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(The FASEB Journal. 2001;15:2642-2648.)
© 2001 FASEB

Effect of graded hypoxia on the rat hepatic tissue oxygenation and energy metabolism monitored by near-infrared and 31P nuclear magnetic resonance spectroscopy

ALEXANDER M. SEIFALIAN1, EL-HAMID EL-DESOKY, DAVID T. DELPY* and BRIAN R. DAVIDSON

Hepatic Haemodynamic Laboratory, University Department of Surgery, Royal Free and University College Medical School, University College London, The Royal Free Hospital, London; and
* Department of Medical Physics and Bioengineering, University College London, London, UK

1Correspondence: University Department of Surgery, Royal Free and University College Medical School, University College London, The Royal Free Hospital, Pond St., London, NW3 2QG, UK. E-mail: a.seifalian{at}rfc.ucl.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Alteration in hepatic cellular adenosine triphosphate (ATP) levels has been shown to be a sensitive index for hypoxic damage. Hepatic ATP metabolism can be monitored by 31P nuclear magnetic resonance (NMR). Near-infrared spectroscopy (NIRS) can measure tissue oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and cytochrome oxidase (Cyt Ox), which reflect ATP production. In this study, hepatic oxygenation parameters have been correlated with ATP metabolism under graded hypoxia. Sprague-Dawley rats underwent laparotomy for liver exposure. NIRS probes and an NMR coil were placed on the liver and the animal was positioned in the NMR magnet. Graded hypoxia was achieved by a stepwise reduction of the fraction of inspired oxygen (FiO2) from 15 to 4%. Recovery between the hypoxic periods was achieved using 30% oxygen. Hepatic tissue oxygenation parameters were measured continuously by NIRS; 31P-NMR spectra obtained at 1 min intervals from energy metabolites and intracellular pH were calculated. All the hypoxic grades produced an immediate reduction in HbO2 with a simultaneous increase in Hb. Cyt Ox was reduced significantly only with FiO2 of <= 10%. 31P-NMR spectra showed a significant decrease in cellular ß nucleoside triphosphate (ß-NTP) only with FiO2 of <= 10%. Significant correlation was seen between ß-NTP and HbO2 (r=0.85), Hb (r=-0.74), and Cyt Ox (r=0.81). Cyt Ox was reduced with intracellular hypoxia and correlated temporally with the reduction of cellular ß-NTP, and therefore could be used as an index for the changes in ß-NTP with hypoxia.—Seifalian, A. M., El-Desoky, E.-H., Delpy, D. T., Davidson, B. R. Effect of graded hypoxia on the rat hepatic tissue oxygenation and energy metabolism monitored by near-infrared and 31P nuclear magnetic resonance spectroscopy.


Key Words: NIMR • liver hypoxia • ß nucleoside triphosphate


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
LIVER HYPOXIA HAS a detrimental effect on hepatic cell function, metabolism, and morphology (1) . It causes depletion of high-energy phosphate moieties such as adenosine triphosphate (ATP), with subsequent impairment of ATP-dependent intracellular homeostatic mechanisms (2) . The measurement of intracellular ATP has been proposed as a sensitive indicator of hypoxic liver damage (3 , 4) . Conventional methods for ATP measurement include enzymatic assay (5) , chromatography (6) , and 31P nuclear magnetic resonance (31P-NMR) (7) . These methods are either invasive and require tissue biopsy or they require a complicated procedure and time for processing of data, making them unsuitable for routine clinical use.

Near-infrared spectroscopy (NIRS) can continuously measure tissue oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and reduction oxidation (redox) changes of cytochrome oxidase (Cyt Ox) (8) . Cyt Ox is the terminal electron carrier of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to H2O, directly coupled with the synthesis of ATP through oxidative phosphorylation (9) . In aerobically respiring hepatocytes, ~90% of the oxygen taken up is consumed to produce ATP through Cyt Ox (10) ; hence, the redox state of Cyt Ox may be useful as a surrogate marker of intracellular ATP levels.

