TY - JOUR
T1 - Preservation of Mitochondrial Structure and Function After Cardioplegic Arrest in the Neonate Using a Selective Mitochondrial KATP Channel Opener
AU - Wang, Lixing
AU - Kinnear, Caroline
AU - Hammel, James M.
AU - Zhu, Wei
AU - Hua, Zhongdong
AU - Mi, Wenyu
AU - Caldarone, Christopher A.
N1 - Funding Information:
Supported by a Scientist Development Grant from the American Heart Association (CAC).
PY - 2006/5
Y1 - 2006/5
N2 - Background: 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. Methods: 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. Results: 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). Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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). Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=33646827646&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646827646&partnerID=8YFLogxK
U2 - 10.1016/j.athoracsur.2005.11.029
DO - 10.1016/j.athoracsur.2005.11.029
M3 - Article
C2 - 16631678
AN - SCOPUS:33646827646
VL - 81
SP - 1817
EP - 1823
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
SN - 0003-4975
IS - 5
ER -