Correlation Between Changes in the Endogenous Energy Stores and Myocardial Function due to Hypoxia in the Isolated Perfused Rat Heart

Dhalla, N.S.; Yates, J. C.; Walz, Daniel A.; McDonald, Veronica; Olson, Robert E.

doi:10.1139/y72-050

Cited by 56 publications

(16 citation statements)

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“…At the end of a specified time, hearts were rapidly frozen with aluminum tongs precooled in liquid N 2 . Hearts were lyophilized, extracted with 6% (wt/vol) perchloric acid, homogenized, centrifuged, and the supernatant fluid neutralized with 3 N K 2 CO : , to pH 5-6, followed by a second centrifugation to remove precipitated KC10 4 . Extracts were assayed by standard spectrophotometric techniques.…”

Section: Analyticalmentioning

confidence: 99%

Effects of acidosis and ischemia on contractility and intracellular pH of rat heart.

Steenbergen

Deleeuw

Rich

et al. 1977

Circulation Research

247

106

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SUMMARY The effects of respiratory and metabolic acidosis on myocardial contractility and energy production have been investigated in the perfused rat heart. Respiratory acidosis, produced by increasing the Pco 2 , caused an 80% inhibition of pressure development at pH 6.7. When artificial buffers (plus HCI) were used in place of bicarbonate and CO 2 , only a 30% inhibition of pressure development was observed at pH 6.7. Respiratory acidosis produced a greater intracellular acidosis than artificial buffer acidosis at the same extracellular pH. We conclude that both intracellular and extracellular H + impair myocardial function but by separate mechanisms. Intracellular acidosis per se was shown to have little effect on the balance between energy production and energy utilization, and energy stores were relatively well maintained under these conditions. The contribution of intracellular acidosis to ischemic heart failure was examined using an ischemia model in which the coronary flow was decreased during diastole. Consequent restricted oxygen delivery produced a pattern of heterogeneous oxygenation. A fall in effluent pH was concomitant with the decline in myocardial performance, and the intracellular pH fell as the extracellular space became more acidotic. The data suggest that the fall of intracellular and extracellular pH were the principal determinants of the decline of pressure development in the tissue as a whole during the early stages of ischemia. We conclude that mechanical function is depressed in ischemia not only in anoxic regions of the heart but also in adjacent aerobic regions because of the pH change.ALTHOUGH it is well documented that decreased oxygen delivery and accumulation of metabolic end products are components of ischemia, the relative contribution of acidosis and hypoxia to ischemic heart failure has not been properly delineated. Myocardial performance is impaired by either anoxia, produced by equilibrating the perfusate with nitrogen instead of oxygen while maintaining the coronary flow, Previous experiments have demonstrated depression of myocardial contractility by acidosis, but the relative importance of intracellular and extracellular pH has not been unequivocally determined. Initially, it was suggested that extracellular pH was the principal determinant of cardiac work,"' 8 but more recently the importance of intracellular pH has been recognized."" 13 A role for intracellular pH was based on the assumption that there is a greater decline in intracellular pH during respiratory acidosis, produced by increasing the Pco 2 , than during metabolic acidosis, produced by decreasing the bicarbonate concentration. This difference is considered to be due to the high permeability of the sarcolemma to CO 2 and its relatively low permeability to protons or bicarbonate. Because metabolic acidosis causes a smaller negative inotropic effect than respiratory acidosis at the same extracellular pH, l3il4 it was concluded that intracellular pH is an important determinant of myocardial contractility. Howe...

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Section: Analyticalmentioning

confidence: 99%

Effects of acidosis and ischemia on contractility and intracellular pH of rat heart.

Steenbergen

Deleeuw

Rich

et al. 1977

Circulation Research

247

106

View full text Add to dashboard Cite

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“…Based on the known effects of impaired oxygen delivery, it has been postulated that the close correlation between function and perfusion reflects corresponding abnormalities in tissue ATP content and/or oxidative ATP production (1,5,6). However, the relationship between contractile performance and tissue energy metabolism has been evaluated only during oxygen deprivation produced by complete coronary artery occlusion or hypoxic/anoxic myocardial perfusion (7)(8)(9)(10)(11)(12)(13). Because of potential differences in the rate of oxygen delivery, residual oxidative energy production, and cellular washout, extrapolation of these results to incomplete coronary flow restriction seems unwarranted.…”

Section: Introductionmentioning

confidence: 99%

Correlation of contractile dysfunction with oxidative energy production and tissue high energy phosphate stores during partial coronary flow disruption in rabbit heart.

