The fundamental hypothesis of this program is that the failure of the Na+/K+ ATPase to maintain the Na+ gradient in the ischemic myocardium marks the onset of regulatory failure. Thus, the premises of this application are as follows: first, that the primary result of ischemia in the myocardium is high-energy phosphate, HEP, depletion and, alterations in the sarcolemmal cation gradients; second, that these processes are interdependent; third, that maintenance of normal myocardial intracellular sodium concentration, [Na+]i, during ischemia depends upon the free energy of ATP hydrolysis; delta/GATP. First, we will establish the temporal responses of the HEP and the Na+ gradient to ischemia and reperfusion. The overall objective is to define the relationship between changes in the HEP and the changes in the Na+ gradient during myocardial ischemia and reperfusion in the intact heart. To accomplish these objectives a model of ischemia and reperfusion in the intact heart. To accomplish these objectives a model of ischemia and reperfusion in the intact pig heart is employed. The lack of pre-formed collateral vessels in the pig heart enables more complete control of the degree of ischemia than is possible with the more commonly employed canine model. The normal human heart does not have collaterals. Thus, the pig heart model may be more relevant to the study of some human ischemic syndromes. NMR spectroscopy is employed to serially measure the phosphorylated metabolites and the Na+ gradient throughout control, ischemia, and reperfusion. Functional parameters and flows will be simultaneously monitored and correlated with the metabolite measurements. The treatment of acute myocardial infarction has recently evolved rapidly through the use of thrombolytic agents, resulting in reperfusion of the ischemic region. Under clinical circumstances such reperfusion limits but, does not prevent necrosis. Identification of the timing and of the relationship of the metabolic events leading to regulatory failure in the ischemic heart is crucial to the rational design of new therapeutic strategies. Thus, it has a potentially broad impact upon cardiac care.
| Liu, Sihao; Hatano, Ben; Zhao, Minghui et al. (2011) Role of peroxisome proliferator-activated receptor {delta}/{beta} in hepatic metabolic regulation. J Biol Chem 286:1237-47 |
