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Am J Physiol Heart Circ Physiol 288: H1586-H1590, 2005. First published November 24, 2004; doi:10.1152/ajpheart.00983.2004
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Plasma ATP during exercise: possible role in regulation of coronary blood flow

Martin Farias, III, Mark W. Gorman, Margaret V. Savage, and Eric O. Feigl

Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington

Submitted 23 September 2004 ; accepted in final form 18 November 2004


   ABSTRACT
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It was previously shown that red blood cells release ATP when blood oxygen tension decreases. ATP acts on microvascular endothelial cells to produce a retrograde conducted vasodilation (presumably via gap junctions) to the upstream arteriole. These observations form the basis for an ATP hypothesis of local metabolic control of coronary blood flow due to vasodilation in microvascular units where myocardial oxygen extraction is high. Dogs (n = 10) were instrumented with catheters in the aorta and coronary sinus, and a flow transducer was placed around the circumflex coronary artery. Arterial and coronary venous plasma ATP concentrations were measured at rest and during three levels of treadmill exercise by using a luciferin-luciferase assay. During exercise, myocardial oxygen consumption increased ~3.2-fold, coronary blood flow increased ~2.7-fold, and coronary venous oxygen tension decreased from 19 to 12.9 mmHg. Coronary venous plasma ATP concentration increased significantly from 31.1 to 51.2 nM (P < 0.01) during exercise. Coronary blood flow increased linearly with coronary venous ATP concentration (P < 0.01). Coronary venous-arterial plasma ATP concentration difference increased significantly during exercise (P < 0.05). The data support the hypothesis that ATP is one of the factors controlling coronary blood flow during exercise.

adenosine triphosphate; dogs; red blood cells; luciferase

THE CENTRAL QUESTION IN CORONARY PHYSIOLOGY is what mechanisms couple coronary blood flow to myocardial oxygen consumption. Multiple candidates have been studied, yet the mechanisms remain elusive (20, 23). The ATP hypothesis proposes the red blood cell as an oxygen sensor and its intracellular content of ATP as a possible blood flow controller (7).

It has long been known that ATP is a powerful coronary dilator (8). Studies by Wolf and Berne (25) and Moir and Downs (16) demonstrated that ATP is more potent than adenosine in producing coronary vasodilation. Bergfeld and Forrester (1) observed that human red blood cells release ATP under hypoxic conditions. Ellsworth and colleagues (6, 7) demonstrated a progressive release of ATP from hamster red blood cells during declines in oxygen tension. They used oxygen tensions of ~35 and ~11 mmHg and maintained a constant pH (7.36) and carbon dioxide tension (35 mmHg). Thus ATP release from red blood cells took place during physiological declines in oxygen tension without the interaction of carbon dioxide or pH.

Once released from the red blood cell, ATP acts on endothelial cell purinergic receptors (12, 19). The injection of ATP inside small arterioles (5, 7, 15), outside capillaries (7), or inside venules (3) results in a retrograde conducted response that dilates the upstream feed arteriole. Duling and colleagues (9, 21) demonstrated that responses caused by several agonists are conducted along microvascular endothelial cells via gap junctions to the upstream feed arterioles. The assumption is that the conducted response due to ATP is also mediated via gap junctions. The relaxation of the feed arteriole increases oxygenated blood flow where oxygen extraction is high. Through its ability to release ATP in areas of low oxygen tension, the red blood cell may serve as a regulator of coronary blood flow during increases in myocardial oxygen consumption.

The purpose of the current study was to test the ATP hypothesis in the coronary circulation during exercise. The major results of the present study are a significant correlation between coronary blood flow and coronary venous plasma ATP concentration and a widening of the coronary venous-arterial plasma ATP difference during exercise. These findings provide evidence that red blood cells may regulate coronary blood flow by releasing ATP when blood oxygen tension is lowered by increased myocardial oxygen extraction.


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Surgical preparation. The studies were approved by the Institutional Animal Care and Use Committee of the University of Washington. Experiments were performed on 10 adult mongrel dogs (23–30 kg) taught to run on a motorized treadmill. The surgical procedures were previously described by Tune et al. (24). Briefly, under isoflurane anesthesia, a left thoracotomy was performed in the fourth intercostal space. A modified Seldinger technique was used to implant a polyurethane catheter into the descending thoracic aorta to obtain arterial blood samples. A second polyurethane catheter for coronary venous blood sampling was placed in the coronary sinus via an incision in the right atrial appendage. A flow transducer was placed around the circumflex coronary artery. A multivitamin pill and iron (FeSO4, 324 mg po) were given daily to aid recovery from surgery. Initial experiments were conducted after a 9- to 17-day recovery period following surgery.

