PRECONDITIONING, ISF ADENOSINE, AND CARDIOPROTECTION

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The broad, long-term aims of the proposed research are to elucidate the cardioprotective actions of adenosine and to enhance our understanding of the cellular events which occur during ischemic preconditioning. In the proposed research, cardiac microdialysis probes will be implanted in the endocardium and epicardium to provide transmural profiles of the changes in interstitial fluid (ISF) levels of adenosine, adenosine metabolites, lactate, and norepinephrine during and after regional myocardial ischemia in anesthetized animals. Microdialysis probes will also be used to assess arterial and coronary venous adenosine levels. Cardioprotection will be evaluated by the recovery of regional ventricular function and by the size of the myocardial infarction following 60 minutes of regional myocardial ischemia. The experimental protocols will address two primary aims: Aim 1. To determine the relationship between graded intracoronary adenosine administration and the changes in: 1) ISF and coronary venous adenosine, and; 2) the degree of myocardiaI protection. Aim 2. To determine the relationship between the magnitude of the transient increase in ISF adenosine induced by ischemic preconditioning and the degree of myocardial protection from subsequent prolonged ischemia. The proposed experiments will assess the adenosine hypothesis for ischemic preconditioning by providing direct evidence for or against the concept that it is the concentration of adenosine in the ISF prior to ischemia that preconditions the heart and affords myocardial protection. As such, these experiments are important to our understanding of how the dramatic protection afforded by preconditioning can be translated into a clinical modality. The proposed experiments will also determine if exogenous adenosine reduces the ischemia-induced norepinephrine release and if preconditioning protects the heart in part by reducing norepinephrine release during a subsequent period of prolonged ischemia.