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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/17/4193    most recent jphysiol.2008.154732v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Wu, F. Articles by Beard, D. A. PubMed PubMed Citation Articles by Wu, F. Articles by Beard, D. A. Related Collections Cardiovascular

¹ Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wiscosin, Milwaukee, WI 53213, USA
² Cardiology Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA

To understand how cardiac ATP and CrP remain stable with changes in work rate – a phenomenon that has eluded mechanistic explanation for decades – data from ³¹phosphate-magnetic resonance spectroscopy (³¹P-MRS) are analysed to estimate cytoplasmic and mitochondrial phosphate metabolite concentrations in the normal state, during high cardiac workstates, during acute ischaemia and reactive hyperaemic recovery. Analysis is based on simulating distributed heterogeneous oxygen transport in the myocardium integrated with a detailed model of cardiac energy metabolism. The model predicts that baseline myocardial free inorganic phosphate (P_i) concentration in the canine myocyte cytoplasm – a variable not accessible to direct non-invasive measurement – is approximately 0.29 mM and increases to 2.3 mM near maximal cardiac oxygen consumption. During acute ischaemia (from ligation of the left anterior descending artery) P_i increases to approximately 3.1 mM and ATP consumption in the ischaemic tissue is reduced quickly to less than half its baseline value before the creatine phosphate (CrP) pool is 18% depleted. It is determined from these experiments that the maximal rate of oxygen consumption of the heart is an emergent property and is limited not simply by the maximal rate of ATP synthesis, but by the maximal rate at which ATP can be synthesized at a potential at which it can be utilized. The critical free energy of ATP hydrolysis for cardiac contraction that is consistent with these findings is approximately –63.5 kJ mol^–1. Based on theoretical findings, we hypothesize that inorganic phosphate is both the primary feedback signal for stimulating oxidative phosphorylation in vivo and also the most significant product of ATP hydrolysis in limiting the capacity of the heart to hydrolyse ATP in vivo. Due to the lack of precise quantification of P_i in vivo, these hypotheses and associated model predictions remain to be carefully tested experimentally.

(Received 2 April 2008; accepted after revision 1 June 2008; first published online 10 June 2008)
Corresponding authors D. A. Beard: Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.  Email: dbeard{at}mcw.edu J. Zhang: Cardiology, University of Minnesota Medical School. MMC 508, Minneapolis, MN 55455, USA. Email: zhang047{at}umn.edu

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