Feeding Sprague-Dawley rats for 3 wk a diet containing 1% by weight of
cyclocreatine increased the reservoir of the high-energy
phosphate compounds but also caused alterations in the levels of the two key
amino acids,
aspartate and
glutamate. Both were decreased by approximately 50% in the presence of an unaltered content of
glutamine. In vitro exposure of these hearts to sequential perfusion, global
ischemia, and reperfusion in the absence of added
amino acids resulted in changes in
aspartate,
glutamate, and
glutamine that were different from those in hearts from control rats. In the
cyclocreatine-fed group,
aspartate concentration ([
aspartate]) and [
glutamate] fell after global
ischemia, whereas [
glutamine] was unaltered. [
Glutamine] decreased, however, in the reperfusion period. In control hearts, the predominant effect was a steady decline in
glutamine, which was accompanied by either less than 10% (after global
ischemia) or 30-50% fall (after reperfusion) in [
aspartate] and [
glutamate]. The concentration of tissue Pi was smaller in hearts from
cyclocreatine-fed rats and appeared to increase more slowly during
ischemia. In the presence of
rotenone and
aminooxyacetate, heart homogenates catalyzed production of
glutamate from
glutamine, which was markedly stimulated by Pi and inhibited by H+. It is postulated that 1)
phosphate-activated glutaminase is an important
enzyme that determines cardiac [
glutamate], 2) lower [
phosphate] in hearts from rats fed
cyclocreatine is responsible for the apparently lesser activity of
glutaminase, 3) breakdown of the high-energy
phosphate compounds and consequent rise in Pi activates
glutaminase, and 4) slow breakdown of
glutamine during global
ischemia is a result of inhibition of
glutaminase by H+.