Diazoxide supplemented Celsior solution improves hypothermic heart preservation effect in rat through activation of mitochondrial ATP-sensitive potassium channel

Abstract

Successful heart preservation is critical for clinical heart transplantation, but even the most successful heart preservation method can only preserve the heart in a time range of approximately 4 h. In the present study, diazoxide (DE)-containing cardioplegia solution was used as the hypothermic heart preservation solution, and hearts were preserved for different time periods before reperfusion. Five groups were randomly divided into the control group, DE groups with different concentrations of DE (15, 30, and 45 μM), and the 5-HD + DE group containing 30 μM DE and 100 μM of 5-hydroxydecanoate (5-HD). Each group was further divided according to the storage time: 3 h and 8 h subgroups. Hemodynamic parameters were monitored continually and myocardial injury markers lactate dehydrogenase (LDH) and creatine kinase (CK) were measured before arrest and during reperfusion. After reperfusion, myocardium water content, myocardium apoptosis, and myocardial mitochondrial superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured. All data were analyzed by independent samples t-test. Our results showed that diazoxide treatment improved impaired hemodynamics parameters and decreased the leakage of myocardial enzymes during reperfusion, compared to the control group. Moreover, diazoxide treatment significantly alleviated myocardial edema, decreased the number of TUNEL-positive cardiomyocytes, prevented the loss of mitochondrial SOD activity, and depressed the mitochondrial MDA content. This study indicated that mitoK_ATP channel opener diazoxide could significantly enhance myocardial protection during long-term hypothermic preservation, and the inhibition of oxidative stress-induced myocardium apoptosis seems to be the mechanism involved in the protective action on the mitoK_ATP channel.

Keywords::

• Mitochondrial ATP-sensitive potassium channel
• ischemia–
• reperfusion
• heart preservation

Acknowledgements

This study was supported by National Natural Science Foundation grant No. 30470635 and Science and Technology Department of Zhejiang Province grants No. 2005C23033 and No. 2007C33026.