Flow measurement. Coronary blood flow was continuously measured throughout the experimental protocol with an ultrasonic transit time, perivascular flow transducer (Transonic, Ithaca, NY). Flow transducers were calibrated before and after implantation. After experiments were completed, the animals were euthanized with pentobarbital sodium, and the circumflex artery perfusion territory was dyed with India ink. The weight of the dyed tissue was used to calculate coronary blood flow per gram of perfused myocardium.

Blood sampling. Arterial and coronary venous blood samples were collected simultaneously during rest and exercise in heparinized glass syringes that were immediately sealed and placed in ice. The samples were analyzed for hydrogen ion concentration, carbon dioxide tension, oxygen tension, and hemoglobin saturation with an Instrumentation Laboratories 1306 pH/blood gas analyzer (Waltham, MA). Oxygen content was determined using the fuel cell method (Total O2X; Hospex, Chestnut Hill, MA). Myocardial oxygen consumption (in µl O2·min–1·g–1) was calculated by multiplying mean coronary blood flow per gram of perfused tissue by the arterial-coronary venous difference in oxygen content. Portions of the arterial and coronary venous blood samples were transferred into NaF-coated vials to prevent glycolysis, and lactate concentration was determined with a YSI model 1500 lactate analyzer (Yellow Springs Instruments, Yellow Springs, OH). Percent myocardial lactate extraction was calculated as the difference in arterial and coronary venous lactate concentration divided by the arterial lactate concentration.

Plasma ATP measurement. A regimen of clopidogrel, aspirin, and heparin was used to inhibit platelet activation and the clotting cascade. Beginning 5 days after surgery, the animals were given clopidogrel bisulfate (Plavix; 75 mg/day po) to inhibit platelet activation. Clopidogrel inhibits platelet activation by blocking the P2Y12 receptors located on platelets (22). Platelet inhibition was done because activated platelets can release ATP during blood sampling. Aspirin (325 mg/ day po) also was given to prevent platelet activation, and heparin was given (300 U/kg iv) before the start of each experiment to further inhibit the clotting cascade.

Arterial and coronary venous ATP measurements were made at rest and during steady-state conditions at each exercise level. Plasma ATP was measured using the firefly luciferase method as previously described by Gorman et al. (11). Briefly, blood samples (3.7 ml) were drawn with a two-syringe arrangement that simultaneously mixed a room temperature stop solution (5.0 ml) with the blood. The stop solution contained S-(4-nitrobenzyl)-6-thioinosine (NBTI; 5 nM; Sigma), 3-isobutyl-1-methylxanthine (IBMX; 100 µM; Sigma), and forskolin (10 µM; Tocris) dissolved in a solution containing EDTA (4.15 mM), NaCl (118 mM), KCl (5 mM), and tricine buffer (40 mM). The nucleoside transport blocker NBTI was used to inhibit ATP release from erythrocytes in the blood samples (1). Forskolin and IBMX (a phosphodiesterase inhibitor) were used to increase platelet cAMP levels. Increasing the platelet cAMP levels inhibits their ability to release ATP. EDTA was used to chelate Mg2+ to reduce plasma ATPase activity. Blood/stop solution samples were immediately transferred to plastic centrifuge tubes and centrifuged for 2 min at 13,000 g. The supernatant was immediately recentrifuged under the same conditions to separate any erythrocytes trapped by surface tension during the initial centrifugation. The supernatant of the second tube was used for ATP and hemoglobin measurements. The hemoglobin concentrations were used as an indicator of hemolysis because small amounts of hemolysis can significantly increase the plasma ATP concentration (11). Hemoglobin measurements were used to correct the plasma ATP concentration for ATP release due to hemolysis, as previously described (11). Plasma hemoglobin concentration averaged 0.19 ± 0.01 mg/dl, resulting in an average reduction in plasma ATP concentration of 3.6 nM. Luminescence, created by the reaction of ATP with luciferin (ATP Bioluminescence assay kit CLS II, no. 1699695; Roche Diagnostics, Indianapolis, IN), was measured in relative light units (RLUs) with a Berthold LB 9507 luminometer (Oak Ridge, TN). The method of standard additions was used to convert RLUs into plasma ATP concentration. For details of the ATP assay, please refer to Gorman et al. (11). ATP assays were performed immediately after sample collection.

