Hearts of chicks fed the
creatine analog,
1-carboxymethyl-2-iminoimidazolidine (
cyclocreatine), accumulated 15 mumol/g wet wt of the synthetic phosphagen,
cyclocreatine-3-P; had total
creatine levels reduced from the normal 6 mumol/g to only 1.8 mumol/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 mumol/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 Pi; 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 less than or equal to 1.2 mumol/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.