AJP-Heart Articles in PresS. Published on December 20, 2001 as DOI 10.1152/ajpheart.00733.2001
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Acute Exercise Reduces the Response to Colon Distension in T5 Spinal Rats
Heidi L. Collins and Stephen E. DiCarlo
Department of Physiology
Wayne State University School of Medicine
Detroit, MI 48201
Running title: Post-exercise dysreflexia
Corresponding Author
Stephen E. DiCarlo, Ph.D.
Department of Physiology
Wayne State University School of Medicine
540 E. Canfield Ave.
Detroit, MI, 48201
E.mail: [email protected]
Phone: (313) 577-1557
Fax: (313) 577-5494
Copyright 2001 by the American Physiological Society.
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ABSTRACT
Individuals with spinal cord injuries above thoracic level 6 (T6) experience life
threatening bouts of hypertension termed autonomic dysreflexia (AD). AD is mediated
by peripheral alpha-adrenergic receptor supersensitivity as well as a reorganization of
spinal pathways controlling sympathetic preganglionic neurons.
A single bout of
dynamic exercise may be a safe therapeutic approach to reduce the severity of AD
since mild to moderate dynamic exercise reduces post-exercise alpha-adrenergic
receptor responsiveness, lowers post-exercise sympathetic nerve activity and reduces
the post-exercise response to stress. Therefore, this study was designed to test the
hypothesis that mild to moderate dynamic exercise attenuates the post-exercise
response to colon distension (mechanism to elicit AD). To test this hypothesis, six male
Wistar rats (406 ± 23 grams), 5 weeks post T5 spinal cord transection, were
instrumented with an arterial catheter. After recovery, the response to graded colon
distension (10, 30, 50, 80 mmHg, in random order) was determined before and after a
single bout of mild to moderate dynamic exercise (9-12m/min, 0% grade for 40
minutes).
After exercise the pressor response to graded colon distension was
significantly attenuated (pre-exercise ∆ 2 ± 1, 9 ± 1, 14 ± 1, and 24 ± 2 versus postexercise ∆ 2 ± 1, 2 ± 1, 9 ± 1 and 12 ± 3 mmHg). Thus, acute exercise is a safe,
therapeutic approach to reduce the severity of AD in paraplegic subjects.
Key Words: autonomic dysreflexia, exercise, spinal cord injury
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INTRODUCTION
Autonomic regulation of the cardiovascular system is abnormal and unstable
after spinal cord injury. Hypotension occurs immediately after the injury because of loss
of tonic supra-spinal excitatory drive to spinal sympathetic neurons (3). Subsequently
resting arterial pressure returns towards normal values however episodic bouts of
hypertension often develop as part of the condition termed autonomic dysreflexia (AD)
(24,27). AD occurs in as many as 85% of individuals with lesions above thoracic level 6
(T6) and is characterized by severe hypertension. The paroxysmal hypertension can be
caused by stimulation of the skin, distension of the urinary bladder or colon and by
muscle spasms (4,23). If not treated promptly, the hypertension may produce cerebral
and sub-arachnoid hemorrhage, seizures, and renal failure and may lead to death (25).
The long-term consequence of repeated episodes of severe hypertension has yet to be
determined.
Exercise may be a safe therapeutic approach for attenuating the severity of AD
by reducing alpha-adrenergic receptor responsiveness.
Several investigators have
demonstrated that a single bout of mild to moderate dynamic exercise significantly
attenuated the post-exercise response to alpha-adrenergic receptor-agonists (1416,29,33). For example, a single bout of dynamic exercise significantly attenuated the
post-exercise response to alpha-adrenergic receptor activation in the intact conscious
rabbit (15), rat (29,33) and man (14). These data suggest that the ability to increase
peripheral vascular resistance following exercise is significantly reduced. Exercise may
also be a counter measure for AD by reducing sympathetic nerve activity since a single
bout of mild to moderate dynamic exercise often lowers post-exercise sympathetic
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nerve activity for at least one hour in individuals and animals (10,13). Therefore, this
study was designed to test the hypothesis that a single bout of dynamic exercise
attenuates the response to colon distension (mechanism to elicit AD) in T5 spinal rats.
