Relative abilities of phosphagens with different thermodynamic or kinetic properties to help sustain ATP and total adenylate pools in heart during ischemia

Abstract

Hearts of chicks fed the creatine analog, 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine), accumulated 15 μmol/g wet wt of the synthetic phosphagen, cyclocreatine-3-P; had total creatine levels reduced from the normal 6 μmol/g to only 1.8 μmol/g; and had their glycogen levels tripled. During total ischemia in vitro these hearts utilized the cyclocreatine-P for synthesis of ATP, had greatly prolonged glycolysis, and exhibited a two- to fivefold delay in depletion of both ATP and the total adenylate pool, relative to controls. Accumulation from the diet of comparable levels of the closely related 1-carboxyethyl-2-imino-3-phosphonoimidazolidine (homocyclocreatine-P) by heart was accompanied by only slight lowering of total creatine to 4.2 μmol/g, and a tripling of glycogen levels. During ischemia these hearts exhibited prolonged glycolysis, but they did not utilize the very stable homocyclocreatine-P (200,000-fold less reactive than creatine-P) and thus formed less P i; most significantly, there was no delay in depletion of ATP levels relative to controls. Feeding of creatine doubled total creatine levels in heart, but had no marked effect on ATP depletion during ischemia; in all dietary groups creatine-P pools had fallen to ≤ 1.2 μmol/g by first tissue sampling. Although adaptive responses were also involved, maximal conservation of ATP and total adenylate pools in heart during ischemia apparently required, in addition to adequate glycogen reserves, substantial levels of a kinetically competent phosphagen that is thermodynamically poised to continue to assist glycolysis in buffering decreases and oscillations in the [ATP]/[free ADP] ratio at the lower phosphorylation potentials and more acid pH characteristic of later stages of ischemia. Decreases and oscillations in the [ATP]/[free ADP] ratio cannot be buffered effectively late in ischemia by the creatine-P system for thermodynamic reasons, or by the homocyclocreatine-P system because of kinetic limitations.