Myocardial creatine phosphate and nucleotides in anoxic cardiac arrest and recovery

Benson, Ellis S.; Evans, Gerald; Hallaway, Ben E.; Phibbs, Clifford M.; Freier, Esther F.

doi:10.1152/ajplegacy.1961.201.4.687

Cited by 88 publications

(14 citation statements)

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“…The values obtained for Pi served as rough indicators of phosphate bond hydrolysis. The levels of Pi found in the arrested hearts were higher than those found in biopsy samples frozen in situ (26), but were equivalent to those found in conventional biopsy samples or in perfused, ar-213 rested hearts (27,44,45). Among the arrested normal and hypertrophied hearts, the values for CrP in the left ventricles equaled those previously reported (27,44), and the values for the right ventricles were higher.…”

Section: Discussionsupporting

confidence: 64%

High Energy Phosphate Compounds in the Myocardium during Experimental Congestive Heart Failure. Purine and Pyrimidine Nucleotides, Creatine, and Creatine Phosphate in Normal and in Failing Hearts*

Fox¹,

Wikler²,

Reed³

1965

J. Clin. Invest.

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High energy phosphate compounds are generally considered essential for muscular contraction although it is not clear how their chemical energy is ultimately made available for transformation into mechanical work (1-3). According to classical concepts, hydrolysis of adenosine triphosphate (ATP) by myofibrillar .ATPase (adenosine triphosphatase) occurs at some time during repetitive cycles of muscular contraction and relaxation, and as a result adenosine diphosphate (ADP) is produced. Delivery of this ADP to mitochondria for regeneration into ATP can serve as an important regulator of the activity of mitochondrial oxidative phosphorylation (4, 5). In failing hearts, changes in oxidative phosphorylation or its products might accordingly reflect primary changes at the mitochondria or altered delivery of ADP from the failing myofibrils (6).Many studies of normal and failing hearts have examined the processes involved in the formation and utilization of high energy phosphate compounds (7). During spontaneous heart failure in man (8-10) and induced heart failure in dogs (11), there were no significant changes in uptake by the myocardium of oxygen or of the diverse substrates from which chemical energy is liberated and then conserved as nucleoside triphosphates or as creatine phosphate (CrP). However, small, long-term, or localized alterations in uptake of exogenous substrates might not have been detected by acute measurements of arteriovenous * Submitted for publication December 19, 1963; accepted October 15, 1964. Supported by grant H-3312 from the National Institutes of Health, U. S. Public Health Service. differences across intact hearts in situ (12). Concentrations of high energy phosphates have been reported to be normal in isolated, acutely failing dog hearts, guinea pig atria, and cat papillary muscles (13)(14)(15) and in chronically failing hearts from dogs with tricuspid insufficiency and pulmonary stenosis or with aortic insufficiency ( 11,16). Muscle preparations from failing canine and human hearts have shown decreased contractility (17, 18) and decreased ATPase activity (19), but myofibrillar proteins from failing canine hearts have been reported to be both normal (20) and altered (21).Recently, changes have been observed in the morphology of mitochondria from failing hearts of dogs with aortic stenosis (22) and in the metabolic responses of mitochondria from failing hearts of guinea pigs with aortic stenosis (23,24). Improved methods for isolation, separation, and specific assay of high energy phosphate compounds have made possible more precise measurements of tissue levels of these labile compounds (25)(26)(27). With the use of such improved techniques, a recent study found significant decreases in levels of ATP, CrP, and creatine (Cr) in failing hearts from guinea pigs with aortic stenosis (28). Since the status of labile phosphate compounds in the chronically failing heart did not yet seem settled, it was considered pertinent to re-examine the content of purine and pyrimidine nucleotides and CrP in h...

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Section: Discussionsupporting

confidence: 64%

High Energy Phosphate Compounds in the Myocardium during Experimental Congestive Heart Failure. Purine and Pyrimidine Nucleotides, Creatine, and Creatine Phosphate in Normal and in Failing Hearts*

Fox¹,

Wikler²,

Reed³

1965

J. Clin. Invest.

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“…Various explanations were proposed, including dysfunction of mitochondria, and lactic acid and pH changes influencing ATP synthesising enzyme kinetics. However, one observation suggested that the basis of this prolonged post anoxic/ischemic ATP depletion was via the loss of ATP precursors from the heart and into the perfusate or blood stream [38] (similar observations were being made by Robert Berne around the same time [39]). The importance of this loss of precursors, which also occurs in man [40], stems from the fact that the heart predominately utilises the purine salvage pathway (Fig.…”