To test this hypothesis, the response to graded colon distension (10, 30, 50, 80
mmHg, in random order with at least 5 minutes between inflations) was determined
before and twenty minutes after a single bout of mild to moderate dynamic exercise. All
surgical and experimental procedures were reviewed and approved by the Institutional
Animal Care and Use Committee and conformed to the American Physiological
Society’s Guiding Principles in the Care and Use of Animals. Six male Wistar rats (406
± 23 grams; age, 93 ± 11 days) underwent T5 spinal cord transection (9). After spinal
cord transection, all rats had a motor score of zero, indicating no weight bearing (34).
Following spinal cord transection, the paraplegic rats were trained to run on a motor
driven treadmill and were familiarized with the experimental procedures (handling,
insertion of the balloon, placed in the study box). Four weeks later, the paraplegic rats
were surgically instrumented for chronic measurements of arterial pressure and heart
rate. In 4 rats, a Micro-Renathane catheter was placed in the descending aorta via the
left common carotid artery for the measurement of arterial pressure, mean arterial
pressure, and heart rate. In two rats, radio-telemetry devices (Model TA11PA-C40;
Data Sciences International) were implanted in the abdominal cavities with the attached
catheter inserted through the femoral artery and advanced into the descending aorta.
After recovery [7 days (20)], the response to graded colon distension (10, 30, 50, 80
mmHg, in random order with at least 5 minutes between inflations) was determined
before and twenty minutes after a single bout of mild to moderate dynamic exercise.
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Two recent studies investigating mechanisms mediating AD examined the spinal rats 30
days post-transection (19,21). Thus, to assure that the animals were fully recovered,
we studied the spinal rats 36 ± 3 days post-transection.
On the day of the experiment, a latex balloon attached to a tygon catheter
(fashioned in our laboratory) was inserted 7-8 cm into the colon through the anus and
secured by taping the catheter to the base of the tail (19). Subsequently, the rat was
placed unrestrained in a large Plexiglass box (30.5 x 30.5 x 30.5 cm, with free access to
water). The animals were allowed to adapt to the laboratory environment for 1 hour to
ensure a stable hemodynamic condition. After all variables obtained a steady state,
pre-exercise baseline values were recorded over a 15 second interval. Subsequently,
the procedure for colon distension was performed.
To generate colon distension curves, a hand held manometer was used to inflate
the balloon to pressures of 10, 30, 50, and 80 mmHg (19). Distension pressures were
applied in a randomized order, maintained for 60 seconds and repeated at 5 minute
intervals. Control levels of arterial pressure and heart rate were averaged over 15
seconds immediately before inflation of the balloon. The responses to colon distension
were averaged during the 60 seconds of balloon inflation. Colon distension produced
pressor and bradycardic responses (Figure 1). Several studies have documented that
colon distension is a suitable, less invasive means of producing autonomic dysreflexia
in spinal rats (19). In this regard, the rats did not resist insertion of the balloon (possibly
because the rats could not feel the procedure) and the rats had minimal movement
during the inflations.
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After generation of the pre-exercise colon distension curves, T5 spinal rats had
their lower bodies secured onto a small cart and “ran” on a motor driven treadmill. The
paraplegic rats propelled themselves with their upper bodies at 9-12 meters/minute for
40 minutes without the use of adversive stimuli (Figure 2).
Approximately twenty
minutes after exercise [the start of sympatho-inhibition and alpha-adrenergic receptor
hypo-responsiveness in intact rats, (18,29,30)], colon distension curves were generated
as described above. Since colon distensions curves were determined before and after
a single bout of dynamic exercise, any differences observed could be due to time and
not the intervening exercise. Therefore, to control for the effect of time during exercise,
colon distension curves were generated in the same rats on an alternate day (>48
hours) before and after 60 minutes (40 minutes sham exercise plus 20 minutes postsham exercise) of sitting on the treadmill.
