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Am J Physiol Heart Circ Physiol 288: H2062-H2067, 2005. First published December 9, 2004; doi:10.1152/ajpheart.00777.2004
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Myocardial oxygenation and adenosine release in isolated guinea pig hearts during changes in contractility

J. Chiaka Ejike,1 Lorilee S. L. Arakaki,1 Daniel A. Beard,2 Wayne A. Ciesielski,5 Eric O. Feigl,3 and Kenneth A. Schenkman1,2,4

Departments of 1Pediatrics, 2Bioengineering, 3Physiology and Biophysics, and 4Anesthesia, University of Washington and 5Children's Hospital and Regional Medical Center, Seattle, Washington

Submitted 2 August 2004 ; accepted in final form 3 December 2004


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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Previous work from this laboratory using near-infrared optical spectroscopy of myoglobin has shown that ~20% of the myocardium is hypoxic in buffer-perfused hearts that are perfused with fully oxygenated buffer at 37°C. The present study was undertaken to determine cardiac myoglobin saturation in buffer-perfused hearts when cardiac contractility was increased with epinephrine and decreased during cardiac arrest with KCl. Infusion of epinephrine to achieve a doubling of contractility, as measured by left ventricular maximum pressure change over time (dP/dt), resulted in a decrease in mean myoglobin saturation from 79% at baseline to 65% and a decrease in coronary venous oxygen tension from 155 mmHg at baseline to 85 mmHg. Cardiac arrest with KCl increased mean myoglobin saturation to 100% and coronary venous oxygen tension to 390 mmHg. A previously developed computer model of oxygen transport in the myocardium was used to calculate the probability distribution of intracellular oxygen tension and the hypoxic fraction of the myocardium with an oxygen tension below 0.5 mmHg. The hypoxic fraction of the myocardium was ~15% at baseline, increased to ~30% during epinephrine infusion, and fell to ~0% during cardiac arrest. The coronary venous adenosine concentration changed in parallel with the hypoxic fraction of the myocardium during epinephrine and KCl. It is concluded that catecholamine stimulation of buffer-perfused hearts increases hypoxia in the myocardium and that the increase in venous adenosine concentration is a reflection of the larger hypoxic fraction of myocardium that is releasing adenosine.

myoglobin; hypoxia; buffer-perfused heart

THE ISOLATED CRYSTALLOID BUFFER-PERFUSED HEART is a useful preparation to study myocardial function in the whole organ. However, unlike hearts in vivo and in red blood cell-perfused hearts, crystalloid-perfused hearts have an inadequate oxygen supply, even when hearts are perfused with fully oxygenated buffer. Previous work from this laboratory using near-infrared optical spectroscopy of myoglobin has shown that there is remarkable heterogeneity in intracellular oxygenation in buffer-perfused hearts with ~20% of the myocardium having an intracellular oxygen tension <0.5 mmHg (6, 24). Adding red blood cells to the buffer to give a hematocrit of only 5% prevents this hypoxic fraction.

Previous work from other laboratories has demonstrated that stimulating isolated buffer-perfused hearts with catecholamines results in a decrease in mean myoglobin oxygen saturation (8) and augmented coronary venous adenosine levels (9, 14). These results suggest that catecholamine stimulation exacerbates the tissue hypoxia found in buffer-perfused hearts.

The present study was designed to determine how the distribution of myocardial oxygenation in buffer-perfused hearts changes when contractility was either increased with epinephrine or decreased during cardiac arrest with potassium. Briefly, catecholamine stimulation increased cardiac contractility, myocardial oxygen consumption (MO2), and coronary flow, whereas coronary venous oxygen tension (PvO2) decreased. Epinephrine increased the hypoxic fraction of the myocardium (the fraction with an oxygen tension below 0.5 mmHg) and the venous adenosine concentration. Cardiac arrest with potassium had the opposite effects.


   METHODS
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Isolated heart preparation. All experiments were performed in accordance with University of Washington Animal Care Committee regulations. Male guinea pigs (500–650 g) were injected with intraperitoneal heparin (1,000 units) and were anesthetized with pentobarbital sodium (100–125 mg/kg). The hearts were rapidly excised and immersed in ice-cold buffer, and the aorta was cannulated for perfusion in the Langendorff manner. A constant coronary perfusion pressure of 65 cmH2O was maintained in a water-jacketed perfusion system at 37°C. Modified Krebs-Henseleit buffer equilibrated with 95% O2-5% CO2 was used for perfusion. All aspects of the perfusion system have been previously described (23). The pulmonary artery was cannulated to collect coronary venous effluent for PvO2 and adenosine measurements.

