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