AJP - Heart AJP citation statistics
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 275: H1663-H1672, 1998;
0363-6135/98 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Duncker, D. J.
Right arrow Articles by Verdouw, P. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Duncker, D. J.
Right arrow Articles by Verdouw, P. D.
Vol. 275, Issue 5, H1663-H1672, November 1998

Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise

Dirk J. Duncker, René Stubenitsky, and Pieter D. Verdouw

Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

A pivotal role for adenosine in the regulation of coronary blood flow is still controversial. Consequently, we investigated its role in the regulation of coronary vasomotor tone in swine at rest and during graded treadmill exercise. During exercise, myocardial O2 consumption increased from 167 ± 18 µmol/min at rest to 399 ± 27 µmol/min at 5 km/h (P <=  0.05), which was paralleled by an increase in O2 delivery, so that myocardial O2 extraction (76 ± 1 and 78 ± 1% at rest and 5 km/h, respectively) and coronary venous PO2 (24.5 ± 1.0 and 22.8 ± 0.3 mmHg at rest and 5 km/h, respectively) remained unchanged. After adenosine receptor blockade with 8-phenyltheophylline (5 mg/kg iv), the relation between myocardial O2 consumption and coronary vascular resistance was shifted toward higher resistance, whereas myocardial O2 extraction rose to 81 ± 1 and 83 ± 1% at rest and 5 km/h and coronary venous PO2 fell to 19.2 ± 0.8 and 18.9 ± 0.8 mmHg at rest and 5 km/h, respectively (all P <=  0.05). Thus, although adenosine is not mandatory for the exercise-induced coronary vasodilation, it exerts a vasodilator influence on the coronary resistance vessels in swine at rest and during exercise.

coronary circulation; myocardial oxygen extraction; myocardial oxygen consumption; pulmonary circulation; systemic circulation

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

THE NORMAL HEART IS characterized by a high myocardial O2 extraction (MEO2), requiring a tight coupling of coronary blood flow to changing metabolic needs (16, 26). The close coupling of coronary blood flow and myocardial O2 demand has been proposed to depend primarily on messengers released from the myocardium, such as adenosine (4, 30). Although adenosine has been shown to contribute to coronary vasodilation in isolated rodent hearts, a pivotal role for adenosine in the regulation of coronary blood flow in the large mammalian in situ heart is still controversial. Thus neither increased adenosine catabolism with adenosine deaminase nor adenosine receptor blockade with the adenosine A1/A2-receptor blocker 8-phenyltheophylline (8-PT) altered resting coronary blood flow in anesthetized or awake dogs (2, 22, 24, 33). In addition, during treadmill exercise, coronary blood flow and resistance, as well as myocardial O2 consumption (MVO2) and MEO2, were not altered by adenosine receptor blockade or adenosine deaminase (2), suggesting that adenosine is not mandatory for the regulation of coronary blood flow in the dog heart at rest or during exercise. In contrast, several studies have reported that adenosine receptor blockade produced by theophylline increased coronary vascular resistance and MEO2 and decreased coronary blood flow and coronary venous  PO2 (PcvO2) in the human heart under basal conditions (11-13), whereas only one study reported no change in resting coronary blood flow after adenosine receptor blockade with aminophylline (32). Also, in closed-chest sedated swine, adenosine deaminase produced a small increase in coronary vasomotor tone under basal conditions (17) while markedly blunting the early coronary blood flow response to intracoronary infusions of isoproterenol (18). Recently, we observed in swine that exercise produced increases in MVO2 that were matched by equivalent increments in coronary blood flow so that MEO2 and PcvO2 were maintained (9). Because interstitial adenosine levels have been reported to increase during beta -adrenergic stimulation with dobutamine in anesthetized swine at a time when PcvO2 or interstitial lactate levels did not change (21), it is possible that adenosine could contribute to the maintained PcvO2 in swine during exercise. Consequently, in the present study we investigated the role of adenosine in the coupling between myocardial O2 delivery (MDO2) and MVO2 in awake swine at rest and during graded treadmill exercise up to 85-90% of maximum heart rate (4a).

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Crossbred Landrace × Yorkshire pigs were used in the present study. All experiments were performed in accordance with the "Guiding Principles in the Care and Use of Laboratory Animals," as approved by the Council of the American Physiological Society and with prior approval of the Animal Care Committee of the Erasmus University Rotterdam. Adaptation of animals to the laboratory conditions started 1 wk before the day of surgery and continued until 10 days postoperative. Full details of the experimental procedures have been published previously (7, 9, 37, 38).