Cells use oxygen via the respiratory chain located in the inner membrane of mitochondria, which comprise a sequence of interlinked, enzyme-controlled reactions (11) . Cytochrome oxidase belongs to a superfamily of proteins that act as the terminal enzymes of the respiratory chain. The heme/copper terminal oxidases catalyze the four-electron reduction of dioxygen to water, coupled with generation of a proton electrochemical gradient across the membrane. This proton gradient is used by ATP synthase to produce ATP through a chemiosmotic mechanism (12) .

When electron transport ceases during hypoxia, the inner membrane potential is developed at the expense of ATP hydrolysis by the mitochondrial ATP synthase (13) . Rapid reduction of cytochrome oxidase therefore can predict a consequent decrease in ATP, whereas the reduction of copper indicates a decrease in ATP under severe hypoxia. Thus, the copper signal in noninvasive near-infrared spectroscopy is a useful parameter for the clinical setting (14) .

Previous studies have shown the effect of hypoxia on hepatic ATP metabolism (15 16 17) , but the correlation between hepatic extracellular (HbO2 and Hb) and intracellular (Cyt Ox) oxygenation with ATP metabolism has not been investigated.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal preparation and surgical procedure
The study was conducted under a project license granted by the home office in accordance with the Animals (Scientific Procedures) Act 1986. Sprague-Dawley rats (397±34 g, n=11) were anesthetized by 25 mg/Kg Sagatal® (pentobarbitone sodium; Rhone Merieux Ltd., Essex, UK) i.p. Laparotomy was performed through a subcostal incision. Ligamentous attachments from the liver to the diaphragm were severed and the liver was exposed. The animals were allowed to breathe spontaneously using a mask connected to an oxygen, carbon dioxide, and nitrogen regulator.

The NIRS probes were positioned, with 10 mm spacing, on the surface of the right lobe of the liver. A single-turn, 2 cm diameter phosphorus tuned coil was placed directly on the liver adjacent to the NIRS probes and used to acquire NMR spectra at 26 MHz (Fig. 1 ). The animals were positioned in the center of the bore of a 4.7 Tesla NMR spectrometer (Oxford Magnet Technology, Oxford, UK) for acquiring the NMR spectra. A hot gel pad was placed under the animal, with further insulation provided by cotton wool to maintain the animal’s temperature.



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  		Figure 1. Diagram of liver showing NIRS probes positioned, with 10 mm spacing, on the surface of the liver and a single turn 20 mm diameter phosphorus tuned NMR coil adjacent to the NIRS probes.

Near-infrared spectroscopy
NIRS (NIRO-500, Hamamatsu Photonics K.K., Hamamatsu, Japan) was used to monitor hepatic tissue oxygenation and blood volume. A NIRS algorithm was developed to measure continuously hepatic HbO2, Hb, and Cyt Ox concentration changes in µmol/l (18 , 19) . The sum of HbO2 + Hb (HbT) was computed continuously and reflects the liver blood volume (18 , 19) . The HbT level measured by NIRS has been shown to correlate well with flow in the hepatic microvasculature measured by laser Doppler flowmetry as well as the total hepatic blood flow calculated using a transonic ultrasound flowmeter system (18 , 20) . To determine absolute changes in chromophore concentration, the optical path length in the tissue must be known as a function of wavelength. The differential path length factor has been determined specifically for the liver by measuring the absorption coefficient as a function of wavelength (18) . The differential path length factor of the liver is 2.7, and this value was used to adjust the NIRS algorithm for calculating the changes in the chromophore concentrations (18 , 21) .

NMR spectroscopy
A typical 31P-NMR spectrum of the liver contains resonances that can be assigned to phosphomonoesters (PME), inorganic phosphate (Pi), and three nucleoside triphosphate (NTP) resonances (7 , 22) . ATP contributes ~70% of the nucleoside triphosphate signal, with other nucleotide triphosphates such as guanosine triphosphate contributing 30% (23) . Changes in NTP therefore imply changes in ATP. We measured changes in ATP from the ß nucleoside triphosphate (ß-NTP) resonance since the {gamma}-NTP and {alpha}-NTP resonances contain contributions from the ß and {alpha} phosphates of ADP. The {alpha}-NTP also contains contributions from nicotine adenine dinucleotide (NAD+), reduced nicotine adenine dinucleotide (NADH), nicotine adenine dinucleotide phosphate (NADP+), and reduced nicotine adenine dinucleotide phosphate (24) . ß-NTP resonance arises solely from the ß phosphate of the ATP (7 , 25) .