Before generation of the pre-exercise colon distension curves, baseline MAP and
heart rate averaged 96 ± 2 mmHg and 427 ± 11 bpm, respectively. After exercise (20
minutes) baseline MAP (p=0.039 ) and heart rate (p=0.050 ) decreased to 88 ± 4 mmHg
and 404 ± 10 bpm, respectively. On the sham exercise day, baseline MAP and heart
rate averaged 97 ± 2 mmHg and 452 ± 15 bpm, respectively. Twenty minutes after
sham exercise, baseline MAP (p=0.070 ) and heart rate (p=0.460 ) were not different
from pre-sham exercise (93 ± 3 mmHg and 442 ± 21bpm, respectively).
Exercise produced typical pressor and tachycardic responses (Figure 2). For
example, MAP at rest was 97±3 mmHg. During exercise (30 minutes), MAP increased
to 104±3 mmHg. Heart rate at rest was 441±12 bpm. During exercise (30 minutes), HR
increased to 486±8 bpm.
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After a single bout of dynamic exercise the pressor response to colon distension
was significantly attenuated (Figure 3, Panel A, two-way ANOVA, p=0.005). However,
the heart rate response to colon distension was not different post-exercise (Figure 3,
Panel B, two-way ANOVA, p=0.087). The post-exercise attenuated pressor response to
colon distension was due to exercise and not the intervening time since the time control
responses were not different (Figure 3, Panels C and D, p>0.05).
These results document that a single bout of dynamic exercise attenuates the
pressor response to colon distension in T5 spinal rats.
Although the mechanisms
mediating this effect were not investigated, post-exercise alpha-adrenergic receptor
hypo-responsiveness (13,15,16,29,33) and sympatho-inhibition may be the primary
factors (10,14).
Exercise may be a counter measure for AD by reducing alpha-adrenergic
receptor responsiveness. We demonstrated that a single bout of dynamic exercise
significantly attenuated the alpha-adrenergic receptor-mediated contraction of vascular
smooth muscle in the rabbit aorta (16).
This in-vitro approach provided a direct
evaluation of the contractile properties of aortic vascular smooth muscle independent of
systemic and baroreflex mediated compensatory mechanisms.
Subsequently, we developed a model that allowed us to directly measure
agonist-induced changes in regional blood flow independent of baroreflex mediated
compensatory mechanisms in an intact conscious rabbit (15) and rat (29,30). In these
studies, a single bout of treadmill running also attenuated the post-exercise vascular
response to alpha-adrenergic receptor activation in the intact conscious rabbit (15) and
rat (29,30) confirming and extending the findings reported for the isolated vessel. The
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reduced post-exercise vasoconstrictor response to alpha-adrenergic receptor activation
was due, in part, to an enhanced buffering of vasoconstriction by nitric oxide (29,30).
These data, and others (14,33) suggest that the ability to increase peripheral vascular
resistance following exercise is significantly reduced.
Exercise may also be a counter measure for AD by reducing sympathetic nerve
activity (10,13). Although the current thinking suggests that AD is primarily mediated by
peripheral alpha-adrenergic receptor super-sensitivity, morphological changes in
sympathetic pre-ganglionic neurons below the level of the lesion may contribute to AD
by reflex increases in sympathetic outflow (22). Studies in animals and humans have
led to conflicting estimates of the amount of spinally generated sympathetic tone that
remains after loss of supra-spinal excitation (26,28,32,35). These conflicting results
may be due to the presence of anesthetics and the acute effects of surgery (35) or from
the fact that visceral sympathetic activity has not been recorded in man (32,35). Direct
recording of cutaneous and somatic sympathetic activity in individuals with quadriplegia
demonstrated very low tonic activity at rest and only moderate increases in response to
bladder distension (32,35). Similarly, individuals with quadriplegia have significantly
lower catecholamine levels than intact subjects at rest and although norepinephrine
increases significantly during episodic hypertension, these levels do not exceed
norepinephrine levels in intact subjects at rest. In contrast, Maiorov and colleagues
demonstrated low, but stable, basal firing of renal sympathetic nerve activity in
conscious rats that increased 6 fold during colon distension (22).
