Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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July 2000 CREATINE AND CREATININE METABOLISM 1149<br />
1. Introduction<br />
Functional recovery after a period of hypoxia, anoxia,<br />
or ischemia depends on environmental factors (e.g.,<br />
temperature) as well as on the severity <strong>and</strong> duration of<br />
low-oxygen stress. Myocardial reperfusion after brief periods<br />
of ischemia is associated with a long-lasting depression<br />
of contractile force despite no evidence for cellular<br />
necrosis or ultrastructural damage. Several factors have<br />
been proposed to contribute to this phenomenon commonly<br />
referred to as “myocardial stunning” (see Refs. 200,<br />
253, 478, 509, 830); nevertheless, the underlying mechanism<br />
is still unknown. One of the potentially contributing<br />
factors is the considerable loss of adenine nucleotides<br />
during ischemia. The progressive fall in [ATP] is accompanied<br />
by a corresponding increase in [ADP] that is degraded<br />
consecutively to AMP, adenosine, inosine, <strong>and</strong><br />
hypoxanthine by way of adenylate kinase, 5�-nucleotidase,<br />
adenosine deaminase, <strong>and</strong> purine nucleoside phosphorylase<br />
(1037; for a review, see Ref. 430). The latter<br />
purine nucleosides <strong>and</strong> bases are membrane permeable<br />
<strong>and</strong> are therefore washed out of the tissue upon resumption<br />
of cardiac perfusion. De novo resynthesis of adenine<br />
nucleotides in the postischemic or postanoxic myocardium<br />
is known to be a slow process (16, 852, 853, 963).<br />
Thus the reduced adenine nucleotide pool size may be<br />
anticipated to limit cardiac contractility. However, a series<br />
of arguments are in contradiction to this hypothesis<br />
(see Refs. 430, 478, 509, 788, 835). The depressed contractile<br />
function of the stunned myocardium might also be<br />
due to a decrease in the capacity of mitochondrial oxidative<br />
phosphorylation <strong>and</strong> high-energy phosphate production<br />
(see Refs. 873, 1118, 1126). As evidenced most convincingly<br />
by the PCr overshoot phenomenon (see below),<br />
this hypothesis again seems unlikely (253, 393, 830, 835).<br />
Prolonged regional or global ischemia of the heart<br />
results in irreversible loss of myocardial contractile activity.<br />
Again, the factors determining irreversible functional<br />
<strong>and</strong> biochemical deterioration of the heart are largely<br />
unknown despite a variety of hypotheses raised. Notably,<br />
even after prolonged ischemia <strong>and</strong> reperfusion, skinned<br />
ventricular strips from rat hearts displayed normal resting<br />
tension, maximal tension, Ca 2� sensitivity, <strong>and</strong> response<br />
to quick length changes in the presence of both PCr <strong>and</strong><br />
MgATP (1062), thus excluding a functional defect at the<br />
level of the myofilaments. What, hence, are the disturbances<br />
of the CK/PCr/Cr system induced by low-oxygen<br />
stress <strong>and</strong> subsequent reperfusion, <strong>and</strong> how do they relate<br />
to the contractile dysfunction observed?<br />
2. The response of the CK/PCr/Cr system to low-oxygen<br />
stress <strong>and</strong> reperfusion<br />
Because the heart relies almost exclusively on mitochondrial<br />
oxidative phosphorylation for high-energy<br />
phosphate production, a decrease in oxygen delivery be-<br />
low a critical limit—due to pathological block of adequate<br />
blood supply, asphyxia, poisoning, experimental, or<br />
surgical intervention—will challenge cardiac energy metabolism.<br />
In line with the notion that the CK reaction is<br />
near equilibrium in the heart under low workload conditions,<br />
[PCr] declines in the initial stages of low-oxygen<br />
stress with just a minor decrease in [ATP]. Only at later<br />
stages when the PCr stores are largely depleted, [ATP]<br />
also decreases considerably (e.g., Refs. 14, 90, 185, 254,<br />
277, 316, 429, 452, 695, 702, 796, 1036, 1063, 1101). Contractile<br />
performance decreases precipitously <strong>and</strong> ceases<br />
when 75% of PCr, but only �20% of ATP is depleted (316).<br />
Even though a direct causal relationship is unlikely, the<br />
time courses of the decrease in [PCr] on one h<strong>and</strong> <strong>and</strong> of<br />
the changes in cardiac contractility are strikingly similar<br />
(14, 695, 1101).<br />
The effect of hypoxia on cardiac CK function was<br />
investigated by 31 P-NMR spectroscopy of rats ventilated<br />
with either 21, 10, or 8% O 2 (67). Under hypoxic conditions,<br />
[PCr] <strong>and</strong> [ATP] were decreased by 11–24% <strong>and</strong><br />
�12%, respectively. Chemical flux through the CK reaction,<br />
however, was decreased by 40% at 10% O 2 <strong>and</strong> by<br />
75% at 8% O 2, relative to normoxic conditions. For comparison,<br />
ventilation with 10 <strong>and</strong> 8% O 2 reduced the ratepressure<br />
product by 34 <strong>and</strong> 49%, respectively. No changes<br />
in total CK activity, proportion of Mi-CK, or total Cr<br />
content were observed in tissue extracts of these hypoxic<br />
rat hearts. It remains to be elucidated why CK flux was<br />
considerably decreased despite no or only minor changes<br />
in total CK activity <strong>and</strong> substrate concentrations, <strong>and</strong><br />
whether the decreased CK flux is, at least in part, responsible<br />
for the reduced cardiac contractile performance<br />
under hypoxic conditions. In a similar set of experiments<br />
on the isolated perfused rat heart, mild hypoxia caused a<br />
52% decrease in forward CK flux, a 55% reduction in<br />
rate-pressure product, <strong>and</strong> a 38% decrease in left ventricular<br />
pressure (299). In both normo- <strong>and</strong> hypothermic rat<br />
hearts as well as under hypoxic conditions, there seemed<br />
to be an almost linear relationship between forward CK<br />
flux <strong>and</strong> rate-pressure product. In chronic anemic hypoxia<br />
induced in rats by dietary iron deficiency, Mi-CK activity<br />
<strong>and</strong> the capacity of Cr-stimulated mitochondrial respiration<br />
as well as MB- <strong>and</strong> BB-CK activity were significantly<br />
increased, whereas total CK activity remained unchanged<br />
(242). On the other h<strong>and</strong>, MM-CK activity <strong>and</strong> the concentrations<br />
of ATP, PCr, <strong>and</strong> total Cr were considerably<br />
depressed.<br />
Ischemia itself had either no effect on total CK activity<br />
(48, 420, 461, 462) or decreased the level of CK protein<br />
or activity only after several hours (879, 894). An exception<br />
may be the pig heart where loss of CK immunoreactivity<br />
was observed within 15 min of acute right ventricular<br />
ischemia (933). On the other h<strong>and</strong>, even after short<br />
periods of ischemia, reperfusion resulted in a considerable<br />
decrease in total CK activity, CK flux measured by