Physiological monitoring. Monitoring of physiological variables has been previously detailed (23). Briefly, a pacing wire in the right ventricular cavity was used to pace the hearts at 280 beats/min with a 2.8-ms pulse duration and 1 V amplitude. Left ventricular pressure was measured with a catheter-tip pressure transducer inside a water-filled latex balloon placed in the left ventricle. The volume of the balloon was adjusted at the beginning of each experiment to give a left ventricular end-diastolic pressure of 5–10 mmHg. Left ventricular maximum pressure change over time (dP/dt) was computed from left ventricular pressure by a standard routine in Labview (National Instruments). Coronary flow was measured with an ultrasonic flow transducer in the aortic inflow tubing just above the heart. Measurements of myocardial temperature were made with a thermocouple placed in the right ventricular cavity. PvO2 was measured using a Clark-type oxygen electrode in a stirred chamber at 37°C through which venous buffer from the cannulated pulmonary artery was passed.

All physiological data were acquired with a 12-bit analog-to-digital converter at a sampling rate of 1 kHz and displayed on a desktop personal computer using software developed in Labview. Values were determined by averaging over 1-s intervals that were synchronized with the acquisition of each optical spectrum.

Experimental protocol. After a 20-min stabilization period, hearts demonstrating a baseline systolic pressure >80 mmHg and a maximum left ventricular dP/dt of over 1.0 mHg/s were deemed acceptable preparations (n = 6). One preparation was discarded because the baseline maximum dP/dt was <1.0 mHg/s, and two experiments were rejected because the coronary venous oxygen electrode failed. Baseline physiological and spectral data were collected for 10 min. Epinephrine (IMS Limited) at 10 µM was then infused into the perfusate for 15 min at 1% of the coronary flow with the use of a syringe pump. The final perfusate concentration of epinephrine was 100 nM. After a period of recovery, 150 mM KCl was infused into the perfusate at 10% of the coronary flow for 15 min. The final perfusate concentration of KCl was 15 mM.

Myocardial oxygen consumption. MO2 was calculated from PvO2 and coronary flow. Arterial oxygen tension (PaO2) was calculated to be 670 mmHg based on complete equilibration of buffer with 95% O2 at 37°C. Oxygen consumption was calculated as MO2 = F·(PaO2 – PvO2)·0.023/760, where F is coronary flow per gram of wet heart weight. The solubility of oxygen in water is 0.023 ml O2·ml water–1·atm–1 at 37°C (1).

HPLC adenosine analysis. Coronary venous effluent was sampled for adenosine at 5-min intervals during the 10-min baseline period. Samples were also collected at 1, 3, 5, 10, and 15 min after initiation of both epinephrine and KCl infusions. During sample collection, ~1 ml of venous effluent from the pulmonary artery was collected into tubes containing 25 µl erythro-9-(2-hydroxy-3-nonyl)adenine (10 µM), an adenosine deaminase inhibitor. As a further precaution, samples were placed in a boiling water bath for 1 min to inactivate adenosine deaminase and were frozen until analysis.

Samples were thawed and centrifuged at 5,000 g for 10 min to remove precipitated salts. The adenosine in each sample was separated isocratically at 0.5 ml/min on a Beckman model 126 HPLC with a C-18 column (5 µM, LiChrospher 100 RP-18, Hewlett-Packard) using a mobile phase of 8 mM K2HPO4-KH2PO4 containing 3.5% methanol. Adenosine was detected using a Beckman model 206 single wavelength detector at 260 nm. Quantification of sample adenosine was accomplished by comparison of retention time and peak area with those of adenosine standards.

Spectral data analysis. Optical reflectance spectra from 600 to 850 nm were acquired every 1.7 s from the left ventricular free wall during diastole as previously described (23).

Mean myoglobin saturation was determined by partial least squares analysis. As described in earlier work (23, 25–27), reference spectra obtained from in vitro solutions of myoglobin, cytochrome c, and cytochrome oxidase in scattering media were acquired to form a partial least squares model. Spectra were preprocessed by taking second derivatives with respect to wavelength to reduce baseline offsets. Partial least squares analysis can be used to accurately predict concentrations of an analyte of interest (in this case, the oxygen saturation of myoglobin) from complex spectra of solutions or tissue in which multiple absorbing species with overlapping spectral features exist. Previous studies have demonstrated successful measurement of myoglobin saturation using this method (25–27).