The authors
concluded that although spinally generated sympathetic nerve activity makes no
apparent contribution to basal arterial pressure, large increases in sympathetic nerve
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activity during colon distension are adequate to cause substantial increases in arterial
pressure. Thus, plastic changes in the spinal cord may contribute to AD (22). The
relative contribution of spinally generated sympathetic nerve activity and alphaadrenergic receptor hyper-responsiveness to AD is questionable. Exercise may be an
effective counter measure for AD since a single bout of dynamic exercise often lowers
post-exercise sympathetic nerve activity in individuals and animals (10,13).
Prior to World War II, 80% of individuals with spinal cord injury died within 3
years of the injury (17) primarily due to kidney and pulmonary infections (31). However,
with the advent of antibiotic drugs and advancements in acute care and rehabilitation,
the life expectancy of individuals with spinal cord lesions has increased to near that for
able-bodied individuals. However, cardiovascular disease, is now the leading cause of
death and morbidity for individuals with spinal cord lesions (1,6). The risk for significant
cardiovascular dysfunction is aggravated by the sedentary lifestyle of the typical
individual with spinal cord lesions.
In fact, individuals with spinal cord injuries are
placed at the lowest end of the human fitness spectrum (5,36). Additionally, individuals
with spinal cord injuries have blood lipid profiles characterized by elevated total
cholesterol and low-density lipoprotein cholesterol, and depressed high-density
lipoprotein cholesterol, a lipid profile normally associated with, if not a direct result of the
sedentary lifestyle (2). Therefore, exercise with the arms is often recommended for
these individuals, based on studies demonstrating improvements in aerobic capacity
and lipoprotein profiles (7,8,11,12). In fact, the Centers for Disease Control (CDC) has
recommended further research to evaluate the efficacy of exercise to prevent the
development of cardiovascular disease in individuals with spinal cord injury (1). The
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results from this study support the recommendation of the CDC in that a single bout of
dynamic exercise attenuated the pressor response to colon distension in T5 spinal rats.
Furthermore, these results suggest that acute exercise may be a safe, therapeutic
approach to reduce the severity of AD in paraplegic subjects.
It is interesting to
speculate that one mechanism contributing to the improved cardiopulmonary status
after exercise in individuals with spinal cord lesions may be a reduced incidence and/or
severity of autonomic dysreflexia.
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ACKNOWLEDGEMENT
This study was supported by the National, Heart, Lung and Blood Institute, Grant
#HL58414.
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REFERENCES
1.
Cardiovascular-cardiopulmonary secondary disabilities.
First colloquim on
preventing secondary disabilities among people with spinal cord injuries.
Center
for Disease Control, Atlanta 47-54, 1991.
2. Bauman, W. A., Adkins, R. H., Spungen, A. M., Herbert, R., Schechter, C., Smith,
D., Kemp, B. J., Gambino, R., Maloney, P., and Waters, R. L. Is immobilization
associated with an abnormal lipoprotein profile? Observations from a diverse
cohort. Spinal Cord 37: 485-493, 1999.
3. Calaresu, F. R. and C. P. Yardley. Medullary basal sympathetic tone. Ann Rev
Physiol 50: 511-524, 1988.
4. Corbett, J. L., O. Debarge, H. L. Frankel, and C. Mathias.
Cardiovascular
responses in tetraplegic man to muscle spasm, bladder percussion and head-up
tilt. Clin Exp Pharmacol Physiol Suppl 2: 189-93, 1975.