As a consequence of using a 4.7 Tesla high-field in vivo NMR system. a broad coresonance of phospholipid components of membranes, nucleic acids, and possibly slowly tumbling phosphorus containing proteins appears between 30 and -30 ppm, coinciding with the metabolites of interest (22 , 26 , 27) . Absolute integration of individual resonance therefore requires the removal of this broad resonance. To assess changes in the groups studied, the peak heights of the five observed metabolites (PME, Pi, {gamma}-NTP, {alpha}-NTP, and ß-NTP) were measured from the spectral baseline that included a component from the phospholipid. Individual peak heights were then divided by the sum of all the peak heights (total phosphorus peak height) (27) . All values are therefore expressed relative to the total phosphorus peak height, and the relative peak height changes are expressed with a component of phospholipid that did not appear to change throughout the experiment (27) .

Intracellular pH (pHi) was calculated from the chemical shift difference between the pH-dependent Pi resonance relative to the pH-independent {alpha}-NTP resonance using the NMR version of Henderson-Hasselbach equation (28) : pHi = 6.75 + log ({varsigma}-10.85/13.25-{varsigma}), where {varsigma} = chemical shift difference between Pi and {alpha}-NTP, 6.75 is the pKa for Pi in liver tissue.

Experimental protocol
After acquisition of baseline NMR spectra and NIRS measurements for 5 min, the animals were exposed to 6 min periods of consecutive graded hypoxia separated by 5 min recovery periods. Graded hypoxia was induced by a stepwise reduction of the FiO2 using 15, 10, 8, 6, and 4% mixtures of oxygen balanced with nitrogen and recovery between the hypoxic periods using 30% oxygen. Recovery periods were allowed between the hypoxia periods to avoid any cumulative effect of hypoxia. At the end of the experiment, the animals were killed by exsanguination.

Data collection and statistical analysis
Data are expressed as mean ± SD. The NIRS data were calculated as 1 min mean values at the beginning of the experiment before induction of hypoxia (baseline) and at the end of each hypoxia period, when the maximum changes in tissue oxygenation occurred. The PME, Pi, and ß-NTP (measured by NMR) were calculated at the end of each hypoxia period when these signals were maximally changed from the baseline. For statistical analysis, Student’s t test was used with Bonferroni adjustment for multiple comparisons. P < 0.05 was considered statistically significant. The relationships between the NIRS measurements (HbO2, Hb, and Cyt Ox) and the energy metabolites (PME, Pi, and ß-NTP) were tested using linear regression analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Hepatic tissue oxygenation measured by NIRS
All animals tolerated and recovered from exposure to FiO2 of 15 and 10%. At FiO2 of 8%, three animals died; with FiO2 of 6%, three animals died; and with FiO2 of 4%, four did not recover after hypoxia. With all hypoxic periods, there was an immediate reduction in hepatic HbO2 and a simultaneous increase in Hb (Table 1 ). Hepatic Cyt Ox was not significantly reduced from the baseline with FiO2 of > 10% but was significantly reduced with further grades of hypoxia (FiO2<=10%) (Table 1) . There was a significant reduction of HbT with FiO2 <= 10% (Table 1) . Figure 2 represents an example of NIRS measurements with graded hypoxia in one animal.


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  		Table 1. Hepatic tissue oxygenation changes with graded hypoxia measured by near-infrared spectroscopy in µmol/la



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  		Figure 2. A typical example of NIRS measurements in one animal with graded hypoxia. The x axis is time (minutes). The y axes are the concentrations of hepatic HbO2, Hb, Cyt Ox, and HbT (µmol/l). The start of hypoxic periods is marked by dotted lines and recovery periods by solid lines.

