Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1147
references see Refs. 140, 401, 700). The most consistent
findings in these pathological conditions are decreases in
the tissue concentrations of Cr and PCr, in total CK
activity and in the chemical flux through the CK reaction,
in the specific activities and relative proportions of Mi-CK
and MM-CK, and in Cr-stimulated mitochondrial respiration.
With the exception of the diabetic rat heart (see
below), the relative proportions of MB- and BB-CK are
increased. It has been suggested that the relative increase
in MB- and BB-CK, which have higher affinity for Cr and
PCr than MM-CK, represents a metabolic adaptation to
the decreased tissue concentrations of these metabolites
(405). No increase in MB-CK has been observed in cardiac
hypertrophy induced by physiological stimuli where [Cr]
and [PCr] most likely are normal, i.e., in mild hypertrophy
caused by swimming in the rat heart or in moderate
hypertrophy in hearts of greyhounds (see Ref. 401).
For illustration, some examples shall be discussed in
more detail. In the heart of rats suffering from streptozotocin-induced
diabetic cardiomyopathy, total CK activity,
flux through the CK reaction, mRNA levels of B-CK and
M-CK, specific enzymatic activities of all CK isoenzymes,
as well as the relative proportion of MB-CK are all significantly
decreased (38, 611, 777, 854, 955). Although in
control hearts CK flux increased in parallel with the workload
imposed, it did not do so in diabetic hearts (611). In
addition, maximal and Cr-stimulated mitochondrial respiration
were considerably depressed, suggesting a functional
deficit at the level of both mitochondrial oxidative
phosphorylation and Mi-CK (458, 851, 1060). Chronic insulin
treatment of streptozotocin-diabetic rats normalized
all deviating parameters. In line with experiments on
GPA- and iodoacetamide-treated animals, contractile dysfunction
became apparent in diabetic rat hearts only at
high work loads (611).
Spontaneously hypertensive rats show progressive
cardiac hypertrophy and undergo transition from stable
compensated hypertrophy to failure between 12 and 18
mo of age. At 12 mo, despite pronounced hypertrophy, LV
tissue displayed normal total CK activity, normal proportions
of MM- and Mi-CK, and normal CK flux at a given
level of cardiac performance (68, 400, 403, 404). On the
other hand, the proportions of MB- and BB-CK were
increased, and the total Cr content decreased at all ages
studied (6, 12, and 18 mo). With the development of pump
failure between 12 and 18 mo of age, total CK activity
decreased by 30–45%, the relative proportion of Mi-CK by
�50% (with apparently no change in mitochondrial volume),
and the flux through the CK reaction by at least
24%. Antihypertensive treatment with hydralazine or
guanethidine reversed both the biochemical and functional
changes. Whether the coincidence between the
time course of changes in the CK/PCr/Cr system and the
mechanical deterioration of the hearts is accidental or not
remains to be clarified.
The time course of development of cardiac failure
and of alterations in the CK/PCr/Cr system has also been
studied in Syrian hamsters with hereditary hypertrophic
cardiomyopathy (strain T02) (1008). Compared with controls,
total CK activity and total Cr content were first
decreased at 17 wk of age, with these changes persisting
to the last time point analyzed, i.e., 43 wk of age. Baseline
isovolumic contractile performance, measured as ratepressure
product (RPP), was first decreased at 30 wk.
Contractile reserve, on the other hand, which was assessed
as the increase in RPP elicited by high calcium
stimulation, was already reduced at 17 wk of age. Interestingly,
for both normal and myopathic hamsters, the
very same linear relationship was observed between the
energy reserve via the CK reaction, estimated as the product
of total CK activity and total Cr content, and the
contractile reserve of the heart (Fig. 12). Based on these
experiments, the authors concluded that “depletion of
energy reserve occurs early in heart failure and is likely to
be one of the many predisposing factors to further functional
deterioration” (1008).
In this same strain of cardiomyopathic Syrian hamsters,
the effect of the angiotensin converting enzyme
(ACE) inhibitor enalapril on cardiac bioenergetics was
tested (689). Results from clinical trials had shown that
therapy of congestive heart failure with ACE inhibitors
ameliorates patients’ symptoms, slows the progression to
heart failure, and reduces mortality. Enalapril treatment
of cardiomyopathic hamsters did not prevent cardiac hypertrophy
but improved isovolumic contractile performance
and survival rate. The 67% decrease in CK flux
FIG. 12. Relationship between the functional capacity of the CK/
PCr/Cr system and contractile reserve of the heart. The increase in rate
pressure product (RPP) observed in isolated isovolumic hearts upon
increasing total calcium concentration in the perfusate from 1.75 to 4
mM was taken as a measure of contractile reserve. The product of total
CK activity and total Cr content was taken as a measure of energy
reserve via the CK reaction. V max, maximum velocity; �, hearts from
normal hamsters; ■, hearts from cardiomyopathic Syrian hamsters,
strain T02. [Data redrawn from Tian et al. (1008).]