Data analysis. Values for mean myoglobin saturation, left ventricular isovolumic maximum dP/dt, coronary flow, PvO2, and MO2 during baseline, epinephrine, and potassium arrest are means determined from the last 3 min of each experimental period for each heart. In addition, during the epinephrine period, means from 3.5 to 6.5 min from the start of infusion were computed for all of these variables.

Baseline adenosine values are means of samples collected at 5 and 10 min after the start of the baseline period (n = 2 for each heart). Adenosine concentrations were determined at 5 min after the start of epinephrine infusion (early in epinephrine infusion, Table 1). In addition, means of samples collected at 10 and 15 min after the start of infusion (n = 2 for each heart) were calculated (late in epinephrine infusion, Table 1). Adenosine concentrations during KCl infusion are the means of samples collected at 10 and 15 min after the start of the infusion (n = 2 for each heart). Because the baseline values of venous adenosine concentration were rather variable among hearts (as indicated by the large SE in Table 1), the adenosine data in Fig. 2 are expressed as percent change from baseline (average of the two baseline measurements). The percent change indicates the change normalized to the baseline value of the individual heart.


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  		Table 1. Physiological variables during baseline, epinephrine, and KCl periods

 


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  		Fig. 2. Time courses of maximum dP/dt (A), mean myoglobin saturation (B), venous PO2 (C), coronary flow (D), myocardial oxygen consumption(E), and venous adenosine (F) during baseline, epinephrine, and KCl periods in six hearts. Mean ± SE at every twentieth data point is shown. Mean values for these physiological variables were calculated from the last 3 min of each experimental period for each heart (see Table 1: baseline, late in epinephrine infusion, and KCl infusion). Venous adenosine values in Table 1 for each of these three experimental conditions are the average of the last two points in each period.

 
The Student's t-paired test was used to compare values during epinephrine and KCl periods to baseline. A P value of <0.05 represented statistical significance.

Model analysis. An estimate of the percentage of hypoxic myocardium during the last 3 min of baseline, epinephrine, and KCl periods was determined by a mathematical model of oxygen transport that was recently developed (6). The model parameters are exactly as given in the previous paper (6). Input variables for the model are measured coronary flow and the constant arterial oxygen tension (670 mmHg). The single free parameter in the model, the maximal rate of intracellular oxygen consumption (GM), was varied to give a best fit between the measured and model-predicted values of mean myoglobin saturation and PvO2 for each condition (baseline, epinephrine, and cardiac arrest) in each heart. Distributions of intracellular oxygen tension and myoglobin saturation were generated from the best-fit model solutions using the optimal estimates of GM for each heart at baseline and during epinephrine and KCl periods. The hypoxic fraction of the intracellular space was computed as the volume fraction for which oxygen tension was <0.5 mmHg, the half-maximal oxygen tension for oxygen consumption using Michaelis-Menten kinetics (12).


   RESULTS
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An example of original recordings from an individual experiment is displayed in Fig. 1. Time courses of left ventricular maximum dP/dt, mean myoglobin saturation, PvO2, coronary flow, MO2, and venous adenosine during baseline, epinephrine, and KCl periods are shown. Figure 2 shows the means ± SE of the time courses of these physiological variables for all six hearts. Values for the physiological variables at the end of the baseline, epinephrine, and KCl periods are shown in Table 1.



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  		Fig. 1. Time courses of maximum pressure change over time (dP/dt) (A), mean myoglobin saturation (B), venous PO2 (C), coronary flow (D), myocardial oxygen consumption (E), and venous adenosine (F) during baseline, epinephrine, and KCl periods in one heart.

 
At the end of the epinephrine infusion, an increase in left ventricular maximum dP/dt of 118% from the baseline was accompanied by an increase in MO2 of 45%. Venous oxygen tension decreased by 45%, indicating increased oxygen extraction. Coronary flow increased by 26%, whereas venous adenosine increased to 103% above baseline (Fig. 2). Mean myoglobin saturation, an indicator of intracellular oxygenation, decreased from 79% to 65%, whereas the hypoxic fraction increased from ~15% to ~30%. Intracellular oxygenation is substantially depleted in the crystalloid-perfused heart during intense contraction. The variations from baseline in all of these variables were statistically significant (P < 0.05).