Surgical Procedures

After an overnight fast, seven pigs (23 ± 1 kg; 3 males and 4 females) were sedated with ketamine (30 mg/kg im; Ketalin, Apharmo, Arnhem, The Netherlands), anesthetized with thiopental sodium (10 mg/kg iv; Rhône-Poulenc, Amstelveen, The Netherlands), intubated, and mechanically ventilated with a mixture of O2 and nitrous oxide (1:2) to which 0.2-1.0% (vol/vol) isoflurane (Forene, Abbott, Amstelveen, The Netherlands) was added. Anesthesia was further maintained with midazolam (2 mg/kg + 1 mg · kg-1 · h-1 iv; Dormicum, Roche, Mijdrecht, The Netherlands) and fentanyl (10 µg · kg-1 · h-1 iv; Janssen-Cilag, Tilburg, The Netherlands). Under sterile conditions, the chest was opened via the fourth left intercostal space, and an 8-Fr fluid-filled polyvinylchloride (PVC) catheter was inserted into the aortic arch for the measurement of central aortic blood pressure and collection of arterial blood samples and secured with a purse-string suture. After the pericardium was opened, an electromagnetic flow probe (14-15 mm ID) was positioned around the ascending aorta for the measurement of ascending aortic blood flow (Transflow 601 Systems, Skalar, Delft, The Netherlands). A high-fidelity pressure transducer (model P4.5, Konigsberg Instruments, Pasadena, CA) was inserted into the left ventricle (LV) via the apical dimple for recording of LV pressure and its first derivative (LV dP/dt; obtained via electrical differentiation). An 8-Fr PVC catheter was also inserted into the LV for calibration of the Konigsberg transducer signal; two 8-Fr PVC catheters were inserted into the pulmonary artery for measurement of pulmonary arterial pressure, withdrawal of mixed venous blood samples, and administration of drugs. Another 8-Fr catheter was inserted into the left atrium for measurement of left atrial pressure. For the measurement of coronary blood flow, a Doppler flow probe (2.0, 2.5, or 3.0 mm ID, emitting frequency = 20 MHz) was placed around the proximal part of the left anterior descending (LAD) coronary artery (model HVPD-20, Crystal Biotech, Northboro, MA) (23). A small angiocatheter (0.8 mm ID, 1.1 mm OD) connected to a larger Tygon catheter (0.8 mm ID, 2.4 mm OD) was inserted directly into the anterior interventricular vein to allow sampling of coronary venous blood (5). Electrical wires and catheters were tunneled subcutaneously to the back, the chest was closed, and the animals were allowed to recover. All electrical wires and catheters were protected with a vest.

Postsurgical period. After surgery the animals received analgesia by daily intramuscular injections of 0.3 mg of buprenorphine (Temgesic, Schering-Plough, Amstelveen, The Netherlands) during the first 48 h and intravenous injections of 25 mg/kg of amoxicillin (Clamoxil, Beecham Farma, Amstelveen, The Netherlands) and 5 mg/kg gentamicin (A.U.V., Cuijk, The Netherlands) on a daily basis during the 1st wk to prevent infections. Catheters were flushed daily with physiological saline containing 2,000 IU/ml heparin (Leo Pharmaceutical Products, Weesp, The Netherlands).

Experimental Protocols

Exercise protocols. Studies were performed 10-20 days after surgery with animals exercising on a motor-driven treadmill. Two experimental protocols were performed on different days and in random order. The first protocol was performed to establish that two consecutive exercise tests performed at 90-min intervals produced reproducible results; in the second protocol the effect of nonselective adenosine A1/A2-receptor blockade was studied.

Reproducibility of responses to exercise. With swine lying quietly on the treadmill, resting hemodynamic measurements, consisting of ascending aortic blood flow, LV pressure and LV dP/dt, blood pressures in the aorta, pulmonary artery, and left atrium, and the coronary Doppler shift, were obtained, and arterial, mixed venous, and coronary venous blood samples were collected (9, 38). Aortic, pulmonary, and left atrial pressures were measured using Combitrans pressure transducers (Braun, Melsungen, Germany) with the reference point at midchest level. In one of the seven animals, samples could not be obtained from the coronary venous catheter. All hemodynamic measurements were repeated, and rectal temperature was measured with animals standing on the treadmill. Subsequently, a five-stage treadmill exercise protocol was started [1, 2, 3, 4, and 5 km/h resulting in 85-90% of maximum heart rate (4a)]; each exercise stage lasted 2-3 min. Hemodynamic variables were continuously recorded, and blood samples were collected during the last 45 s of each exercise stage, at a time when hemodynamics had reached a steady state. After completing the exercise protocol, animals were allowed to rest on the treadmill for 90 min, and then resting measurements were obtained and the five-stage exercise protocol was repeated.

Adenosine receptor blockade. Ninety minutes after swine had undergone a control exercise period, animals received an infusion of 8-PT (5 mg/kg administered over 5 min into a pulmonary artery catheter) to produce adenosine receptor blockade (20). It has previously been shown that this dose of 8-PT produces >95% inhibition of adenosine-induced coronary vasodilation in anesthetized swine (8) and awake dogs (2, 10). Five minutes after completion of the 8-PT infusion, resting measurements were obtained and the exercise protocol was repeated.

Contribution of changes in pH and PCO2 to the 8-PT-induced alterations in MEO2. Because we observed that 8-PT decreased arterial and coronary venous PCO2 and increased arterial pH, which could potentially increase coronary vasomotor tone, we determined the effects of equivalent hyperventilation-induced decreases in arterial and coronary venous PCO2 and increases in pH on MEO2 and PcvO2 in five swine (2 chronically instrumented ketamine-sedated swine and three pentobarbital-anesthetized intubated open-chest animals) (15). After 5 min of hyperventilation, arterial and coronary venous samples were obtained. In addition, we obtained arterial and coronary venous blood samples before and 5 min after infusion of 1 M sodium hydrogen bicarbonate (Lansberg, Uden, The Netherlands), which produced similar increases in pH in the two chronically instrumented ketamine-sedated swine.

