Creatine and Creatinine Metabolism - Physiological Reviews

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