Hepatic energy metabolism measured by 31P-NMR
There was no significant change in energy metabolites with FiO2 of 15%. With further hypoxia (FiO2<=10%), there was an increase in PME and Pi resonance with a concomitant decrease in ß-NTP resonance (Table 2 and Fig. 3 ). Intracellular acidosis occurred only with FiO2 of <= 8% (Table 2) .


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  		Table 2. Hepatic energy metabolism and tissue pH with graded hypoxia measured by 31P nuclear magnetic resonancea



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  		Figure 3. In vivo changes associated with the PME, Pi, and ß-NTP. All values are calculated as a percentage of total phosphate signals, which remains constant throughout the experiment. Data are presented together with their respective SE.

Correlation between tissue oxygenation measured by NIRS and hepatic ATP measured by 31P-NMR spectroscopy
The correlation between hepatic tissue oxygenation parameters (HbO2, Hb, and Cyt Ox) and ß-NTP levels are shown in Fig. 4 . ß-NTP showed a positive correlation with HbO2 and Cyt Ox (r=0.85 and 0.81, respectively, P<0.001) and a negative correlation with Hb (r=0.74, P<0.001).



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  		Figure 4. The relationship between the hepatic HbO2 (A), Hb (B), and Cyt Ox (C) measured by NIRS, and ß-NTP measured from 31P-NMR liver spectra, at the end of the hypoxic periods. Each point is the change observed at the end of one hypoxic period in one animal. The FiO2 of 15, 10, 8, 6 and 4% had 11,11, 9, 6, 6 animals; the other animals did not recover.

Mild hypoxia (FiO2 of 15%) reduced HbO2 with no significant reduction of Cyt Ox and ß-NTP. Further hypoxia (FiO2 of<=10%) produced significant reductions in HbO2, Cyt Ox, and ß-NTP. The reduction in Cyt Ox measured by NIRS correlated temporally with the reduction of ß-NTP measured by 31P-NMR spectroscopy (Fig. 5 ).



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  		Figure 5. Temporal association of Cyt Ox and ß-NTP in one animal during the different hypoxic periods, FiO2 of 15 (A), 10 (B), 8 (C), 6 (D), and 4% (E). Cyt Ox (µmol/l), measured by NIRS. ß-NTP, measured from 31P-NMR, calculated as a percentage of the total phosphorus signal height. The x axes for Cyt Ox and ß-NTP are time (minutes). Cyt Ox measured continuously during the hypoxic (1–6 min) and recovery periods (7–11 min). ß-NTP data are shown as 1 min values at baseline (0), with 6 min hypoxia (1 2 3 4 5 6) and 5 min recovery (7 8 9 10 11) .


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Oxygen is the energy source for living cells, as it acts as the terminal electron acceptor in the oxidative phosphorylation process that leads to ATP production in the mitochondria (9) . Oxygen deprivation and reoxygenation resulting in tissue necrosis with subsequent organ failure is a major clinical problem for liver surgery and transplantation (29) .

ATP depletion is one of the first alterations detectable in the hypoxic liver cell, and the depression of ATP synthesis due to oxygen limitation of Cyt Ox activity has been accepted as the decisive functional lesion responsible for hypoxic cell death (30 , 31) . A failure of membrane ion homeostasis resulting from ATP depletion is considered to be a critical factor for cell death with hypoxia (32 , 33) . In view of the central role of ATP to cellular metabolism, the correlation between the tissue ATP level and the severity of hypoxic liver damage may be anticipated (3 , 4) .

With hypoxia, there was an instantaneous decrease of hepatic tissue HbO2 with a simultaneous increase in Hb, which reflects the dissociation of oxygen from hemoglobin as oxygen is extracted by the hepatic tissue. The liver normally extracts less than 40% of oxygen presented to it at baseline blood flow. However, its oxygen extraction capacity approaches 100% during ischemia or hypoxia (34 , 35) , the main mechanism for matching hepatic oxygen supply with need. There was a significant reduction of the HbT with severe hypoxia (FiO2 of<=10%), which reflects the marked reduction in arterial blood flow due to the sympathetic vasoconstriction response to hypoxia (36 , 37) .