Section: Basis For Atp Depletionmentioning

confidence: 77%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity. Far from this being a disadvantage, the ATP-impoverished slice can serve as a useful and experimentally-tractable surrogate for the injured brain, which experiences similar depletion of cellular ATP. We have shown that the restoration of cellular ATP in brain slices to in vivo values is possible with a simple combination of d-ribose and adenine (RibAde), two substrates for ATP synthesis. Restoration of ATP in slices to physiological levels has implications for synaptic transmission and plasticity, whilst in the injured brain in vivo RibAde shows encouraging positive results. Given that ribose, adenine, and a third compound, allopurinol, are all separately in use in man, their combined application after acute brain injury, in accelerating ATP synthesis and increasing the reservoir of the neuroprotective metabolite, adenosine, may help reduce the morbidity associated with stroke and traumatic brain injury.

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“…4. The 30-min time course demonstrates a typical sequence of high-energy phosphate depletion during cardiac arrest (29,30). As phosphocreatine decreases over the first 10 min to an undetectable concentration, Pi concentration increases while ATP concentration remains the same.…”

Section: Resultsmentioning

confidence: 98%

Analysis of rat heart in vivo by phosphorus nuclear magnetic resonance.

Grove¹,

Ackerman²,

Radda³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

109

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High-resolution 31P nuclear magnetic resonance spectra at 73.83 MHz are reported for rat heart in vivo. In live rats, it was possible to observe the cardiac content of ATP, phosphocreatine,.and Pi. Only a small amount of wholeblood 2,3-diphosphoglycerate was observed in the spectra, precluding the possibility that blood phosphate compounds were masking the spectra of cardiac phosphate compounds. The 31p nuclear magnetic resonance spectra of in vivo and perfused rat hearts were similar and sup ort the utilization of the perfused rat heart as a model system for studying high-energy phosphate metabolism of the heart in vivo. The dynamic flux of highenergy phosphate compounds was investigated by subjecting the rat to respiratory arrest. In this experiment, the heart followed the classic metabolic pattern known to occur during cardiac arrest; phosphocreatine and then ATP decreased in concentration while Pi increased in concentration. The 31p nuclear magnetic resonance analysis of rat heart in vivo is demonstrated to be a practical and feasible method for studying cardiac high-energy phosphate metabolism.Much information has been gained from the in vitro study of isolated biochemical reactions and physiological functions. However, the ultimate description of these processes must be in terms of their regulation and integration within the living organism. High-resolution 31p nuclear magnetic resonance (NMR) spectroscopy can be used to investigate and monitor molecular events occurring within intact, living cells. This noninvasive, nondestructive method allows the simultaneous and continuous detection of intracellular phosphate compounds such as ATP, phosphocreatine, Pi, and 2,3-diphosphoglycerate and has proved valuable in the study of a variety of cell and organ preparations including bacteria (1, 2), yeast (3), erythrocytes (4, 5), skeletal muscle (6, 7), brain (8), liver (9), kidney (10), and heart (11-13). The application of 31P NMR to the detection of phosphate compounds in intact, living animals was first attempted by Chance et al: (8), who measured the 31p NMR spectrum of the head of a mouse. We report here a different application in which we selectively placed the NMR receiver coil around the organ to be analyzed. Using this technique, we have successfully measured the intracellular level and dynamic flux of ATP and phosphocreatine in the hearts of live rats.MATERIALS AND METHODS Animals. Male Wistar rats (250-350 g) maintained on a standard diet were used throughout.Whole-Animal Procedure. Animals were anesthetized with intraperitoneal Sagatal (60 mg/kg of body weight; sodium pentobarbitone, 60 mg/ml). The trachea was intubated via a tracheostomy and the animal was mechanically ventilated 704-0 breaths per min with 50% nitrous oxide/50% oxygen. The abdomen was entered through an upper midline incision and the diaphragm was incised anterially. Access to the heart was completed by a lower median stenotomy. The animal was then secured in the NMR probe in a vertical position. The NMR receiver coil was intro...

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Myocardial creatine phosphate and nucleotides in anoxic cardiac arrest and recovery

Cited by 88 publications

References 0 publications

High Energy Phosphate Compounds in the Myocardium during Experimental Congestive Heart Failure. Purine and Pyrimidine Nucleotides, Creatine, and Creatine Phosphate in Normal and in Failing Hearts*

High Energy Phosphate Compounds in the Myocardium during Experimental Congestive Heart Failure. Purine and Pyrimidine Nucleotides, Creatine, and Creatine Phosphate in Normal and in Failing Hearts*

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Analysis of rat heart in vivo by phosphorus nuclear magnetic resonance.

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