arrest. Newborn piglets (age, approximately 14 days) underwent cardiopulmonary bypass and 60 minutes of cardioplegic arrest using cold crystalloid cardioplegic solution (CCP, n = 5) or cold crystalloid cardioplegic solution with diazoxide (CCP+D, n = 5). After 6 hours of recovery, myocardium was harvested. Control myocardium from piglets that did not undergo cardiopulmonary bypass (non-CPB, n = 5) was obtained. Cardioplegic arrest was associated with translocation of Bax to the mitochondria, which was not prevented by diazoxide. Nevertheless, by electron microscopy, CCP-associated remodeling of mitochondrial structure was subjectively diminished in CCP+D hearts. In addition, CCP-associated mitochondrial permeabilization and cytochrome c release into the cytosol were prevented with CCP+D (p < 0.05). In vitro oxygen consumption of isolated mitochondria demonstrated deficient function of mitochondrial complex I in CCP, but it was preserved in the CCP+D myocardial mitochondria (p < 0.05). Complex II and IV activity was not different among groups. In parallel with impaired complex I function, the cardiac adenosine triphosphate content was diminished in CCP hearts, but well maintained in CCP+D hearts (p < 0.05). Although early apoptotic signaling events (Bax translocation) are not prevented by diazoxide, addition of the mitochondrial-selective adenosine triphosphate-sensitive potassium-channel opener to the cardioplegic solution is associated with protection of mitochondrial structural and functional integrity in a clinically relevant model of neonatal cardiac surgery. The mitochondrial-protective effects of diazoxide may contribute to improved postoperative myocardial function in the neonate.