5. Dearwater, S. R., LaPorte, R. E., Robertson, R. J., Brenes, G., Adams, L. L., and
Becker, D. Activity in the spinal cord-injured patient: an epidemiologic analysis of
metabolic parameters. Med Sci Sports Exerc 18: 541-544, 1986.
6. DeVivo, M. J., Black, K. J., and Stover, S. L. Causes of death during the first 12
years after spinal cord injury. Arch Phys Med Rehabil 74: 248-254, 1993.
H0733-2001.R2
13
7. DiCarlo, S. E. Improved cardiopulmonary status after a two-month program of
graded arm exercise in a patient with C6 quadriplegia: a case report. Phys Ther
62: 456-459, 1982.
8. DiCarlo, S. E. Effect of arm ergometry training on wheelchair propulsion endurance
of individuals with quadriplegia. Phys Ther 68: 40-44, 1988.
9. DiCarlo, S. E. and Collins, H. L. Acute exercise reduces the response to colon
distension in T5 spinal rats. FASEB J 15: A1151, 2001.
10. DiCarlo, S. E., H. L. Collins, M. G. Howard, C.-Y. Chen, T. J. Scislo, and R. D.
Patil. Postexertional hypotension: A brief review. Sports Med Training and Rehab
5: 17-27, 1994.
11. DiCarlo, S. E., M. D. Supp, and H. C. Taylor. Effect of arm ergometry training on
physical work capacity of individuals with spinal cord injuries. Phys Ther 63: 11041107, 1983.
12. Glaser, R. M. Exercise and locomotion for the spinal cord injured. Exerc Sport Sci
Rev 13: 263-303, 1985.
13. Halliwill, J. R. Mechanisms and clinical implications of post-exercise hypotension in
humans. Exerc Sport Sci Rev 29: 65-70, 2001.
H0733-2001.R2
14
14. Halliwill, J. R., J. A. Taylor, and D. L. Eckberg. Impaired sympathetic vascular
regulation in humans after acute dynamic exercise. J Physiol 495: 279-288, 1996.
15. Howard, M. G. and S. E. DiCarlo. Reduced vascular responsiveness after a single
bout of dynamic exercise in the conscious rabbit. J Appl Physiol 73: 2662-2667,
1992.
16. Howard, M. G., S. E. DiCarlo, and J. N. Stallone. Acute exercise attenuates
phenylephrine-induced contraction of rabbit isolated aortic rings. Med Sci Sports
Exerc 24: 1102-1107, 1992.
17. Jackson, R. W. and Fredrickson, A. Sports for the physically disabled. The 1976
Olympiad (Toronto). Am J Sports Med 7: 293-296, 1979.
18. Kulics, J. M., H. L. Collins, and S. E. DiCarlo. Postexercise hypotension is
mediated by reductions in sympathetic nerve activity. Am J Physiol Heart Circ
Physiol 276: H27-H32, 1999.
19. Landrum, L. M., G. M. Thompson, and R. W. Blair. Does postsynaptic α1adrenergic receptor supersensitivity contribute to autonomic dysreflexia? Am J
Physiol Heart Circ Physiol 274: H1090-H1098, 1998.
20. Lawson, D. M., Duke, J. L., Zammit, T. G., Collins, H. L., and DiCarlo, S. E.
Recovery
from
Carotid
Artery
Catheterization
Performed
under
Various
H0733-2001.R2
15
Anesthetics in Male, Sprague-Dawley Rats. Contemp Top Lab Anim Sci 40: 1822, 2001.
21. Leman, S., Bernet, F., and Sequeira, H. Autonomic dysreflexia increases plasma
adrenaline level in the chronic spinal cord-injured rat. Neurosci Lett 286: 159-162,
2000.
22. Maiorov, D. N., L. C. Weaver, and A. V. Krassioukov. Relationship between
sympathetic activity and arterial pressure in conscious spinal rats. Am J Physiol
Heart Circ Physiol 272: H625-H631 , 1997.
