Myocardial protection during ischemia by prior feeding with the creatine analog: Cyclocreatine

Jacobstein, Mark D.; Gerken, Thomas A.; Bhat, Aashiq Hussain; Carlier, Pierre

doi:10.1016/0735-1097(89)90081-8

Cited by 9 publications

(13 citation statements)

References 23 publications

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“…The effect of feeding Cy in the current study confirms the demonstration of its pro tective effect during ischemia shown earlier either by the delayed onset of rigor [ 1 ] or by assessing mechanical function in a perfused heart following reperfusion [5]. In all cases, loss of ATP during ischemia was slowed.…”

Section: Comparison Of Our Data With Previous Worksupporting

confidence: 75%

“…(7) no balloon was placed in the left ven tricle, and (8) hearts were allowed to beat spontaneously, not paced electrically. Fur thermore, the duration of ischemia was the same for Cy-fed and control rats in the pre vious NMR experiments [5], while in the experiments reported here, ischemia was con tinued until ATP was no longer NMR visible for all three groups of rats (CON. CR and CY).…”

Section: Comparison Of Our Data With Previous Workmentioning

confidence: 99%

“…PCy was often NMR visible when ATP was not. 5 In CY. the ATP levels were main tained at significantly higher levels for longer times than in the other two groups.…”

Section: P Nmr Datamentioning

confidence: 99%

“…In all cases, loss of ATP during ischemia was slowed. In the first study [1], the phosphate metabolites were determined chemically and in the sec ond [5]. by 3IP NMR.…”

Section: Comparison Of Our Data With Previous Workmentioning

confidence: 99%

“…Previ ous studies suggest that cyclocreatine (Cy, 1-carboxymethyl-2-iminoimidazolidine. a syn thetic analogue of creatine, Cr) might provide this type of protection to the ischemic myocar dium [1][2][3][4][5]. Cy is converted to phosphocyciocreatine (PCy), which has a higher equilibrium concentration and an extended buffering range and capacity to maintain ATP than phosphocreatinc (PCr) [2.…”

Section: Introductionmentioning

confidence: 99%

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Creatine and Cyclocreatine Effects on Ischemic Myocardium: <sup>31</sup>P Nuclear Magnetic Resonance Evaluation of Intact Heart

et al. 1992

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The purpose of this study was to investigate the effects of prior dietary supplementation with creatine (Cr) or cyclocreatine (Cy, a synthetic analogue of Cr) on high energy phosphate metabolism of the ischemic myocardium. To this end, 48 rats were fed the following powdered rat chow diet for 21 days: 16 were fed chow without additives (CON); 16 were fed a diet containing 1 % Cr by weight (CR); 16 were fed a diet containing 1 % Cy by weight (CY). At the end of the feeding period, rats were anesthetized, hearts harvested and perfused in the Langendorff mode using Krebs-Henseleit buffer (maintained at 37 °C, equilibrated with 95% 02/5% CO2) to which 11 mM glucose was added. ³¹P nuclear magnetic resonance (NMR) studies of myocardial bioenergetics were done using a Bruker AM 500 spectrometer. After acquisition of preischemic spectra, global ischemia was produced by clamping aortic inflow. Ischemia was maintained until adenosine triphosphate (ATP) became NMR invisible (CON =34 ± llmin;CR = 32 ± 13min;CY = 56 ± 13min;p < 0.05 CY vs. CR and CON). Half-lives of ATP were 19 min for CON and CR and 37.5 min for CY; half-lives of phosphagen were 4 min for CON and CR and 11 min for CY. Time for return of mechanical function (heart rate × systolic pressure) after ischemia was similar for all three groups (CON = 28 ± 28, CR = 34 ± 22, and CY = 22 ± 15 min), even though the CY group was subjected to longer periods of ischemia). These data indicate that CY, but not CR, pretreatment provides myocardial protection either during and/or after ischemia and allows return of mechanical function after much longer episodes of ischemia than in CON and CR. One factor in the mechanism of protection may be the prolonged maintenance of phosphagen due to the higher equilibrium concentration of phosphocyclo-creatine which in turn provides substrate for continued synthesis of ATP during and after ischemia, thus defining Cy as a bioenergetic protective agent. Other mechanisms of protection remain to be defined.

