Ann Thorac Surg 2006;81:1416
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Invited commentary
David J. Chambers, PhD
Cardiac Surgical Research, Cardiothoracic Surgery, The Rayne Institute, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Campus, London, SE1 7EH United Kingdom
(Email: david.chambers{at}kcl.ac.uk; david.chambers{at}gstt.nhs.uk).
The study by Deja and colleagues [1] is an interesting and important study concerning the potential cardioprotective efficacy of a putative mitochondrial-specific ATP-dependent potassium channel (mKATP-channel) opener (diazoxide) in the clinical setting of cardiac surgery. Studies were conducted in isolated right atrial trabeculae obtained from patients undergoing cardiac surgery; the results are controversial as they do not conform to those obtained from a large number of animal-based studies. Essentially these studies demonstrate that optimum protection is seen when diazoxide is present throughout a prolonged period of simulated ischemia (referred to as hypoxia), with protection being enhanced if diazoxide was also administered as a short pre-treatment, whereas a pharmacological preconditioning protocol failed to provide cardioprotection. In addition, KATP-channel blockers (either the nonspecific blocker glibenclamide, or the specific mKATP-channel blocker 5-hydroxydecanoate), administered before and during the simulated ischemia, did not abolish the cardioprotection seen with diazoxide. This suggests that diazoxide is either acting differently in human atrial tissue to that seen in myocardium from various animal species, or that diazoxide has alternative mechanisms of action to that previously defined.
A number of aspects of this study may account for these discrepancies; these include the use of atrial tissue compared with ventricular tissue in animal studies, superfusion versus perfusion with the potential for improved drug access to the myocardial tissue (although this would also apply to the inhibitory drugs), and simulated ischemia and reperfusion. Another possibility relates to the transfer of tissue from the operating theater to the laboratory, which must involve some ischemia and hypoxia, and hence may trigger the preconditioning mechanism and explain why the pharmacological preconditioning protocol failed. The stabilization period of 30 minutes is of insufficient duration to be outside the preconditioning memory (of approximately 2 hours), and the studies have not included a group that demonstrates whether classical simulated ischemia-induced preconditioning can be induced in this tissue.
Of significant interest is that diazoxide treatment during the simulated ischemia prevented or reduced the development of contracture, suggesting a mechanism of action involving prevention of calcium overload. Could measurement of intracellular calcium levels be used in this system to demonstrate whether contracture correlates with calcium? However, if calcium is involved, it is perhaps surprising that contracture did not reoccur when KATP-channel blockers were used. The release of reactive oxygen species as part of the preconditioning mechanism has been shown to be suppressed by diazoxide [2], also occurring in the absence of potassium (inferring that potassium-selective channels may not be involved). Hence, for drugs such as diazoxide, evidence is increasing that they induce protective mechanisms that do not involve preconditioning, and this could include influencing mitochondrial calcium homeostasis [2].
Thus, this study adds to the increasing evidence that diazoxide may have alternative mechanisms of action from the proposed activation of mKATP-channels as part of a preconditioning cascade, and it has importance as it is conducted in human tissue. However, areas of this study leave considerable questions that need addressing, and these will hopefully be conducted in future investigations.
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References
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- Deja MA, Golba KS, Malinowski M, et al. Diazoxide provides maximal KATP channels independent protection if present throughout hypoxia Ann Thorac Surg 2006;81:1408-1416.[Abstract/Free Full Text]
- O'Rourke B. Evidence for mitochondrial K+ channels and their role in cardioprotection Circ Res 2004;94:420-432.[Abstract/Free Full Text]
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