Creatine and Creatinine Metabolism - Physiological Reviews

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1152 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80 tested as an early marker for AMI diagnosis by Delanghe and co-workers (for references, see Refs. 174, 176). Because Cr is considerably smaller than an MB-CK molecule, it might be expected that it is released into the circulation at an earlier stage of tissue injury and may thus allow diagnosis of AMI more quickly. In fact, Cr levels in serum and urine transiently increased after AMI, with a mean time to peak concentration of 3–4 h and a mean half-life of Cr in serum of �6 h. Because of the large variability between individuals and the expected low specificity for cardiac disease, serum Cr determinations are, however, unlikely to become a routine method for early AMI diagnosis. 4. Increasing the functional capacity of the CK/PCr/Cr system as a strategy to improve ischemic tolerance? After all, can the knowledge gained in the preceding sections be used to devise strategies for preventing ischemic myocardial damage? Emphasis is given here on those treatments in which the beneficial effect may be brought about directly or indirectly by an intervention in the CK/PCr/Cr system. As already mentioned above, the catecholamine dobutamine prevents both myocardial stunning and PCr overshoot in the pig heart (478). The calcium antagonist verapamil displayed favorable effects in both hereditary dilated cardiomyopathy (599) and ischemia (see Refs. 104, 531). Verapamil was shown to reduce infarct size and hemodynamic deterioration of the ischemically injured myocardium. It also slowed the rate of CK release into the circulation and preserved highenergy phosphate stores during both hypoxia or ischemia and reperfusion, possibly by reducing the energy demand of the heart (694, 701). When initiated early after myocardial infarction, treatment with the �-blocker bisoprolol prevented the changes in the CK/ PCr/Cr system in intact LV tissue of the infarcted rat heart (533). In sham hearts, bisoprolol treatment resulted even in a 40% increase in total Cr levels above control. Possibly, these results are related to the beneficial effects of long-term �-blocker treatment in patients with chronic myocardial infarction. Similarly, long-term treatment with ACE inhibitors (captopril, enalapril, quinapril, or trandolapril) partially prevented the decreases in [ATP], [PCr], and [total Cr] in noninfarcted LV and RV tissue and, at the same time, diminished the reduction in cardiac output or LV developed pressure and attenuated the rise in LV end-diastolic pressure seen in nontreated infarcted rat hearts (381, 841). Unexpectedly, however, quinapril treatment also increased the susceptibility of both normal and infarcted hearts to acute hypoxia/reoxygenation injury (381). All approaches toward decreasing the concentration of reactive oxygen species in reperfused myocardium are expected to improve mechanical recovery of the heart and to prevent loss of CK activity (see above). In fact, perfusion with the lipophilic spin trap �-phenyl-t-butyl nitrone improved recovery of contractile function, [PCr], and [ATP], and diminished CK release from ischemic and reperfused rat hearts (90). Preceding ischemic episodes (“ischemic preconditioning”) reduced infarct size after 40–60 min of sustained ischemia in dogs and pigs (see Ref. 477). Ischemic preconditioning also slowed ATP and PCr depletion, tissue acidification, and ultrastructural damage during the final episode of ischemia. Furthermore, it increased postischemic ATP levels and [PCr]/[P i] during the reperfusion period in the rat heart (see Refs. 346, 770, 988). When AMI patients were followed for 2 yr, those with a peak serum concentration of Cr �0.1 mM after AMI displayed a considerably lower incidence of death and major cardiovascular complications (3 of 41) than those with a peak Cr concentration of �0.1 mM (16 of 44) (174, 177). This finding may be related to the ability of Cr to inhibit ADP- or collagen-induced platelet aggregation in concentrations as low as 0.15 mM. By possibly inhibiting intravasal thrombocyte aggregation, oral Cr supplementation (at doses and intervals still to be specified) may therefore become a simple and nonproblematic prevention of AMI having, most likely, minimal if any side effects. In cultured cardiomyocytes of newborn rats, the intracellular concentrations of Cr and PCr were reported to rise with increasing [Cr] in the medium (876). Incubation with Cr, however, did not protect the cardiomyocytes against ischemic damage (640). Clinical and laboratory trials have shown that PCr displays a variety of cardioprotective effects and is an effective agent for the treatment of AMI, congestive heart failure, and for myocardial protection during heart surgery (for overviews, see Refs. 140, 505, 836). PCr shows antiarrhythmic and antifibrillatory properties (607, 821). Experimental evidence suggests that this effect of PCr is due to inhibition of phospholipase A 2, thereby reducing the degradation of membrane phospholipids and depressing accumulation of lysophosphoglycerides (which are highly arrhythmogenic compounds) in ischemic myocardium. This finding is particularly relevant since arrhythmias turning into fibrillation and heart rupture are among the reasons for mortality from AMI. In cardiac ischemia, PCr treatment preserved twofold higher levels of intracellular ATP and PCr, decreased CK release as well as the size of the ischemic zone, and resulted in better recovery of developed tension as well as in a faster decrease in end-diastolic pressure during reperfusion. PCr also improved diastolic function parameters in patients with chronic ischemic cardiomyopathy (855). In addition, it provided functional protection against ox-