Experimental protocol. Coronary blood flow and heart rate were continuously measured while the dogs were resting in a sling and during three levels of treadmill exercise at 1) 3 miles/h (mph), 5% grade; 2) 4 mph, 10% grade; and 3) 5 mph, 15% grade, in ascending order except for two experiments. The exercise periods were continued beyond the time when heart rate and coronary blood flow became stable. During the stable hemodynamic period, simultaneous arterial and coronary venous samples were drawn as exercise continued. The average exercise period was 2.7 min. The animals were allowed to rest ~10 min between each exercise level while plasma ATP was analyzed in the previously drawn exercise samples.

Data analyses. Hemodynamic variables were recorded with Windaq analysis data software (Dataq Instruments, Akron, OH). Analog signals from the recording instruments were digitized and stored on disk. The values for mean coronary blood flow and heart rate at rest and during exercise were averaged over a 30-s period while simultaneous arterial and coronary venous blood samples were drawn. Replicate measurements for an individual animal were averaged to give single values for rest and the three levels of exercise.

Standard linear regression lines were fit to the mean responses for the key variables shown. The Draper method (2, 4) was used to determine regression lines for the response variables for the 10 individual dogs. The Wilcoxon signed rank test was then used to determine the significance of the average Draper slope. The Draper slope is equal to the standard error of the y variable divided by the standard error of the x variable (with appropriate sign), and the midpoint of the line is determined from the mean values of y and x. This method is advantageous because the regression line obtained for a given association accounts for the variability in both x and y variables. The Draper method is appropriate for the present experiments because neither coronary blood flow nor ATP concentrations were controlled. Table 1 presents means by exercise level but does not include P values. Instead, the key associations shown in the figures have been tested for significance. Data are presented as means ± SE.


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  		Table 1. Hemodynamic and metabolic variables at rest and during graded treadmill exercise

 

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Hemodynamic and metabolic data for the 10 dogs at rest and during the three levels of treadmill exercise are given in Table 1. Myocardial oxygen consumption increased ~3.2-fold from rest to the highest level of exercise. Consistent with increased myocardial oxygen consumption, coronary blood flow increased ~ 2.7-fold. Coronary venous oxygen tension decreased from 19 mmHg to 12.9 mmHg during exercise. These results illustrate the rather tight matching of coronary blood flow to myocardial oxygen consumption, albeit with increased oxygen extraction by the myocardium during exercise.

Figure 1 shows the relationship between arterial and coronary venous plasma ATP concentration and myocardial oxygen consumption both at rest and during exercise. Arterial and coronary venous plasma ATP concentrations increased significantly as myocardial oxygen consumption increased during exercise. The significant correlation between coronary venous plasma ATP and myocardial oxygen consumption is a key test of the hypothesis that ATP is a controller of coronary blood flow.



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  		Fig. 1. Linear regression lines for mean arterial and coronary venous plasma ATP concentrations on myocardial oxygen consumption during rest and exercise. Both arterial and coronary venous plasma ATP concentrations increased significantly (P < 0.01) above resting ATP concentrations. The finding that coronary venous plasma ATP concentration increased during exercise is necessary to support the ATP hypothesis of coronary blood flow control (P values are based on Draper slopes for 10 dogs).

 
Figure 2A shows that coronary blood flow increased as the coronary venous plasma ATP concentration rose during exercise. The coronary venous plasma ATP concentration reflects the ATP that remains after acting on the endothelial cells of the microcirculation. The increase in coronary blood flow as the coronary venous plasma ATP concentration increased indicates that ATP may be one of the mechanisms controlling coronary blood flow. Coronary blood flow also increased as the paired venous-arterial plasma ATP concentration difference widened (Fig. 2B). Widening of the coronary venous-arterial plasma ATP concentration difference indicates that ATP originated in the coronary circulation.



