Transmural high energy phosphate distribution and response to alterations in workload in the normal canine myocardium as studied with spatially localized <sup>31</sup>P NMR spectroscopy

Robitaille, Pierre‐Marie; Merkle, Hellmut; Lew, Brian; Path, G.; Hendrich, Kristy; Lindstrom, Paul; From, Arthur H. L.; Garwood, Michael; Bache, Robert J.; Uğurbil, Kâmil

doi:10.1002/mrm.1910160110

Cited by 85 publications

(59 citation statements)

References 48 publications

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“…[4][5][6][7] The changes in highand low-energy phosphates suggest that phosphate metabolites could participate in the control of oxidative phosphorylation in this experimental model. In the isolated rabbit heart, oxygen consumption following a step in heart rate adapts with a response time of many seconds and is substantially longer than the corresponding time constants of the phosphate metabolites.…”

Section: Generalmentioning

confidence: 79%

“…[4][5][6][7] In other studies, changes in these metabolites were reported under specific experimental circumstances.5,32-34 For example, Heineman and Balaban5 showed that in mature dog hearts the PCr-to-ATP ratio only changed with heart rate when there was a concomitant decrease in coronary flow and arterial blood pressure. Portman et aP34 showed that changes in the PCr-to-ATP ratio due to increases in work load occurred in newborn lambs but not in mature sheep.…”

Section: Generalmentioning

confidence: 96%

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Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

Eijgelshoven

Beek

Mottet

et al. 1994

Circulation Research

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To investigate the dynamic control of cardiac ATP synthesis, we simultaneously determined the time course of mitochondrial oxygen consumption with the time course of changes in high-energy phosphates following steps in cardiac energy demand. Isolated isovolumically contracting rabbit hearts were perfused with Tyrode's solution at 28°C (n=7) or at 37°C (n=7). Coronary arterial and venous oxygen tensions were monitored with fast-responding oxygen electrodes. A cyclic pacing protocol in which we applied 64 step changes between two different heart rates was used. This enabled nuclear magnetic resonance measurement of the phosphate metabolites with a time resolution of =2 seconds. Oxygen consumption changed after heart-rate steps with time constants of 14±1 (mean±SEM) seconds at 28°C and 11±1 seconds at 37°C, which are already corrected for diffusion and vascular transport delays. Doubling of the heart rate resulted in a significant decrease in phosphocreatine (PCr) in inorganic phosphate (Pi) content, although oxygen supply was shown to be nonlimiting. The time constants for the change of both Pi and PCr content, =5 seconds at 28°C and 2.5 seconds at 37°C, are significantly smaller than the respective time constants for oxygen consumption. The changes in phosphate metabolites during changes in oxygen consumption suggest that regulation of oxidative phosphorylation could occur partly via products of ATP hydrolysis, but the unequal time constants of PCr and oxygen consumption suggest that other regulatory mechanisms also play a role. These dissimilar time constants further suggest that there might be an appreciable transient contribution of nonaerobic, presumably glycolytic, ATP synthesis to buffer the high-energy phosphates during fast transitions in cardiac work. (Circ Res. 1994;75: 751-759.) Key Words * myocardial energy metabolism * rabbit hearts * mitochondrial control * 31P nuclear magnetic resonance spectroscopy * oxidative phosphorylation changes in high-energy phosphates and Pi despite increases in myocardial oxygen consumption suggested that the phosphate metabolites may not be the primary regulators of cardiac mitochondrial respiration.The absence of a change in ATP or phosphocreatine (PCr) after a change in metabolic demand would also mean that mitochondrial ATP production and hence oxygen consumption must adapt immediately to a change in cytosolic ATP hydrolysis. In the isolated perfused rabbit heart, this is not the case, because oxygen consumption adapts to a new work load with a mean response time of at least 6 seconds.

