| Background and AimSuccessful organ preservation is an important component of transplantation. Despite the extensive and continued research aimed at improving cardioplegic solutions and perfusion techniques, patients undergoing transplantation almost invariably experience some degree of postoperative dysfunction. Currently, heart hypothermia preservation in vitro for clinical transplantation is limited to approximately 4 hours. This is in contrast to preservation of the liver, kidney, and pancreas, which have been successfully preserved for 24 to 36 hours although graft function may be transiently compromised. Although satisfactory function has been reported in a few hearts stored for up to 6 hours, there is a steep rise in acute mortality associated with preservation times in excess of 2 hours (9.8% less than 2 hours rising to 17.6% greater than 4 hours), and ischemia-reperfusion injury after heart preservation is considered to be the most serious cause of postoperative morbidity and mortality.More recently, there have been a number of challenging concepts regarding the possibility of the heart to initiate endogenous adaptive effects such as ischemia preconditioning which result in significant improvements in cardioprotection. Mitochondrial ATP-sensitive potassium (mitoK_ATP) channel has been reported to play a predominant role in diversified preconditioning-induced cardioprotection. Selective mitoK_ATP opener diazoxide pharmacologically preconditioning could closely mimic the salutary effects of classical ischemic preconditioning, resulting in reduce of infarct size and enhancement of post-ischemic cardiac contractile recovery. Recently, interest has been shifted to possible application of mitoK_ATP channel openers to donor heart preservation. Some studies have shown that mitoK_ATP channel opener preconditioning allowed a markedly improvement of the myocardial diastolic function after long-term hypothermic preservation, and combining Na+-H+ exchange inhibitor and mitoK_ATP channel activator together enhanced the recovery of preserved cardiac output. However, as a potent hypotensive durg, diazoxide administration before arrest could potentially impact the hemodynamic instability commonly seen at the time of donor heart harvest. Furthermore, although ischemic and pharmacological preconditioning is a good cardioprotective strategy, its clinical feasibility is rather limited by the inablility to predict the onset of ischemia.It is well accepted that the burst of free radical production associated with reperfusion of previously ischemic tissues is an important mediator of tissue damage. Although the cell loss in the post-ischemic period has been classically considered to occur via necrosis, it is becoming apparent that oxidative stress may also induce apoptosis. Up to now, the precise mechanism by which opening of mitochondrial K_ATP channel elicits cardio-protection is not yet elucidated, and we postulated the possible protective mechanism of opening mitoK_ATP channel may be related to inhibition of apoptosis induced by oxidative stress.In the present study, we used a model of hypothermic preservation of rat hearts in vitro toinvestigate the effect of different concentration of diazoxide (15, 30, 45 μM) as an additive to cardioplegia solution on rat hearts during 3, 5, 8, or 10 hours hypothermic preservation respectively and to explore the underlying mechanisms. The main point of this study is to make clear the exact roles of mitoK_ATP channel in the hypothermic preserved rat myocardium.Methods1. Establishment of hypothermic preserved myocardium modelImmediately after stunning and cervical dislocation, the male Sprague-Dawley rat hearts were rapidly excised and mounted on a Langendorff apparatus for perfusion at 37°C with Rrebs-Henseleit buffer at constant pressure (76 mmHg). The left atrium was opened, and a fluid filled latex balloon was inserted into the left ventricle, the balloon was connected via a short plastic tube to another pressure transducer and computer. After approximately 30 minutes perfusion for stabil... |
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