Mechanistic and therapeutic aspects of ischemic myocardial preconditioning

To obtain a better understanding of myocardial ischemia-reperfusion injury and to advance therapeutical application of cardiac adaptation to ischemia, this thesis investigates several mechanistic aspects of ischemic preconditioning with respect to triggers, mediators and possible end-effectors. Adenosine is a well established trigger of ischemic preconditioning which is released during ischemia as a breakdown product of ATP. At least four adenosine receptor subtypes have been identified: A1-, A2a-, A2b- and A3- receptors.221 Both the A1- and the A3- receptor subtypes are believed to trigger myocardial preconditioning.131·153·222 The cardioprotective role of adenosine has been confirmed in all species used for experimental investigation.38 However, based on several studies using selective adenosine receptor antagonists which failed to block ischemic preconditioning, its role in rats is still controversial. 155•156 In these studies the duration of the ischemic stimuli were 3-5 min. Interestingly, Schulz et al. 133 demonstrated in the porcine heart that adenosine plays a significant role after 10-min of coronary artery occlusion. Therefore in chapter 2 we studied the role of adenosine in ischemic preconditioning in rats with respect to the duration of the ischemic stimulus