July 2000 CREATINE AND CREATININE METABOLISM 1153 idative damage (i.e., lipid peroxidation) caused by perfusion of the isolated heart with H 2O 2. Even though intravenous administration of PCr increased the intracellular concentrations of ATP and PCr in the heart of living rats (194), PCr is generally accepted not to be membrane permeable. Because in contrast to PCr, Cr plus P i did not protect the ischemic myocardium, cardioprotection is believed to be brought about by extracellular effects of PCr. It may interact electrostatically with membrane phospholipids, thus decreasing the fluidity and possibly increasing the stability of the plasma membrane. The half-life of PCr in blood or plasma was estimated to be between 4 and 5 min (505) and �1.3 h (194). Close structural analogs like PCrn (821), creatinol O-phosphate (288), and O-benzyl-phosphocreatine (1024) were also shown to afford cardioprotection, possibly in the same manner as PCr. In contrast, P i plus Cr, PArg (see Refs. 505, 836), O-benzyl-phosphoglycocyamine (1024), and O-benzyl-phosphocreatine ethyl ester (1025) were ineffective. A substance displaying most likely still another mode of action is cCr. As already discussed in section VIIIB, cCr competes with Cr for uptake into heart (and other tissues) where it is accumulated, together with its phosphorylation product, PcCr, in large concentrations at the expense of Cr and PCr. PcCr serves as a slowly hydrolyzable reservoir of high-energy phosphates for ATP regeneration. During cardiac ischemia upon long-term feeding of rats and chickens with cCr, the reduction in tissue [ATP], exhaustion of high-energy phosphates, and onset of rigor tension were all significantly delayed (419, 738, 808, 1028, 1076). Upon reperfusion, the number of hearts recovering mechanical function was significantly higher and the ratepressure product comparable in cCr-treated rats relative to controls, despite a considerably longer period of ischemia (56 vs. 34 min) (738). Spontaneous defibrillation upon reperfusion occurred sooner in hearts of cCr-fed rats than in controls (178 vs. 346 s) (419). Surprisingly, favorable effects were observed also after short-term cCr or PcCr treatment. Intravenous injection in dogs, rats, and rabbits of cCr or PcCr 30–120 min before 1) killing of the animals and heart removal, 2) aortic cross-clamping, or 3) coronary artery occlusion, all followed by a period of ischemia, resulted in a significant protection of the PCr and ATP pools (13, 218) and in a remarkable improvement of cardiac function upon reperfusion (13, 219, 383). In addition, cCr treatment reduced the cardiac production of neutrophil chemotactic factors (217, 218) as well as the accumulation of neutrophils in the heart after ischemia and reperfusion (217). Neutrophil accumulation in ischemic myocardium has been implicated to be involved in postischemic damage of the heart (see Refs. 217, 218). cCr has no inotropic or chronotropic effect on the dog heart (383). Unexpectedly, cCr showed no beneficial effects in Syrian hamsters with congestive heart failure. If anything, its effect was slightly negative when given in high amounts to animals already experiencing heart failure. Even though the reason for this discrepancy remains to be established, the results on normal hearts are encouraging and hint at the potential for cCr in organ transplantation. To close the gap between animal experiments and organ transplantation in humans, and because endothelial cells may be the primary target of reperfusion injury (548), we tested the effects of cCr on human umbilical vein endothelial cells (HUVEC) in cell culture. Despite the rather low levels of Cr, PCr, and CK activity in endothelial cells, preincubation with cCr for 24 h delayed ATP depletion during cold hypoxia, diminished release of lactate dehydrogenase during subsequent reperfusion, and better preserved the viability of the HUVEC in preliminary experiments (M. Wyss, T. Eberl, Y. Ishida, R. Margreiter, and R. Kaddurah-Daouk, unpublished results). Even though use of cCr seems particularly attractive at present in heart transplantation, beneficial effects on the preservation of other organs (e.g., skin flaps in reconstructive surgery, Ref. 147) should not be ruled out. 5. Conclusions The findings discussed in this section provide a long list of arguments, although admittedly still not conclusive, for a correlation between the functional capacity of the CK/PCr/Cr system and ischemic tolerance of a given tissue. This has recently been corroborated by experiments on transgenic mice expressing high levels of BB-CK in liver, a tissue normally displaying only very low levels of CK activity (642). The concentrations of Cr and PCr in transgenic liver increased with the level of Cr in the diet. In transgenic liver with an initial [PCr]/[ATP] of 4.5, a delayed and less pronounced depletion of ATP as well as a smaller drop in pH were observed during 40 min of ischemia. Within 30 min of reperfusion, pH as well as P i and ATP levels returned to preischemic values in transgenic liver, whereas only incomplete recovery of [P i] and [ATP] was seen in normal liver. In addition, during 90 min of hypoxia, release of lactate dehydrogenase was prevented in transgenic liver containing high levels of PCr. Protection against low-oxygen stress was not seen in normal liver containing elevated concentrations of Cr, or in transgenic liver low in PCr. Therefore, protection against low-oxygen stress and reperfusion injury depends on the presence of both CK and PCr. In conclusion, strategies toward improving the functional capacity of the CK/PCr/Cr system may represent effective means for improving the ischemic tolerance of a tissue. As shown above, cCr is a promising candidate for such a purpose and may improve cold preservation of organs, e.g., in heart transplantation.
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