Creatine and Creatinine Metabolism - Physiological Reviews

1148 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80
observed in untreated cardiomyopathic hamster hearts
was almost completely reversed. Surprisingly, however,
enalapril treatment normalized neither [PCr], [Cr], total
CK activity, nor CK isoenzyme distribution (see also Ref.
865), thus calling for an alternative explanation on how
the increase in CK flux was brought about.
Changes in the CK/PCr/Cr system similar to those in
hereditary dilated cardiomyopathy in the Syrian hamster
(458, 476, 599, 1058) were also observed in dilated cardiomyopathy
in humans: total CK, MM-CK, and Mi-CK activities,
Cr-stimulated mitochondrial respiration, and total
Cr content were all considerably decreased, whereas MB-
CK activity was significantly increased (403, 476, 690, 778,
832, 967). Mi-CK activity was also decreased relative to
citrate synthase activity, which excludes a general loss of
mitochondria. Energy reserve via the CK reaction, defined
as above, was reduced by 83% in the failing human myocardium
(690). A decrease in mitochondrial adenine nucleotide
translocase activity—despite increased ANT
mRNA and protein levels—that is due most likely to autoimmunological
reactions against the ANT protein may
contribute to the disturbances in cardiac energy metabolism
in dilated cardiomyopathy (193, 967).
Surprisingly, total CK, MM-, and Mi-CK activities as
well as total Cr content were also decreased considerably
in organ donors maintained in an intensive care unit
before heart harvesting, i.e., in hearts presumed to be
normal (690). It has been hypothesized that these latter
changes are due to increased production of stress hormones
associated with intensive life support treatment,
an idea that is supported by the fact that an increased
adrenergic drive can modulate the contents of Cr and CK
in the heart. The more important lesson to be learned
from these findings is that energy metabolism of the donor
heart may already be compromised at the time of
organ transplantation, which may have a serious impact
on the outcome of the intervention. Perhaps, simple Cr or
PCr infusion in the organ donor, either alone or in conjunction
with parasympathetic cholinergic agents like carbachol
(1075) or �-adrenergic receptor antagonists like
propranolol, atenolol, and bisoprolol (117, 533), may preserve
the energetic reserve in the donor heart and thereby
improve the survival rate of the transplanted organ (see
also sect. IXC).
As early as in the 1930s, ingestion of the Cr precursor
Gly was proposed as a therapy for cardiac disease and was
reported to have favorable effects (see Ref. 55). It is only in
recent years that the idea of treating heart failure with Cr
supplementation has been revived (138, 140, 241, 297). In the
study of Constantin-Teodosiu et al. (138), sustained hypertension
was induced in the rat by prolonged oral administration
of N G -nitro-L-arginine methyl ester (L-NAME), an inhibitor
of NOS. Concomitant ingestion of Cr prevented the
decreases in [ATP], [PCr], [Cr], and [total Cr] as well as the
increase in lactate concentration in ventricular tissue asso-
ciated with L-NAME treatment, but failed to ameliorate the
mechanical disturbances of the heart at intermediate workloads.
In chronic heart failure in humans, Cr supplementation
improved LV ejection fraction neither at rest nor during
exercise (297). However, it increased the concentrations of
Cr, PCr, and total Cr in quadriceps femoris muscle by 12–
24%, which was accompanied by a significant increase in
different measures of skeletal muscle performance (see also
Ref. 22).
Evidently, there is no strict mutual dependence between
disturbances in Cr metabolism and defects in cardiac
contractile performance. For example, defects in
excitation-contraction coupling may reduce contractile
performance in the absence of any changes in the CK/
PCr/Cr system. Furthermore, disturbances in the CK/
PCr/Cr system do not have to be expressed at all stages of
the disease, and both functional and biochemical deficits
may not be observed at low or intermediate workloads.
Therefore, it comes as no surprise that in some studies on
cardiac disease, no defects in the CK system were detected
(e.g., Refs. 54, 753, 856, 1122).
Despite these latter caveats, a wealth of evidence
suggests a close correlation between the functional capacity
of the CK/PCr/Cr system and cardiac contractile
performance. Even though most arguments in support of
such a correlation come from studies on small laboratory
animals like the rat and hamster, having a cardiac CK/
PCr/Cr system admittedly quite distinct from that of humans,
similar conclusions can also be drawn from investigations
on human cardiac disease. Although initial
experiments on Cr supplementation in cardiac disease
failed to demonstrate a beneficial effect on the mechanical
function of the heart (138, 297), even though supplementation
of the diet of normal rats with 1–7% Cr for 40
days neither increased total Cr content, flux through the
CK reaction, or [PCr]/[ATP], nor had an impact on the
mechanical function of the heart (380), and in spite of
conflicting arguments (241), interventions toward improving
the energy reserve via the CK reaction as a means for
treating cardiac disease should be given further thought.
C. Low-Oxygen Stress, CK Function,
and the Potential of Cyclocreatine
for Organ Transplantation
Although a strict separation from what has been
discussed in section IXB is impossible, this section focuses
on the impact of hypoxia, anoxia, ischemia, reoxygenation
and reperfusion on the functional capacity of the
CK/PCr/Cr system, as well as on the possibilities for preventing
damage induced by low-oxygen stress and subsequent
reperfusion.