Infusion of excess potassium into the perfusate arrested contraction. In all hearts, effects opposite to those induced by epinephrine were observed. MO2 decreased by 49% and PvO2 increased by 152% relative to baseline. Coronary flow was not significantly different from baseline, showing a decrease of 5.6%. Venous adenosine fell by 92%, whereas myoglobin saturation increased from 79% to 100%. The model calculation indicated that no part of the myocardium was hypoxic (hypoxic fraction ~0) during cardiac arrest.

The mean values are given in Table 1, whereas the model-estimated distributions for myoglobin saturation and intracellular oxygen tension are illustrated in Fig. 3. Note the remarkable bimodal distribution of myoglobin saturation. Some areas of the heart are well oxygenated, whereas others are severely hypoxic.



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  		Fig. 3. Probability distributions of myoglobin saturation (A) and intracellular PO2 (B) during baseline, late epinephrine, and KCl periods. Bimodal distributions during baseline and epinephrine periods reflect the two states of myoglobin: oxymyoglobin and deoxymyoglobin. Distributions are very similar, although the mean myoglobin saturation is 81% and 66% during baseline and late epinephrine infusion, respectively. During KCl infusion, myoglobin is fully saturated. With catecholamine stimulation, mean intracellular PO2 is 109 mmHg, compared with 204 mmHg at baseline. Hypoxia is fully resolved during potassium arrest. Bars indicate the mean values on the x-axis for each condition.

 
Figure 4 illustrates the ability of the model calculation to simulate the measured mean myoglobin saturation and measured PvO2 during the several experimental conditions. The model solutions seem reasonable considering that the GM is the only free parameter in the model calculation.



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  		Fig. 4. Comparisons of computational model predictions with experimentally measured data. A: model-predicted mean myoglobin saturation is plotted against experimental values for the four experimental steady-states measured. Plotted data points correspond to baseline, 3.5–6.5 min after start of epinephrine infusion (early epinephrine), 12–15 after start of epinephrine infusion (late epinephrine), and following KCl infusion. B: model-predicted venous PO2 is plotted against experimental values for the four experimental steady states. Model predictions for the KCl case exactly reproduce experimental measures because in this case, the tissue is fully oxygenated and the model reduces to a linear mass balance. In both panels, the line of unity is shown for reference.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The principal finding in the present study is that the hypoxic fraction of the myocardium (with an intracellular oxygen tension of <0.5 mmHg) is increased during catecholamine stimulation of buffer-perfused hearts. Cardiac arrest with potassium chloride eliminates the hypoxic areas. Coronary venous adenosine concentrations increased during epinephrine infusion and decreased during cardiac arrest, reflecting the hypoxic fraction of the myocardium releasing adenosine.

The increase in left ventricular isovolumic maximum dP/dt, MO2, and coronary flow during catecholamine infusion observed in the present study is consistent with previous reports in buffer-perfused hearts (5, 9). A fall in coronary PvO2 during catecholamine stimulation in a constant pressure-perfused Langendorff preparation has been observed previously (4, 5). A transient increase in coronary venous adenosine concentration followed by a partial decline has also been previously observed with catecholamine infusion (9, 15, 16). Thus the current experiments are representative of the usual buffer-perfused guinea pig heart preparation, and the present myoglobin saturation measurements should pertain to previously published experiments.

Average myoglobin saturation has been previously measured in buffer-perfused hearts. A dual-wavelength optical method in the buffer-perfused isolated rabbit heart was used to show that myoglobin is not fully saturated under baseline conditions and that myoglobin becomes further saturated during potassium chloride arrest (18). 1H nuclear magnetic resonance has been used to monitor deoxymyoglobin in isolated rat hearts. When the pressure rate product was doubled by a combination of cardiac pacing and dobutamine infusion, average myoglobin oxygen saturation decreased (8). The present measurements of average myoglobin oxygen saturation (Fig. 2, Table 1) are consistent with these previous results.