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  		Fig. 2. Linear regression lines for mean coronary blood flow on coronary venous plasma ATP concentration (A) and for mean coronary blood flow on the paired coronary venous-arterial plasma concentration difference (B) during rest and exercise. There was a significant increase in coronary blood flow with coronary venous plasma ATP concentration (P < 0.01) and with the coronary venous-arterial plasma ATP concentration difference (P < 0.05). These findings indicate that ATP may contribute to the increase in coronary blood flow and that ATP originates in the coronary circulation (P values are based on Draper slopes for 10 dogs).

 
Coronary venous plasma ATP concentration increased as the coronary venous oxygen tension (Fig. 3A) or hemoglobin oxygen saturation (Fig. 3B) declined. These findings indicate that the coronary venous plasma ATP concentration is sensitive to oxygen extraction from the blood by the myocardium.



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  		Fig. 3. Linear regression lines for mean coronary venous plasma ATP concentration on coronary venous oxygen tension (A) and for mean coronary venous plasma ATP concentration on oxyhemoglobin saturation (B) during rest and exercise. There was a significant increase in coronary venous plasma ATP concentration as the coronary venous oxygen tension or hemoglobin saturation declined (P < 0.01). These findings indicate that the coronary venous plasma ATP concentration is sensitive to the oxygen level of the coronary venous blood (P values are based on Draper slopes for 10 dogs).

 

   DISCUSSION
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 ABSTRACT
 METHODS
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 DISCUSSION
GRANTS
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The major findings of the present study are that 1) the coronary venous plasma ATP concentration increased during exercise, 2) the increase in coronary venous plasma ATP concentrations correlated with the decline in coronary venous oxygen tension during exercise, and 3) coronary blood flow correlated well with coronary venous plasma ATP concentration and with the coronary venous-arterial plasma ATP concentration difference. The present correlations are evidence that red blood cells may control coronary blood flow by releasing ATP in areas of low oxygen tension caused by increased myocardial oxygen extraction. Of course, correlation is necessary but not sufficient to demonstrate causality. Therefore, the present correlations represent a critical first test of the ATP hypothesis. If these correlations had not been observed, the hypothesis could be discarded.

The release of ATP from erythrocytes in a low oxygen environment has been reported by others (1, 7), and the data illustrated in Fig. 3 are consistent with this. The working hypothesis is that deoxyhemoglobin acts on phosphofructokinase to stimulate ATP production via glycolysis and that ATP exit is modulated by a G protein-coupled mechanism (13, 17, 18). In light of the research done on ATP release from erythrocytes, it is assumed that red blood cells are the source of the ATP difference across the coronary circulation observed in the present study (Figs. 1 and 2B). However, it is possible that the ATP is released from endothelial cells. In contrast to other species, canine red blood cells were found to release little ATP when the oxygen tension was lowered to ~35 mmHg in vitro (6). The data in Fig. 3 suggest that, in vivo, canine erythrocytes release ATP when the oxygen tension falls below 20 mmHg.

The hypothesis is that ATP released from red blood cells in the low-oxygen environment of the microcirculation acts on endothelial cell purinergic receptors to produce a conducted retrograde signal, via gap junctions, to dilate the upstream feed arteriole (3, 5, 7, 15). The present experiments do not address the mechanisms involved in the conducted response.

The arterial plasma ATP concentration of 26 nM reported in Table 1 is probably the first such measurement where adequate precautions were taken to prevent platelet activation and hemolysis that result in artifactually high values (11). The value of 26 nM is much lower than ~600 nM (10) or ~1,000 nM (14) reported in human plasma or 3,400 nM in rat plasma (13). Arterial and coronary venous samples from initial experiments were analyzed for ADP and AMP (11), but the levels were below the detection limits of the assay, and the practice was discontinued.

In summary, coronary venous plasma ATP concentrations increased significantly when coronary venous oxygen content declined during exercise. There was a significant correlation among coronary blood flow, coronary venous plasma ATP concentration, and the coronary venous-arterial plasma ATP concentration difference. These findings suggest that ATP released within the coronary microcirculation contributes to coronary vasodilation during exercise. The present experiments do not prove the ATP hypothesis of coronary blood flow control, but they are a critical first step.


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This work was supported by National Heart, Lung, and Blood Institute Grants HL-49822 and HL-07828.


   FOOTNOTES
 

Address for reprint requests and other correspondence: E. O. Feigl, Dept. of Physiology and Biophysics, 357290, Univ. of Washington School of Medicine, Seattle, WA 98195-7290 (E-mail: efeigl{at}u.washington.edu)

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.


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