Marshall¹

1988

J. Clin. Invest.

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The relationships between contractile function, myocardial oxygen consumption, and tissue high energy phosphate and lactate content were investigated during partial coronary flow disruption. The experimental preparation was an isolated, isovolumic retrograde blood-perfused rabbit heart. Both developed pressure (r = 0.94) and dp/dt (r = 0.95) exhibited strong linear correlations with myocardial oxygen consumption that were stable for up to 45 min after blood flow reduction. In contrast, tissue high energy phosphate content exhibited nonlinear relationships with both developed pressure and oxygen consumption such that systolic mechanical function and oxidative metabolism declined to 20 and 30% of control values, respectively, before significant abnormalities in myocardial high energy phosphate stores were observed. Similarly, developed pressure and oxygen consumption decreased to 36 and 48% of control, respectively, before abnormal tissue lactate content was detected. The results of this study indicate that: (a) mechanical function is closely related to the rate of oxidative energy production during partial coronary flow disruption, and (b) despite the development of significant contractile dysfunction, tissue high energy phosphate content remains at normal levels except under the most severely flow-deprived conditions. The preservation of tissue energy stores can be explained by the apparent coupling of contractile performance to oxidative energy production, which could function to maintain myocardial energy balance during partial coronary flow restriction.

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Abstract IntroductionThis study investigates the relation between myocardial oxygen consumption (MV 02), function, and high energy phos- Severe hypoxia ultimately leads to contractile failure, which is attributed to an imbalance between myocardial oxygen supply and demand (1)(2)(3)(4). Sudden extreme oxygen deprivation causes rapid depletion of energy stores in the form of the high energy phosphates, phosphocreatine, and ATP, as well as accumulation of ATP hydrolysis products.

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mentioning

confidence: 99%

Relation of myocardial oxygen consumption and function to high energy phosphate utilization during graded hypoxia and reoxygenation in sheep in vivo.

Portman¹,

Standaert²,

Ning³

1995

J. Clin. Invest.

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IntroductionThis study investigates the relation between myocardial oxygen consumption (MV 02), function, and high energy phos- Severe hypoxia ultimately leads to contractile failure, which is attributed to an imbalance between myocardial oxygen supply and demand (1)(2)(3)(4). Sudden extreme oxygen deprivation causes rapid depletion of energy stores in the form of the high energy phosphates, phosphocreatine, and ATP, as well as accumulation of ATP hydrolysis products. In isolated myocytes (5) and buffer-perfused hearts (5, 6) anoxia or hypoxia results in a reduced oxidative phosphorylation rate. Myocardial respiration wanes despite increasing ADP and intracellular phosphate (Pi),' which both stimulate mitochondrial ATP production under aerobic conditions. The intact animal generally maintains or increases myocardial oxygen consumption during early or moderate hypoxia (7-9). Small decreases in myocardial phosphocreatine content with no depletion of the cytosolic ATP pool have been documented during moderate hypoxic conditions (10, 11). However, myocardial oxygen consumption rates have not been directly measured during periods of rapid high energy phosphate depletion and repletion in the intact animal. The purpose of this study was to examine the relation between myocardial oxygen consumption, function, and high energy phosphates during severe hypoxia and reoxygenation in vivo. Additionally, rephosphorylation parameters were measured to determine if evidence of respiratory uncoupling or mitochondrial damage occurs during reoxygenation in vivo. Graded hypoxia was performed in an effort to gradually reduce arterial oxygen tension to attain the P02 at which high energy phosphate stores rapidly decreased. Highly time-resolved 31P nuclear magnetic resonance (NMR) spectroscopy enabled monitoring of myocardial phosphates throughout hypoxia and recovery with simultaneous measurement of oxygen consumption. Consequently, these measurements enhanced analysis of mitochondrial function in vivo during reoxygenation. MethodsAnimal preparation. Animals used in this study were handled in accordance with institutional and National Institutes of Health animal care and use guideline. Sheep between 30 and 70 d old (mean 47 d±6.8) were sedated with an intramuscular injection of 10 mg/kg ketamine, and 0.2-0.4 mg/kg xylazine, intubated, and then ventilated (C-900 pediatric ventilator; Siemens Corp., Schaumberg, IL) with room air and oxygen, followed by an intravenous dose of alpha-chloralose (40 mg/ kg). Femoral arterial cannulation was performed for monitoring systemic blood pressure and sampling blood. Arterial pH was maintained between 7.35 and 7.45 by adjustment of ventilatory tidal volume and 1. Abbreviations used in this paper: FIo2, fractional inspiratory oxygen

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Correlation Between Changes in the Endogenous Energy Stores and Myocardial Function due to Hypoxia in the Isolated Perfused Rat Heart

Cited by 56 publications

References 0 publications

Effects of acidosis and ischemia on contractility and intracellular pH of rat heart.

Effects of acidosis and ischemia on contractility and intracellular pH of rat heart.

Correlation of contractile dysfunction with oxidative energy production and tissue high energy phosphate stores during partial coronary flow disruption in rabbit heart.

Relation of myocardial oxygen consumption and function to high energy phosphate utilization during graded hypoxia and reoxygenation in sheep in vivo.

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