Blood Gas Measurements

Blood samples were maintained in iced syringes until the conclusion of each exercise trial. PO2 (mmHg), PCO2 (mmHg), and pH were then immediately measured with a blood gas analyzer (Acid-Base Laboratory model 505, Radiometer, Copenhagen, Denmark). O2 saturation (SO2) and Hb (g/100 ml) were measured with a hemoximeter (model OSM2, Radiometer, Copenhagen, Denmark).

Data Acquisition and Analysis

All hemodynamic data were recorded and digitized (400 Hz/channel) on-line using an eight-channel data-acquisition program (ATCODAS, Dataq Instruments, Akron, OH) and stored on a computer for later postacquisition off-line analysis with a program written in MatLab (Mathworks, Natick, MA). A minimum of 15 consecutive beats were selected for analysis of the digitized hemodynamic signals. From these selected beats the LV peak systolic pressure, mean aortic blood pressure, mean pulmonary arterial and mean left atrial pressure, mean ascending aortic blood flow, and mean coronary Doppler shift were determined for each beat and averaged.

Cardiac output was computed as the sum of ascending aortic blood flow (measured with the electromagnetic flow probe) and total coronary blood flow. Because the LAD coronary artery supplies ~40% of the LV, total coronary blood flow was taken as 2.5 times flow in the LAD coronary artery. Systemic and coronary vascular resistance were calculated as the ratios of mean aortic pressure to cardiac output and mean aortic pressure to LAD coronary blood flow, respectively. Blood O2 content (µmol/ml) was computed as (0.621 · Hba · SO2) + (0.00131 · PO2), where Hba is arterial Hb. MDO2 was computed as the product of arterial O2 content and LAD coronary blood flow; whole body O2 delivery was calculated as the product of arterial O2 content and cardiac output. MVO2 in the region perfused by the LAD coronary artery was calculated as the product of coronary blood flow and the difference in O2 content between arterial and coronary venous blood; whole body O2 consumption (BVO2) was calculated as the product of cardiac output and difference in O2 content between arterial and mixed venous blood. MEO2 was computed as the ratio of arterial-coronary venous O2 content difference to arterial O2 content; whole body O2 extraction (BEO2) was calculated as the ratio of arterial-mixed venous O2 content difference to arterial O2 content.

Statistical analysis of the exercise data was performed using two-way (exercise and treatment) ANOVA for repeated measures. When a significant effect of exercise was observed, post hoc testing was done using Dunnett's test. When a significant effect of treatment was observed, post hoc testing was done using paired t-test or Wilcoxon signed rank test as appropriate. The effect of hyperventilation was tested using paired t-test or Wilcoxon signed rank test. P <=  0.05 was considered statistically significant (2-tailed). Values are means ± SE.

Drugs

8-PT (Sigma-Aldrich, Bornem, Belgium) was dissolved in 20 ml of demineralized water at 30°C (pH 10-11). Fresh drug solutions were prepared on each day.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Reproducibility of Responses to Exercise

Exercise increased cardiac output from 3.5 ± 0.2 l/min at rest (supine) to 7.9 ± 0.5 l/min at 5 km/h (P <=  0.01), which was principally due to an increase in heart rate from 110 ± 4 to 242 ± 4 beats/min (P <=  0.01) as stroke volume increased ~10% (Table 1). Because afterload increased (reflected by the increase in LV systolic pressure from 120 ± 4 mmHg at rest to 145 ± 5 mmHg at 5 km/h, P <=  0.01), the increase in stroke volume was likely the result of an increase in LV filling pressure (reflected by the increase in left atrial pressure from 6 ± 1 to 14 ± 2 mmHg, P <=  0.01) and an increase in LV contractility (reflected by the increase in LV dP/dtmax from 3,080 ± 290 to 6,220 ± 380 mmHg/s, P <=  0.01). Mean aortic pressure decreased slightly when the animals went from a supine to an upright position, but during exercise, aortic pressure increased from 92 ± 4 mmHg while animals were standing to 97 ± 4 mmHg at 5 km/h (P <=  0.05). The 5% increase in mean aortic blood pressure in the presence of a doubling of cardiac output implies that systemic vascular resistance had decreased. In contrast, mean pulmonary arterial pressure increased from 14 ± 1 to 33 ± 2 mmHg (P <=  0.01), and the driving pressure across the pulmonary vascular bed increased virtually in parallel with cardiac output, so that pulmonary vascular resistance was not significantly altered. Blood flow through the LAD coronary artery increased from 45 ± 4 ml/min at rest to 95 ± 11 ml/min during the highest level of exercise (P <=  0.01; Table 1). After 90 min of rest, at a time when all hemodynamic variables had returned to baseline resting values, the second period of exercise resulted in almost identical hemodynamic responses to exercise, with the exception of heart rate and LV dP/dtmax, which were slightly (<10%) lower during exercise at 2-5 km/h than during the first run (Table 1).

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Reproducibility of hemodynamic responses in swine during consecutive periods of graded treadmill exercise

Exercise resulted in a decrease in arterial PCO2 from 43 ± 1 mmHg at rest to 39 ± 1 mmHg at 5 km/h and an increase in arterial pH from 7.44 ± 0.01 to 7.47 ± 0.01 (both P <=  0.05; Table 2). Arterial SO2 did not change, but Hb and, hence, O2 content increased by 12% at the highest level of exercise compared with resting conditions. Mixed venous PO2, SO2, and O2 content decreased during exercise, whereas mixed venous PCO2 increased and pH decreased slightly. Because cardiac output and the arteriovenous O2 content difference nearly doubled, BVO2 increased fourfold from 7.9 ± 0.5 to 30.9 ± 2.1 mmol/min (P <=  0.01; Table 2, Fig. 1). All variables returned to baseline resting values within 90 min; a second period of exercise resulted in nearly identical responses, with the exception of a slightly lower Hb and arterial O2 content at 3-5 km/h and a slightly lower BVO2 at 5 km/h (Table 2, Fig. 1).

