The goal of the proposed research is to investigate the regulation of cellular membrane transport and metabolism of the important energy compounds, ATP, ADP, AMP and adenosine in the beating heart. When oxygen delivery to the heart is reduced, this causes disturbances in energy balance that may lead to tissue death. However, the heart possesses adaptive mechanisms to alter energy metabolism when oxygen is reduced, that may be of critical importance in maintaining cellular viability. Membrane transport and cellular metabolism will be studied by injecting radioactive tracers into the coronary arterial inflow of isolated perfused hearts of rabbits and guinea pigs, and analyzing the tracer kinetics in the venous outflow, and tracer uptake into myocardial tissue, using a physically realistic mathematical model.
Specific aims will include the study of the key enzymes of adenosine metabolism in capillary endothelial cells in the heart. We will also investigate whether myocardial hypoxia causes a shift in the metabolism of adenosine from the salvage pathway (adenosine -> AMP) to the degradation pathway (adenosine -> inosine). A related question to be studied is whether hypoxia causes a shift in the metabolism of hypoxanthine from the degradation pathway (hypoxanthine -> uric acid) to the salvage pathway (hypoxanthine -> IMP). We will also investigate whether brief ischemia or norepinephrine stimulation causes increased extracellular adenosine production, via the activation of the enzyme.ecto-5'-nucleotidase (AMP -> Adenosine). In addition, we will investigate whether membrane permeability of AMP is high enough to explain the observed rate of extracellular adenosine production. Finally, an anatomically, physiologically, and biochemically realistic mathematical model providing an integrated description of the metabolism and transport of ATP, ADP, AMP, adenosine and related purine metabolites in the major tissue regions of the heart will be developed.
| Yipintsoi, Tada; Kroll, Keith; Bassingthwaighte, James B (2016) Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy. Am J Physiol Heart Circ Physiol 310:H351-64 |
| Bassingthwaighte, James B; Beard, Daniel A; Carlson, Brian E et al. (2012) Modeling to link regional myocardial work, metabolism and blood flows. Ann Biomed Eng 40:2379-98 |
| Bassingthwaighte, James B; Raymond, Gary M; Butterworth, Erik et al. (2010) Multiscale modeling of metabolism, flows, and exchanges in heterogeneous organs. Ann N Y Acad Sci 1188:111-20 |
| Bassingthwaighte, James B (2008) Linking cellular energetics to local flow regulation in the heart. Ann N Y Acad Sci 1123:126-33 |
| Kellen, Michael R; Bassingthwaighte, James B (2003) Transient transcapillary exchange of water driven by osmotic forces in the heart. Am J Physiol Heart Circ Physiol 285:H1317-31 |
| Bassingthwaighte, J B; Beard, D A; Li, Z (2001) The mechanical and metabolic basis of myocardial blood flow heterogeneity. Basic Res Cardiol 96:582-94 |
| Schwartz, L M; Bukowski, T R; Ploger, J D et al. (2000) Endothelial adenosine transporter characterization in perfused guinea pig hearts. Am J Physiol Heart Circ Physiol 279:H1502-11 |
| Schwartz, L M; Bukowski, T R; Revkin, J H et al. (1999) Cardiac endothelial transport and metabolism of adenosine and inosine. Am J Physiol 277:H1241-51 |
| Bassingthwaighte, J B (1997) Design and strategy for the Cardionome Project. Adv Exp Med Biol 430:325-39 |
| King, R B (1996) Modeling membrane transport. Adv Food Nutr Res 40:243-62 |
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