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Section: Generalmentioning

confidence: 79%

Section: Generalmentioning

confidence: 96%

Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

Eijgelshoven

Beek

Mottet

et al. 1994

Circulation Research

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“…Although controversial, some heterogeneity in energy metabolism probably also exists across the left ventricular wall ( 19). This postulate is reinforced by 31P NMR studies which have used homogenous radiofrequency fields in association with localization pulse sequences and found small transmural variations in PCr/ATP (20). In the present experiments relative concentrations in phosphorous metabolites summed across the sampling area were analyzed, with the understanding that specific portions of myocardium may have more or less change during hypoxia and recovery.…”

Section: F102(%)mentioning

confidence: 83%

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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“…Along with electrical heterogeneity, regional differences in mechanical function have also been previously reported (12,29,44). The basis for this has never been fully addressed.…”

Section: Discussionmentioning

confidence: 99%

Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,I_toK⁺currents, and [Ca²⁺]_itransients

Kaprielian

Sah

Nguyen

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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(Ito) has been shown to vary between different regions of the normal myocardium and to be reduced in heart disease. In this study, we measured regional changes in action potential duration (APD), I to, and intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) transients of ventricular myocytes derived from the right ventricular free wall (RVW) and interventricular septum (SEP) 8 wk after myocardial infarction (MI). At ϩ40 mV, I to density in sham-operated hearts was significantly higher (P Ͻ 0.01) in the RVW (15.0 Ϯ 0.8 pA/pF, n ϭ 47) compared with the SEP (7.0 Ϯ 1.1 pA/pF, n ϭ 18). After MI, I to density was not reduced in SEP myocytes but was reduced (P Ͻ 0.01) in RVW myocytes (8.7 Ϯ 1.0 pA/pF, n ϭ 26) to levels indistinguishable from post-MI SEP myocytes. These changes in I to density correlated with Kv4.2 (but not Kv4.3) protein expression. By contrast, Kv1.4 expression was significantly higher in the RVW compared with the SEP and increased significantly after MI in RVW. APD measured at 50% or 90% repolarization was prolonged, whereas peak [Ca 2ϩ ]i transients amplitude was higher in the SEP compared with the RVW in sham myocytes. These regional differences in APD and [Ca 2ϩ ]i transients were eliminated by MI. Our results demonstrate that the significant regional differences in I to density, APD, and [Ca 2ϩ ]i between RVW and SEP are linked to a variation in Kv4.2 expression, which largely disappears after MI. right ventricle; septum; heart disease; contraction THERE ARE MARKED DIFFERENCES in the action potential duration (APD) in different regions of the mammalian ventricle (4,15,18,39,58). This electrical heterogeneity in normal myocardium correlates with regional differences in the Ca 2ϩ -independent transient outward K ϩ current density (I to ) (5,15,18,34,35,43) as well as in gene expression of K ϩ channels (8,16,58). APD prolongation and reductions in I to density occur in rat heart after left anterior descending coronary artery ligation (2, 43, 58), aortic banding (5, 22, 55), as well as after treatment with either catecholamine (11) or monocrotaline (32, 33). Depending on the model, the extent of I to density changes in disease may not be uniform throughout the ventricle (2, 5, 11, 22, 55), thereby leading to possible losses of electrical heterogeneity and increased susceptibility to arrhythmias (3).Aside from electrical heterogeneity, regional differences in other myocardial properties also exist. For example, systolic intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is higher in the endocardium than in the epicardium (19,54), consistent with the notion that the endocardium may play a more important role in contraction compared with the epicardium. The underlying basis for the regional differences in contraction is currently unknown but may be related to a heterogeneous transmural expression of Ca 2ϩ handling proteins (26, 31). Alternatively, APD might also play a key role because the action potential profile is an important determinant of the inotropic state of the heart in both normal (7,42,54) and hy...

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Transmural high energy phosphate distribution and response to alterations in workload in the normal canine myocardium as studied with spatially localized ³¹P NMR spectroscopy

Cited by 85 publications

References 48 publications

Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

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

Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,I_toK⁺currents, and [Ca²⁺]_itransients

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Transmural high energy phosphate distribution and response to alterations in workload in the normal canine myocardium as studied with spatially localized 31P NMR spectroscopy

Cited by 85 publications

References 48 publications

Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

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

Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,ItoK+currents, and [Ca2+]itransients

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Transmural high energy phosphate distribution and response to alterations in workload in the normal canine myocardium as studied with spatially localized ³¹P NMR spectroscopy

Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,I_toK⁺currents, and [Ca²⁺]_itransients