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Reproducibility of blood gas and O2 transport responses in swine during consecutive periods of graded treadmill exercise


View larger version (28K):
[in this window]
[in a new window]
  		Fig. 1.   Effects of saline (A and B) and adenosine receptor blockade produced by 8-phenyltheophylline (8-PT, 5 mg/kg iv; C and D) on relations between whole body O2 consumption (body VO2) and systemic vascular resistance (SVR) and between whole body VO2 and mixed venous PO2. Values (means ± SE) were obtained at rest (supine) and during 5 levels of treadmill exercise. * P <=  0.05 vs. control.

Exercise had no effect on coronary venous PCO2, pH, PO2, SO2, or O2 content (Table 2, Fig. 2). MVO2 increased from 172 ± 15 to 420 ± 61 µmol/min, whereas MDO2 increased from 214 ± 25 to 535 ± 81 µmol/min (both P <=  0.01). Consequently, MEO2 (i.e., the ratio of MVO2 to MDO2) was not altered during exercise. All variables returned to baseline resting values within 90 min. Despite the slightly lower heart rate, LV dP/dtmax, and arterial O2 content during the second control run, there were no differences between the two control runs with respect to coronary vascular resistance, MEO2, MDO2, and PcvO2 when plotted as a function of MVO2 (Fig. 2).


View larger version (24K):
[in this window]
[in a new window]
  		Fig. 2.   Effects of saline (A-D) and adenosine receptor blockade produced by 8-PT (5 mg/kg iv; E-H) on relations between myocardial O2 consumption (MVO2) and coronary vascular resistance (CVR), myocardial O2 delivery (MDO2), myocardial O2 extraction (MEO2), and coronary venous PO2 (PcvO2). Values (means ± SE) were obtained at rest (supine) and during 5 levels of treadmill exercise. * P <=  0.05 vs. control.

Adenosine Receptor Blockade

Except for a 10% increase in heart rate, 8-PT had no effects on systemic and pulmonary hemodynamics at rest (Table 3). During exercise, heart rate at 5 km/h and coronary blood flow at 1 km/h were slightly higher than during control conditions.

                              
View this table:
[in this window]
[in a new window]
  		Table 3.   Hemodynamic effects of adenosine receptor blockade in swine during graded treadmill exercise

8-PT decreased PCO2 and increased pH in arterial, mixed venous, and coronary venous blood (Table 4). Arterial PO2, SO2, and O2 content were maintained, but mixed venous PO2, SO2, and O2 content were lower in the presence of adenosine receptor blockade, reflecting an increase in BEO2 (Table 4, Fig. 1). The latter could only in part be explained by the increments in BVO2, inasmuch as the relation between BVO2 and BEO2 shifted upward toward higher BEO2 (not shown). The relation between BVO2 and systemic vascular resistance was also shifted upward toward higher resistance values (Fig. 1), suggesting that adenosine receptor blockade produced systemic vasoconstriction, which limited systemic O2 delivery, thereby resulting in an increase in BEO2 and, hence, a decrease in mixed venous PO2.

                              
View this table:
[in this window]
[in a new window]
  		Table 4.   Effects of adenosine receptor blockade on O2 balance in swine during graded treadmill exercise

Administration of 8-PT resulted in increases in MVO2 that reached levels of statistical significance during exercise at 1 and 3 km/h. Thus the increase in coronary blood flow and MDO2 at 1 km/h was likely due to an increase in O2 requirements. Importantly, after administration of 8-PT, MDO2 was slightly lower at each level of MVO2 than under control conditions (P <=  0.05) so that MEO2 increased and PcvO2 decreased (Table 4, Fig. 2), indicating an increase in vasomotor tone in the coronary resistance vessels that restricted MDO2. In support of this finding, the relation between MVO2 and coronary vascular resistance was shifted toward higher vascular resistance values (Fig. 2).

Contribution of Changes in pH and PCO2 to 8-PT-Induced Alterations in MEO2

Mechanical hyperventilation decreased arterial PCO2 from 47 ± 5 to 38 ± 5 mmHg and increased pH from 7.44 ± 0.03 to 7.51 ± 0.04 (all P <=  0.05); similar changes were observed in the coronary venous blood. However, no changes were observed in PcvO2 or MEO2 (Table 5). Similarly, an increase in arterial pH from 7.39 ± 0.03 to 7.50 ± 0.04 produced by infusion of 1 M HCO-3 in two sedated swine had no effect on PcvO2 (23.6 ± 0.6 and 23.3 ± 1.8 mmHg before and after HCO-3 administration, respectively) or on MEO2 (77 ± 3 and 77 ± 4%, respectively). These findings indicate that 8-PT-induced changes in PCO2 and pH were not responsible for its vasoconstrictor actions.

