ADENOSINE ENHANCED MYOCARDIAL PROTECTION DURING SURGERY

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Protection of the ischemic myocardium during cardiac surgery presently involves the use of hypothermia, ischemica arrest, and chemical cardioplegia. Despite these interventions, irreversible ischemic myocardial injury may occur. In order to further decrease the incidence of myocardial damage after surgery, a better understanding of the biochemical abnormalities associated with postoperative ventricular dysfunction is needed. The long-term objectives of this study are to provide insight into the relationship between intracellular compartmentalization of ATP and cardiac contractile function in the setting of ischemia and reperfusion. Specifically, we will determine: (1) if the rate of restoration of myocardial nucleotide pool can be enhanced by manipulating endogenous cardiac tissue adenosine levels with (a) dipyridamole, (b) adenosine-5' alpha, beta methylene diphosphate (AOPCP), and (c) erythro-9-(2)-hydroxy-3-nonyladeninehydrochloride (EHNA); (2) if the recovery of ventricular function is influenced by the rate of nucleotide repletion, (3) if the increase in ATP via augmented retention of endogenous adenosine or AMP reflects a change in the distribution of cellular ATP between mitochondrial and cytosolic compartments, and (4) if increased cytosolic ATP content results in improved function in an in vivo dog preparation. An isolated, Langendorff-perfused, isovolumetrically contracting rat heart preparation and a cardiopulmonary bypass model using dogs will be employed to determine temporal changes in adenine nucleotide pools and ventricular function in response to ischemia and reperfusion. Ventricular function will be assessed by determining dP/dt max and function curves, while nucleotide concentrations will be determined from freeze clamped tissue by high performance liquid chromatography. Subcellular distribution of adenine nucleotides will be evaluated by employing a non-aqueous tissue fractionation technique. Analysis of variance and regression analysis will be employed to determine difference among treatments and dependence of ventricular function on ATP. This research could lead to a possible treatment to enhance ventricular recovery after an ischemic episode.