Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1151
1126). It will therefore be interesting to further study the
effects of NO and peroxynitrite on CK activity, both in
vitro and in the reperfused myocardium. In conclusion,
there are several different possibilities how CK inactivation
during reperfusion may be brought about. The detailed
contributions of all these mechanisms to in vivo CK
inactivation are worthy of future investigation.
A further peculiarity of the CK/PCr/Cr system in the
reperfused myocardium is the “PCr overshoot phenomenon.”
After a period of ischemia (or anoxia), [PCr] recovers
very quickly to supranormal values as soon as reperfusion
is initiated (e.g., Refs. 17, 252, 478, 699, 852, 853,
963). In contrast, [ATP] recovers only slowly and incompletely.
This indicates that the major determinant of the
decreased contractility in the stunned myocardium is not
a limitation in mitochondrial oxidative capacity and highenergy
phosphate production, but rather a defect in energy
utilization or signal transmission. Myristic acid treatment
of rats, which increases catalase activity in the
heart, suppressed the PCr overshoot phenomenon and
improved mechanical and bioenergetic recovery (461,
462). Evidently, reactive oxygen species may play a critical
role both in the PCr overshoot phenomenon and in the
postischemic depression of cardiac contractility. It remains
to be determined whether CK inactivation by reactive
oxygen species at sites of ATP utilization (MM-CK
bound to myofibrils, the SR, or the sarcolemma) is contributing
to these phenomena. Interestingly, treatment of
pigs with dobutamine during reperfusion after 15 min of
coronary artery occlusion prevented both myocardial
stunning and PCr overshoot but did not improve the
recovery of [ATP] (478).
3. Implications for human pathological conditions
involving ischemia
Left ventricular hypertrophy due to systemic hypertension
in association with coronary ischemic heart disease
has been recognized as a major risk factor for sudden
death, postinfarction heart failure, and cardiac
rupture (see Ref. 104). Therefore, it seemed desirable to
investigate the combined effects of cardiac hypertrophy
and ischemia on cardiac metabolism and contractility.
Patients with severe left ventricular hypertrophy caused
by valvular aortic stenosis, as well as rats or dogs with
cardiac hypertrophy due to pressure overload or hyperthyroidism,
proved to be particularly susceptible to hypoxia
or ischemia (see Refs. 34, 104, 403, 766, 916, 1098).
After 30 min of global ischemia, the rate-pressure product
recovered to only 40% in hypertrophied hearts but to 83%
in normal hearts (104). In hyperthyroid rats, systolic and
diastolic dysfunction during hypoxia occurred in those
hearts containing the lowest prehypoxic levels of PCr
(403). In contrast to these findings, the cardiac PCr content
was decreased in hypertensive rats by 14%; however,
during 12 min of hypoxia, the rates of PCr and ATP
depletion as well as the changes in intracellular pH were
indistinguishable between hypertrophied and normal
hearts, even though diastolic dysfunction was more pronounced
in the hypertrophied hearts (1098). Thus a correlation
between ischemic susceptibility and the tissue
concentration of PCr seems still questionable.
Another frequent human disease involving ischemia
is acute myocardial infarction (AMI). In experimentally
induced myocardial infarction in rats and pigs, energy
reserve via the CK reaction was reduced substantially also
in the residual intact (nonischemic, “remodeled”) left ventricular
tissue: [ATP] was unchanged or slightly decreased,
whereas [PCr], [total Cr], total CK activity, MMand
Mi-CK activity, and flux through the CK reaction were
reduced by 16–50% (see Refs. 265, 532, 533, 678, 698, 841).
The B-CK, M-CK, and sarcomeric Mi-CK mRNA levels in
the remodeled rat heart were considerably increased, decreased,
and unchanged, respectively (698). In analogy to
the results on the combined effects of cardiac hypertrophy
and low-oxygen stress discussed above, MI hearts
displayed impaired mechanical recovery following a period
of hypoxia, thus suggesting that reduced energy reserve
may contribute to increased susceptibility of MI
hearts to acute metabolic stress. In remodeled left ventricular
tissue of infarcted pig hearts, total CK activity and
M-CK mRNA level were unchanged, whereas Mi-CK
mRNA level as well as the protein contents of sarcomeric
Mi-CK and M-CK were decreased by 30–53% (366). In
contrast, B-CK protein content was increased by 77%. In
humans, no difference in total Cr content was observed
between noninfarcted regions of MI hearts and myocardium
of healthy controls (87).
For clinical diagnosis of AMI, the release of CK from
damaged ischemic tissue has been instrumental. After
experimentally induced myocardial infarction, as much as
75% of the CK activity may be released from injured
myocardial tissue (for reviews, see Refs. 327, 749, 789,
1120). Total plasma CK activity generally increases 4–8 h
after onset of chest pain, peaks within 12–14 h, and returns
to normal within 72–96 h. Because CK may also be
released from other tissues, while MB-CK is normally
found in highest concentration in the heart, the latter was
an accepted marker of AMI for many years. Only recently,
the conviction that under certain conditions, MB-CK may
also be increased in tissues other than the heart (327) as
well as the finding of even more specific and therefore
more reliable myocardial markers (e.g., cardiac troponins
I and T) (240, 508, 891) have reduced interest in MB-CK as
an AMI marker. Mi-CK is also released from infarcted
myocardium, in a time course similar to, but a peak
activity that is considerably lower than that of MB-CK
(411, 966). The apparent half-lives of MB-CK and Mi-CK in
serum were estimated to be �11 and 60 h, respectively.
Over the last decade, release of Cr itself has been