                              
View this table:
[in this window]
[in a new window]
  		Table 5.   Effects of hyperventilation on blood gases and MEO2

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

The present study describes the contribution of adenosine in maintaining the balance between MVO2 and MDO2 in awake swine at rest and during treadmill exercise. The major findings of the present study were as follows:1) MEO2 and PcvO2 were not altered from resting levels during treadmill exercise at up to 80-90% of maximum heart rate (4a), indicating that the exercise-induced increases in MVO2 were matched by equivalent increases in MDO2. 2) Adenosine receptor blockade increased MEO2 and decreased PcvO2 under resting conditions as well as during exercise, indicating that endogenously released adenosine exerted a vasodilator influence that contributed to maintaining MDO2 commensurate with O2 demands. 3) Adenosine was not mandatory for the exercise-induced coronary vasodilation. 4) Changes in arterial or coronary venous PCO2 or pH could not account for these findings.

Adenosine has been proposed as one of the messengers that couples myocardial O2 demand to vasomotor tone of the coronary resistance vessels (4, 30). Adenine nucleotides do not cross the cell membrane of cardiac myocytes, but adenosine formed from the action of nucleotide phosphorylase on AMP can be transported out of myocytes into the interstitial space (36). On entering the interstitial space, adenosine can interact with A2 receptors on coronary vascular smooth muscle to produce vasodilation and an increase in coronary blood flow (30). Previous studies in dogs have demonstrated that endogenous adenosine production is not mandatory for maintaining resting coronary blood flow. Thus studies in anesthetized open-chest dogs have generally failed to demonstrate an effect of intracoronary adenosine deaminase (22, 24, 33) or intravenous aminophylline to block adenosine receptors (19, 34) on basal coronary blood flow, although some studies have reported an increase in coronary vascular resistance after administration of the selective adenosine receptor antagonist sulfophenyltheophylline (27). Similarly, in doses that caused marked inhibition of exogenous adenosine-induced coronary vasodilation, intracoronary adenosine deaminase or intravenous 8-PT had no effect on resting coronary blood flow, MEO2, or PcvO2 in awake dogs (2).

In the in vivo canine heart, adenosine release is enhanced during conditions of increased myocardial O2 demand (1, 14, 28, 39). However, demonstration of an essential role for adenosine in mediating exercise-induced coronary vasodilation requires that interruption of the adenosine effect interferes with exercise-induced coronary vasodilation. Bache et al. (2) examined the effects of adenosine receptor blockade with 8-PT as well as augmented adenosine catabolism produced by intracoronary adenosine deaminase in exercising dogs. Adenosine antagonism inhibited coronary vasodilation evoked by ischemia; adenosine deaminase caused a 33-39% decrease in reactive hyperemia after 5- to 20-s coronary occlusions, whereas 8-PT caused a 40-62% decrease in reactive hyperemia. Neither agent significantly changed heart rate or arterial pressure during treadmill exercise. Furthermore, neither the absolute values for MVO2, coronary blood flow, and PcvO2 nor the relationship between these variables was altered by adenosine receptor blockade or adenosine deaminase (2). These findings indicate that adenosine is not obligatory for the increase in coronary blood flow produced by exercise in the dog heart.

In contrast to the results obtained in the dog heart, there is ample evidence that adenosine contributes to regulation of coronary vasomotor tone in the human heart. Edlund et al. (11-13) examined the effect of adenosine receptor blockade with theophylline on coronary sinus blood flow measured at rest and during supine bicycle exercise in normal young adult human subjects. Theophylline (3-6 mg/kg iv) caused a small increase in heart rate (13) and the rate-pressure product (12), but, despite increased myocardial O2 demands, coronary blood flow and coronary venous SO2 were lower, whereas coronary vascular resistance and MEO2 were higher, after theophylline at rest and during exercise (11-13). The results of the present study obtained in awake swine support the findings by Edlund and co-workers and suggest that endogenous adenosine exerts a vasodilator influence on the coronary circulation at rest and during exercise but is not mandatory for the increase in coronary blood flow and decrease in coronary vascular resistance produced by exercise in swine and humans. These findings could be interpreted to suggest that adenosine contributes to a basal offset point of coronary vasomotor tone but that adenosine does not contribute to the decrease in vasomotor tone produced by exercise. However, in closed-chest sedated swine, increased adenosine catabolism with intracoronary administration of adenosine deaminase, which had no effect on the steady-state coronary blood flow response to isoproterenol (after 10 min of infusion), markedly blunted the early (at 1 min) coronary blood flow response to intracoronary infusions of isoproterenol (18). In the present study we obtained measurements after 2-3 min of exercise, so we cannot exclude the possibility that adenosine may have contributed to the early adaptation of vasomotor tone (<= 1 min) during treadmill exercise. In addition, it is possible that adenosine also contributes to coronary vasodilation during steady-state exercise but that other vasodilator mechanisms, e.g., NO or ATP-sensitive K+ channel activation, act to compensate and mediate the vasodilation when adenosine receptors are blocked (26). Future studies, employing a combination of blockers of these different vasodilator systems, are needed to determine whether adenosine contributes to the coronary vasodilation produced by exercise in swine. However, the present study clearly demonstrates that adenosine is not mandatory for steady-state exercise-induced vasodilation in swine.

