There is uncertainty about which metabolic pathway is most important for controlling myocardial cytosolic adenosine concentrations in the normoxic heart: AMP hydrolysis, linked to energetic status, or energy independent transmethylation (via S-adenosylhomocysteine hydrolysis) To answer this question, intracellular cycling of AMP and adenosine was abolished using an intracoronary infusion of the adenosine kinase blocker iodotubercidin (ITC), in the presence of adenosine deaminase inhibition. ITC caused a 10-fold increase in the coronary venous release rate of adenosine to 3.4 + 0.3 (mean + SE, n=5) nmol min-1g-1, representing total normoxic myocardial adenosine production. To determine the relative roles of AMP hydrolysis and transmethylation, parallel experiments tested the effect of ITC during blockade of transmethylation using adenosine dialdehyde. In these experiments, venous adenosine release increased to similar levels of 3.4 + 0.5 (n=6) nmol min-1g-1. The possibility that ITC caused increased adenosine release by interfering with myocardial energetics was ruled out in separate 31P NMR experiments. Mathematical modeling analysis of the adenosine results indicated that AMP-adenosine cycling causes increased sensitivity of cytosolic adenosine concentrations to increases in the rate of AMP hydrolysis. It is concluded that 1) at least 90% of the adenosine produced intracellularly is normally rephosphorylated to AMP without escaping into the venous effluent, 2) AMP hydrolysis is the dominant pathway for normoxic adenosine production, and 3) AMP-adenosine cycling serves to amplify the relative importance of energy dependent AMP hydrolysis over that of transmethylation in controlling cytosolic adenosine concentrations.
| Bassingthwaighte, James B; Butterworth, Erik; Jardine, Bartholomew et al. (2012) Compartmental modeling in the analysis of biological systems. Methods Mol Biol 929:391-438 |
| Dash, Ranjan K; Bassingthwaighte, James B (2010) Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng 38:1683-701 |
| 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 |
| Dash, Ranjan K; Bassingthwaighte, James B (2006) Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate, and hydrogen ion. Ann Biomed Eng 34:1129-48 |
| Dash, Ranjan K; Bassingthwaighte, James B (2004) Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng 32:1676-93 |
| 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 |
| Kellen, Michael R; Bassingthwaighte, James B (2003) An integrative model of coupled water and solute exchange in the heart. Am J Physiol Heart Circ Physiol 285:H1303-16 |
| Wang, C Y; Bassingthwaighte, J B (2001) Capillary supply regions. Math Biosci 173:103-14 |
| Swanson, K R; True, L D; Lin, D W et al. (2001) A quantitative model for the dynamics of serum prostate-specific antigen as a marker for cancerous growth: an explanation for a medical anomaly. Am J Pathol 158:2195-9 |
| Swanson, K R; Alvord Jr, E C; Murray, J D (2000) A quantitative model for differential motility of gliomas in grey and white matter. Cell Prolif 33:317-29 |
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