The current study incorporates a model-based analysis of the data, which provides estimates of the heterogeneous distribution of oxygen tension and myoglobin saturation in the tissue (Fig. 3). The distributions of myoglobin saturation during baseline and epinephrine infusion are bimodal, reflecting populations of the two states of myoglobin: oxymyoglobin and deoxymyoglobin. Figure 3 illustrates that mean myoglobin saturations do not tell the whole story. A relatively small decrease in mean myoglobin saturation during epinephrine infusion relative to baseline (decrease in saturation of 17%) results in a substantial increase in the hypoxic fraction of the myocardium. The hypoxic fraction, with an oxygen tension <0.5 mmHg, increased from ~15% to ~30% with epinephrine infusion and fell to ~0% during potassium chloride cardiac arrest.

The present results may be used to interpret the adenosine measurements in this study and similar published data cited above. It is well known that cardiac hypoxia results in adenosine release from cardiac myocytes (11, 14, 28), and the venous concentration of adenosine in buffer-perfused hearts may be a reflection of the fraction of the myocardium that is hypoxic. Previously, the increased release of adenosine during catecholamine infusion in buffer-perfused hearts was interpreted to represent the physiological control mechanism dilating the coronary circulation when MO2 was increased (4, 9, 17). However, the present results indicate that this is a pathological mechanism due to cellular hypoxia. The concordant increase and decrease in adenosine levels with the hypoxic fraction during catecholamine infusion and potassium chloride arrest make this a parsimonious interpretation. (The low venous adenosine concentration during cardiac arrest is probably the result of residual injury due to hypoxia.) This interpretation is consistent with in vivo measurements where adenosine was not found to be the physiological mediator of coronary vasodilation during exercise (2, 29, 30).

There was not a linear relationship between the myocardial hypoxic fraction and the coronary venous adenosine concentration. Also, there was a transient increase in venous adenosine concentration early in the epinephrine infusion period followed by a partial decline as the epinephrine infusion continued, as has been observed by others (9, 15, 16). As shown in Fig. 2, the variables other than venous adenosine concentration reached steady values during the period when the spike in venous adenosine concentration was observed. The model-determined maximal MO2 (i.e., GM) also reached a steady value early in the epinephrine infusion period during the spike in venous adenosine concentration (Table 1). The present experiments do not elucidate the exact mechanism whereby myocardial hypoxia causes adenosine release. The threshold for hypoxia was set at 0.5 mmHg, which is the KM for Michaelis-Menten oxygen consumption used in previous analyses (6, 12). If the threshold for hypoxia were different from 0.5 mmHg, then the comparison between hypoxic fraction and adenosine release would be somewhat different.

The increase in coronary flow observed during epinephrine infusion in the present experiments may be attributed to adenosine in the hypoxic regions of the myocardium and {beta}-adrenoceptor-mediated coronary vasodilation (10, 13). It is well known that adenosine infusion causes coronary vasodilation in buffer-perfused hearts (7, 22).

In vivo studies demonstrate strikingly different results from those using isolated hearts. With 1H nuclear magnetic resonance spectroscopy, baseline myoglobin saturation was measured at over 90% (3, 19–21, 31). Even when MO2 was two to three times higher than baseline, no myoglobin desaturation was observed (3, 20, 21, 31). The enhanced oxygen supply provided by blood and the ability of in vivo hearts to vasodilate more effectively than isolated buffer-perfused hearts result in high mean myoglobin saturations, even during elevated oxygen consumption.

In conclusion, during baseline conditions the hypoxic fraction of myocardium in buffer-perfused hearts at 37°C was ~15%, which increased to ~30% during epinephrine infusion and decreased to ~0% during potassium chloride cardiac arrest. Epinephrine increased cardiac contractility, MO2, coronary flow, and coronary venous adenosine concentration. Cardiac arrest reversed these findings. The changes in coronary venous adenosine concentration are probably due to the changes in the hypoxic fraction, not a physiological response to the change in MO2.


   GRANTS
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 ABSTRACT
 METHODS
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 DISCUSSION
 GRANTS
REFERENCES
 
This research was funded in part by the Whitaker Foundation Research Grant RG-00-0220 and by National Heart, Lung, and Blood Institute Grant HL-072011.


   ACKNOWLEDGMENTS
 
Present address for J. C. Ejike: Dept. of Pediatrics, Loma Linda University Children's Hospital, Loma Linda, CA, 92354. Present address for D. A. Beard: Dept. of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. A. Schenkman, Critical Care Medicine, Mail Stop B9524, Children's Hospital and Regional Medical Center, 4800 Sandpoint Way NE, Seattle, WA 98105 (E-mail: ken.schenkman{at}seattlechildrens.org)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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