In dogs the exercise-induced increase in coronary blood flow does not fully match the increase in myocardial O2 demand, so even during mild-to-moderate exercise (<70% of maximum heart rate) MEO2 increases and, hence, PcvO2 decreases (2, 14, 28). In contrast, in humans, minimal changes in MEO2 occur at mild-to-moderate levels of exercise, although an increase in MEO2 and a decrease in coronary venous O2 content have been reported in humans during heavy exercise (>85% of maximum heart rate) (26). Similar to humans, MEO2 and PcvO2 did not change significantly in swine during treadmill exercise in the present study. Interestingly, Hall et al. (21) reported that interstitial levels of adenosine increased during beta -adrenergic stimulation with dobutamine in anesthetized swine in the presence of maintained PcvO2 and interstitial lactate levels, suggesting that adenosine could have contributed to the maintained PcvO2 during exercise in the present study. However, the results of the present study do not support such a role for adenosine, inasmuch as 8-PT resulted in similar decreases in PcvO2 at rest and during exercise.

In the present study, adenosine receptor blockade increased coronary as well as systemic vascular resistance at rest and during exercise. Because we did not measure regional blood flows, we cannot determine which vascular beds responded with an increased vascular resistance. However, during exercise a major part of cardiac output is directed toward the active skeletal muscle groups (26). Adenosine has been invoked in the regulation of skeletal muscle vascular tone during exercise. Thus the exercise-induced skeletal muscle hyperemia was blunted by increased adenosine catabolism with adenosine deaminase (35), whereas a decrease in adenosine uptake produced by dipyridamole increased skeletal muscle blood flow during exercise (25). The results from the present study are consistent with a vasodilator influence exerted by adenosine on skeletal muscle resistance vessels during treadmill exercise.

Adenosine receptor blockade had no effect on pulmonary vascular resistance, which would appear to indicate that endogenous adenosine did not contribute to regulation of pulmonary vascular resistance at rest or during exercise. However, A1 and A2 receptors, both of which are present in the pulmonary bed, mediate pulmonary smooth muscle contraction and relaxation, respectively (3). Because 8-PT is a nonselective A1/A2-receptor antagonist, we cannot exclude the possibility that endogenous adenosine may contribute to regulation of pulmonary resistance vessel tone but that lack of effect of 8-PT on the pulmonary bed could be due to its opposing vasomotor actions via simultaneous A1 and A2 blockade. Future studies using selective A1- and A2-receptor antagonists are required to determine the role of A1- and A2-receptor subtypes.

In conclusion, MEO2 and PcvO2 were not altered from resting levels in swine exercising on a treadmill at levels up to 80-90% of maximum heart rate, indicating that the exercise-induced increases in MVO2 were matched by equivalent increases in MDO2. Adenosine receptor blockade resulted in an increased MEO2 and a decreased PcvO2 under resting conditions and during exercise, indicating that endogenously released adenosine exerted a vasodilator influence that contributed to maintaining MDO2 commensurate with O2 demands. However, adenosine was not mandatory for the exercise-induced coronary vasodilation in swine.

    ACKNOWLEDGEMENTS

The authors gratefully acknowledge the technical assistance of Rob H. van Bremen.

    FOOTNOTES

The research of D. J. Duncker has been made possible by a Research Fellowship of the Royal Netherlands Academy of Arts and Sciences.

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. §1734 solely to indicate this fact.

Address for reprint requests: D. J. Duncker, Experimental Cardiology, Thoraxcenter, Erasmus University Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

Received 22 April 1998; accepted in final form 21 July 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

1.   Bacchus, A. N., S. W. Ely, R. M. Knabb, R. Rubio, and R. M. Berne. Adenosine and coronary blood flow in conscious dogs during normal physiological stimuli. Am. J. Physiol. 243 (Heart Circ. Physiol. 12): H628-H633, 1982.

2.   Bache, R. J., S. Z. Dai, J. S. Schwartz, and D. C. Homans. Role of adenosine in coronary vasodilation during exercise. Circ. Res. 62: 846-853, 1988[Abstract/Free Full Text].

3.   Barnes, P. J., and S. F. Liu. Regulation of pulmonary vascular tone. Pharmacol. Rev. 47: 87-131, 1995[Medline].

4.   Berne, R. M., and R. Rubio. Regulation of coronary blood flow. Adv. Cardiol. 12: 303-317, 1974[Medline].

4a.   Breisch, E. A., F. C. White, L. E. Nimmo, M. D. McKirnan, and C. M. Bloor. Exercise-induced cardiac hypertrophy: a correlation of blood flow and microvasculature. J. Appl. Physiol. 60: 1259-1267, 1979.

5.   Canty, J. M., Jr., and T. P. Smith. Adenosine-recruitable flow reserve is absent during myocardial ischemia in unanesthetized dogs studied in the basal state. Circ. Res. 76: 1079-1087, 1995[Abstract/Free Full Text].

6.   Dewitt, D. F., R. D. Wangler, C. I. Thompson, and H. V. Sparks, Jr. Phasic release of adenosine during steady state metabolic stimulation in the isolated guinea pig heart. Circ. Res. 53: 636-643, 1983[Abstract/Free Full Text].

7.   Duncker, D. J., D. B. Haitsma, I. E. J. Van Der Geest, R. Stubenitsky, J. R. van Meegen, A. J. Man in 't Veld, and P. D. Verdouw. Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise. Br. J. Pharmacol. 120: 1101-1113, 1997[Medline].

8.   Duncker, D. J., C. Klassen, S. K. Herrlinger, T. J. Pavek, and R. J. Bache. Effects of temperature on myocardial infarction in swine. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H1189-H1199, 1996[Abstract/Free Full Text].