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Section: Comparison Of Our Data With Previous Worksupporting

confidence: 75%

Section: Comparison Of Our Data With Previous Workmentioning

confidence: 99%

“…PCy was often NMR visible when ATP was not. 5 In CY. the ATP levels were main tained at significantly higher levels for longer times than in the other two groups.…”

Section: P Nmr Datamentioning

confidence: 99%

“…In all cases, loss of ATP during ischemia was slowed. In the first study [1], the phosphate metabolites were determined chemically and in the sec ond [5]. by 3IP NMR.…”

Section: Comparison Of Our Data With Previous Workmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Creatine and Cyclocreatine Effects on Ischemic Myocardium: <sup>31</sup>P Nuclear Magnetic Resonance Evaluation of Intact Heart

et al. 1992

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Therapeutic Use of Creatine in Brain or Heart Ischemia: Available Data and Future Perspectives

Perasso

Spallarossa

Ruggeri

et al. 2011

Medicinal Research Reviews

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Creatine (Cr) is essential in safeguarding ATP levels and in moving ATP from its production site (mitochondria) to the cytoplasmic regions where it is used. Moreover, it has effects unrelated to energy metabolism, such as free radical scavenging, antiapoptotic action, and protection against excitotoxicity. Recent research has studied Cr-derived compounds (Cr benzyl ester and phos-pho-Cr-magnesium complex) that reproduce the neuroprotective effects of Cr while better crossing the neuronal plasma membrane and, hopefully, the blood-brain barrier (BBB). Intracellular levels of Cr can be increased by incubation with Cr or some of its derivatives, and this increase is protective against anoxic or ischemic damage. A large amount of experimental evidence shows that pretreatment with Cr is capable of reducing the damage induced by ischemia or anoxia in both heart and brain, and that such treatment may also be useful even after stroke or myocardial infarction (MI) has already occurred. Cr has been safely administered to patients affected by several neurological diseases, yet it has never been tested in human brain ischemia, the condition where its rationale is strongest. Phosphocreatine (PCr) has been administered after human MI, where it proved to be safe and probably helpful. Cr should be tested in the prophylactic protection against human brain ischemia and either Cr or PCr should be further tested in MI. Moreover, Cr- or PCr-derived drugs should be developed in order to overcome these molecules' limitations in crossing the BBB and the cell plasma membrane.

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Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease

et al. 2016

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Creatine is of paramount importance for maintaining and managing cellular ATP stores in both physiological and pathological states. Besides these "ergogenic" actions, it has a number of additional "pleiotropic" effects, e.g., antioxidant activity, neurotransmitter-like behavior, prevention of opening of mitochondrial permeability pore and others. Creatine supplementation has been proposed for a number of conditions, including neurodegenerative diseases. However, it is likely that creatine's largest therapeutic potential is in those diseases caused by energy shortage or by increased energy demand; for example, ischemic stroke and other cerebrovascular diseases. Surprisingly, despite a large preclinical body of evidence, little or no clinical research has been carried out in these fields. However, recent work showed that high-dose creatine supplementation causes an 8-9 % increase in cerebral creatine content, and that this is capable of improving, in humans, neuropsychological performances that are hampered by hypoxia. In addition, animal work suggests that creatine supplementation may be protective in stroke by increasing not only the neuronal but also the endothelial creatine content. Creatine should be administered before brain ischemia occurs, and thus should be given for prevention purposes to patients at high risk of stroke. In myocardial ischemia, phosphocreatine has been used clinically with positive results, e.g., showing prevention of arrhythmia and improvement in cardiac parameters. Nevertheless, large clinical trials are needed to confirm these results in the context of modern reperfusion interventions. So far, the most compelling evidence for creatine and/or phosphocreatine use in cardiology is as an addition to cardioplegic solutions, where positive effects have been repeatedly reported.

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Myocardial protection during ischemia by prior feeding with the creatine analog: Cyclocreatine

Cited by 9 publications

References 23 publications

Creatine and Cyclocreatine Effects on Ischemic Myocardium: <sup>31</sup>P Nuclear Magnetic Resonance Evaluation of Intact Heart

Creatine and Cyclocreatine Effects on Ischemic Myocardium: <sup>31</sup>P Nuclear Magnetic Resonance Evaluation of Intact Heart

Therapeutic Use of Creatine in Brain or Heart Ischemia: Available Data and Future Perspectives

Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease

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