The redox state of Cyt Ox is dependent on intracellular oxygen availability (38) . In the presence of oxygen, electron transfer takes place and the enzyme becomes oxidized. With lack of oxygen, the flow of electrons from Cyt Ox decreases and transfer becomes reduced (38) . The reduction of the cellular oxygen supply is paralleled by decreases in the ATP/ADP and NAD+/NADH concentration ratios and by an increase in the reduction state of the mitochondrial respiratory enzymes such as Cyt Ox (39 40 41) . Thus, assessment of the redox state of Cyt Ox could be used as an indicator of intracellular oxygen availability (10 , 38) . In this study, a significant reduction in Cyt Ox was found only with severe hypoxia (FiO2 of<=10%). The reduction of Cyt Ox only with severe hypoxia can be explained by its high affinity to oxygen, as its half-maximal oxidation (Km) for oxygen is < 1 µmol in isolated mitochondria (42) , < 3.5 µmol in hepatocytes (43) , and < 6.8 µmol in the isolated perfused liver (44) . This high affinity of Cyt Ox for oxygen with enzyme reduction only in severe hypoxia may reflect the vital importance of the mitochondrial respiratory enzymes to cellular homeostasis and viability.

A mild grade of hypoxia (FiO2 of 15%) did not induce significant changes in ATP metabolism. With more severe hypoxia (FiO2 of<=10%), there was significant reduction of ATP with a simultaneous increase in PME and Pi and intracellular acidosis. These results agree with other in vitro and in vivo studies that have investigated hepatic energy metabolism with hypoxia (16 , 17 , 45) . In aerobic conditions, ATP degrades to ADP and Pi with the release of protons. These metabolic products are used for ATP resynthesis through oxidative phosphorylation (46) . Hypoxia severely limits the capability of the cell to produce ATP, so the demand for ATP exceeds supply resulting in ADP, Pi, and proton accumulation (2 , 47) . The increase of PME with hypoxia could be explained by the increase in AMP from hydrolysis of ATP and ADP, increased glycolytic activity, and an increase in phosphocholine from phospholipid breakdown (45) .

In this study, the intracellular pH before hypoxia was similar to the pHi levels reported in other studies using NMR (16 , 22 , 28) . The intracellular acidosis that occurred with severe hypoxia is due to proton accumulation from ATP hydrolysis, decreased H+ consumption through gluconeogenesis, and the degradation of glycogen and glucose to lactate (16 , 17 , 22) .

This study has investigated the relationship between hepatic tissue ATP metabolism and tissue oxygenation (HbO2, Hb, and Cyt Ox) measured by NIRS. Mild hypoxia (FiO2 of 15%) rapidly reduced Hemoglobin oxygen saturation but did not affect intracellular oxygenation (Cyt Ox levels) or ATP formation. In severe hypoxia (FiO2 of<=10%), a fall in Hb saturation was associated with a significant reduction in intracellular oxygenation (Cyt Ox) and ATP levels. ATP reduction was an indicator of critical tissue hypoxia that correlated temporally with the changes in Cyt Ox but not with Hb oxygen saturation. Measurement of Cyt Ox by NIRS could therefore be used as a surrogate marker of ATP availability with critical tissue hypoxia.


   ACKNOWLEDGMENTS
 
Dr. Richard Morris, Senior Lecturer in Medical Statistics, Academic Department of Public Health and Primary Care at the Royal Free and University College Medical School, advised on statistical methods. Dr. Kumar Changani and Mr. Paul Kinchesh, Department of Chemistry at Queen Mary and Westfield College, assisted in nuclear magnetic resonance spectroscopy. This work was supported by the Royal Free Hospital Special Trustees (grant 493), the Stanley Thomas Johnson Foundation, Switzerland, and the Egyptian Government in the sponsorship of Dr. El-Desoky. The Wellcome Trust and Hamamatsu Photonics funded the near-infrared spectroscopy calibration equipment. The nuclear magnetic resonance spectrometer was provided by the University of London Intercollegiate Research Service scheme and is located at Queen Mary and Westfield College.

Received for publication May 4, 2001. Revision received September 4, 2001.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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