9.   Duncker, D. J., R. Stubenitsky, and P. D. Verdouw. Autonomic control of vasomotion in the porcine coronary circulation during treadmill exercise: evidence for feed-forward beta -adrenergic control. Circ. Res. 82: 1312-1322, 1998[Abstract/Free Full Text].

10.   Duncker, D. J., N. S. Van Zon, Y. Ishibashi, and R. J. Bache. Role of K+ATP channels and adenosine in regulation of coronary blood flow during exercise with normal and restricted coronary blood flow. J. Clin. Invest. 97: 996-1009, 1996[Medline].

11.   Edlund, A., T. Conradsson, and A. Sollevi. A role for adenosine in coronary vasoregulation in man. Effects of theophylline and enprofylline. Clin. Physiol. 15: 623-636, 1995[Medline].

12.   Edlund, A., and A. Sollevi. Theophylline increases coronary vascular tone in humans: evidence for a role of endogenous adenosine in flow regulation. Acta Physiol. Scand. 155: 303-311, 1995[Medline].

13.   Edlund, A., A. Sollevi, and A. Wennmalm. The role of adenosine and prostacyclin in coronary flow regulation in healthy man. Acta Physiol. Scand. 135: 39-46, 1989[Medline].

14.   Ely, S. W., R. M. Knabb, A. N. Bacchus, R. Rubio, and R. M. Berne. Measurements of coronary plasma and pericardial infusate adenosine concentrations during exercise in conscious dogs: relationship to myocardial oxygen consumption and coronary blood flow. J. Mol. Cell. Cardiol. 15: 173-183, 1983[Medline].

15.   Fan, D., L. K. Soei, R. Stubenitsky, E. Boersma, D. J. Duncker, P. D. Verdouw, and R. Krams. Contribution of asynchrony and nonuniformity to mechanical interaction in normal and stunned myocardium. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H2146-H2154, 1997[Abstract/Free Full Text].

16.   Feigl, E. O. Coronary physiology. Physiol. Rev. 63: 1-205, 1983[Abstract/Free Full Text].

17.   Gewirtz, H., R. A. Olsson, D. L. Brautigan, P. R. Brown, and A. S. Most. Adenosine's role in regulating basal coronary arteriolar tone. Am. J. Physiol. 250 (Heart Circ. Physiol. 19): H1030-H1036, 1986.

18.   Gewirtz, H., R. A. Olsson, and A. S. Most. Role of adenosine in mediating myocardial blood flow response to isoproterenol: observations in closed chest, sedated, domestic swine. Cardiovasc. Res. 20: 504-511, 1986[Medline].

19.   Giles, R. W., and D. E. L. Wilcken. Reactive hyperaemia in the dog heart: interrelationships between adenosine, ATP, and aminophylline and the effect of indomethacin. Cardiovasc. Res. 11: 113-121, 1977[Medline].

20.   Griffith, S. G., P. Meghji, C. J. Moody, and G. Burnstock. 8-Phenyltheophylline: a potent P1-purinoceptor antagonist. Eur. J. Pharmacol. 75: 61-64, 1981[Medline].

21.   Hall, J. L., D. G. L. Van Wylen, R. D. Pizzuro, C. D. Hamilton, C. M. Reiling, and W. C. Stanley. Myocardial interstitial purine metabolites and lactate with increased work in swine. Cardiovasc. Res. 30: 351-356, 1995[Medline].

22.   Hanley, F. L., M. T. Grattan, M. B. Stevens, and J. I. E. Hoffman. Role of adenosine in coronary autoregulation. Am. J. Physiol. 250 (Heart Circ. Physiol. 19): H558-H566, 1986.

23.   Ishida, T., R. M. Lewis, C. J. Hartley, M. L. Entman, and J. B. Field. Comparison of hepatic extraction of insulin and glucagon in conscious and anesthetized dogs. Endocrinology 112: 1098-1109, 1983[Abstract].

24.   Kroll, K., and E. O. Feigl. Adenosine is unimportant in controlling coronary blood flow in unstressed dog hearts. Am. J. Physiol. 249 (Heart Circ. Physiol. 18): H1176-H1187, 1985.

25.   Laughlin, M. H., R. E. Klabunde, M. D. Delp, and R. B. Armstrong. Effects of dipyridamole on muscle blood flow in exercising miniature swine. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H1507-H1515, 1989[Abstract/Free Full Text].

26.   Laughlin, M. H., R. Korthuis, D. J. Duncker, and R. J. Bache. Regulation of blood flow to cardiac and skeletal muscle during exercise. In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. Physiol. Soc., 1996, sect. 12, chapt. 16, p. 705-769.

27.   Martin, S. E., W. C. Tidmore, and R. E. Patterson. Adenosine receptor blockade with 8-sulfophenyltheophylline aggravates coronary constriction. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H1753-H1759, 1991[Abstract/Free Full Text].

28.   McKenzie, J. E., R. P. Steffen, and F. J. Haddy. Relationship between adenosine and coronary resistance in conscious exercising dogs. Am. J. Physiol. 242 (Heart Circ. Physiol. 11): H24-H29, 1982[Abstract/Free Full Text].

29.   Merrill, G. F., F. J. Haddy, and J. M. Dabney. Adenosine, theophylline, and perfusate pH in the isolated, perfused guinea pig heart. Circ. Res. 42: 225-229, 1978[Free Full Text].

30.   Olsson, R. A., R. Bunger, and J. A. E. Spaan. Coronary circulation. In: The Heart and Cardiovascular System, edited by H. A. Fozzard, E. Haber, R. B. Jennings, A. M. Katz, and H. E. Morgan. New York: Raven, 1992, p. 1393-1426.

31.   Randall, M. D. The involvement of ATP-sensitive potassium channels and adenosine in the regulation of coronary flow in the isolated perfused rat heart. Br. J. Pharmacol. 116: 3068-3074, 1995[Medline].

32.   Rossen, J. D., H. Oskarsson, R. L. Minor, C. L. Talman, and M. D. Winniford. Effect of adenosine antagonism on metabolically mediated coronary vasodilation in humans. J. Am. Coll. Cardiol. 23: 1421-1426, 1994[Abstract].

33.   Saito, D., C. R. Steinhart, D. G. Nixon, and R. A. Olsson. Intracoronary adenosine deaminase reduces canine myocardial reactive hyperemia. Circ. Res. 49: 1262-1267, 1981[Abstract/Free Full Text].

34.   Schutz, W., M. Zipfer, and G. Raberger. Effect of aminophylline on coronary reactive hyperaemia following brief and long occlusion periods. Cardiovasc. Res. 11: 507-511, 1977[Medline].

35.   Schwartz, L. M., and J. E. McKenzie. Adenosine and active hyperemia in soleus and gracilis muscle of cats. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H1295-H1304, 1990[Abstract/Free Full Text].

36.   Sparks, H. V., Jr., and H. Bardenheuer. Regulation of adenosine formation by the heart. Circ. Res. 58: 193-201, 1986[Abstract/Free Full Text].

37.   Stubenitsky, R., R. W. P. van der Weerd, D. B. Haitsma, P. D. Verdouw, and D. J. Duncker. Cardiovascular effects of the novel Ca2+-sensitizer EMD 57033 in chronically instrumented pigs at rest and during exercise. Br. J. Pharmacol. 122: 1257-1270, 1997[Medline].

38.   Stubenitsky, R., P. D. Verdouw, and D. J. Duncker. Autonomic control of cardiovascular performance and whole body O2 delivery and utilization in swine during treadmill exercise. Cardiovasc. Res. 39: 459-474, 1998[Abstract/Free Full Text].

39.   Watkinson, W. P., D. H. Foley, R. Rubio, and R. M. Berne. Myocardial adenosine formation with increased cardiac performance in the dog. Am. J. Physiol. 236 (Heart Circ. Physiol. 5): H13-H21, 1979[Free Full Text].

Am J Physiol Heart Circ Physiol 275(5):H1663-H1672
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society


This article has been cited by other articles:


Home page
 Physiol. Rev.Home page
D. J. Duncker and R. J. Bache
Regulation of Coronary Blood Flow During Exercise
Physiol Rev, July 1, 2008; 88(3): 1009 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
V. J. de Beer, O. Sorop, D. A. Pijnappels, D. H. Dekkers, F. Boomsma, J. M. J. Lamers, D. J. Duncker, and D. Merkus
Integrative control of coronary resistance vessel tone by endothelin and angiotensin II is altered in swine with a recent myocardial infarction
Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2069 - H2077.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
D. J. Duncker and D. Merkus
Exercise hyperaemia in the heart: the search for the dilator mechanism
J. Physiol., September 15, 2007; 583(3): 847 - 854.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
D. Merkus, B. Houweling, V. J. de Beer, Z. Everon, and D. J. Duncker
Alterations in endothelial control of the pulmonary circulation in exercising swine with secondary pulmonary hypertension after myocardial infarction
J. Physiol., May 1, 2007; 580(3): 907 - 923.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, O. Sorop, B. Houweling, B. A. Hoogteijling, and D. J. Duncker
KCa+ channels contribute to exercise-induced coronary vasodilation in swine
Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2090 - H2097.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. D. Tune
Withdrawal of vasoconstrictor influences in local metabolic coronary vasodilation
Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2044 - H2046.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, B. Houweling, M. van Vliet, and D. J. Duncker
Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction
Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1306 - H1313.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, B. Houweling, A. H. van den Meiracker, F. Boomsma, and D. J. Duncker
Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction
Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H871 - H880.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. D. Tune, M. W. Gorman, and E. O. Feigl
Matching coronary blood flow to myocardial oxygen consumption
J Appl Physiol, July 1, 2004; 97(1): 404 - 415.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, B. Houweling, A. Zarbanoui, and D. J. Duncker
Interaction between prostanoids and nitric oxide in regulation of systemic, pulmonary, and coronary vascular tone in exercising swine
Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1114 - H1123.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, D. B. Haitsma, T.-Y. Fung, Y. J. Assen, P. D. Verdouw, and D. J. Duncker
Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways
Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H424 - H433.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, D. J. Duncker, and W. M. Chilian
Metabolic regulation of coronary vascular tone: role of endothelin-1
Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1915 - H1921.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. B. Haitsma, D. Merkus, J. Vermeulen, P. D. Verdouw, and D. J. Duncker
Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction
Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2198 - H2209.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl
Control of Coronary Blood Flow during Exercise
Experimental Biology and Medicine, April 1, 2002; 227(4): 238 - 250.
[Abstract] [Full Text] [PDF]

Home page