23. Mathias, C. J. and H. L. Frankel. Clinical manifestations of malfunctioning
sympathetic mechanisms in tetraplegia. J Auton Nerv Sys 7: 303-312, 1983.
24. Mathias, C. J. and H. L. Frankel. The Cardiovascular System in Tetraplegia and
Paraplegia. Handbook of Clinical Neurology. Amsterdam, Elsevier Science
Publishers. 1992, 435-456.
25. McGuire, T. J. and Kumar, V. N. Autonomic dysreflexia in the spinal cord injured:
what the physician should know about this medical emergency . Postgrad Med 80:
81-89, 1986.
26. McKenna, K. E. and L. P. Schramm. Sympathetic preganglionic neurons in the
isolated spinal cord of the neonatal rat. Brain Res 269: 201-10, 1983.
H0733-2001.R2
16
27. Naftchi, N. E. Mechanism of autonomic dysreflexia: contributions of catecholamine
and peptide neurotransmitters. Ann New York Acad Sci 579: 133-148, 1990.
28. Osborn, J. W., R. F. Taylor, and L. P. Schramm. Determinants of arterial pressure
after chronic spinal transection in rats. Am J Physiol Reg Integ Comp Physiol 256:
R666-R673, 1989.
29. Patil, R. D., DiCarlo, S. E., and Collins, H. L. Acute exercise enhances nitric oxide
modulation of vascular response to phenylephrine. Am J Physiol Heart Circ Physiol
265: H1184-H1188, 1993.
30. Rao, S. P., H. L. Collins, and S. E. DiCarlo.
Post-exercise alpha-adrenergic
receptor hypo-responsiveness is due to nitric oxide in hypertensive rats. Articles in
PresS: Am J Physiol Regulatory Integrative Comp Physiol 2001.
31. Stauffer, E. S. Long-term management of traumatic quadriplegia . The total care of
spinal cord injuries. Boston, Little, Brown. 1978, 81-102.
32. Stjernberg, L., H. Blumberg, and B. G. Wallin. Sympathetic activity in man after
spinal cord injury: outflow to muscle below the lesion. Brain 109 : 695-715, 1986.
33. VanNess, J. M., H. J. Takata, and J. M. Overton. Attenuated blood pressure
responsiveness during post-exercise hypotension. Clin Exp Hypertens 18: 891900, 1996.
H0733-2001.R2
17
34. Von Euler, M., E. Akesson, E. B. Samuelsson, A. Seiger, and E. Sundstrom. Motor
performance score: a new algorithm for accurate behavioral testing of spinal cord
injury in rats. Exp Neurol 137: 242-254, 1996.
35. Wallin, B. G. and Stjernberg, L. Sympathetic activity in man after spinal cord injury.
Outflow to skin below the lesion. Brain 107 : 183-198, 1984.
36. Washburn, R. A. and Figoni, S. F. Physical activity and chronic cardiovascular
disease prevention in spinal cord injury: a comprehensive literature review. Topics
Spinal Cord Injury Rehab 3: 16-32, 1998.
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FIGURE LEGENDS
Figure 1. Analog recording of arterial pressure and heart rate before and in response
to 60 seconds of colon distension (50 mmHg) in one representative animal. Colon
distension produced typical pressor and bradycardic responses.
Figure 2.
Mean arterial pressure and heart rate at rest and during 40 minutes of
treadmill running at 12 m/min, 0% grade in 6 paraplegic Wistar rats. Paraplegic rats
had their lower bodies secured onto a small cart and “ran” on a motor driven treadmill
by propelling themselves with their upper bodies without the use of adversive stimuli.
Treadmill exercise produced pressor and tachycardic responses.
Figure 3. Change in mean arterial pressure (Panel A) and heart rate (Panel B) to
graded colon distension in T5 spinal rats before and after a single bout of mild to
moderate dynamic exercise. A single bout of dynamic exercise significantly attenuated
the pressor response to graded colon distension. The post-exercise attenuated pressor
response to colon distension was due to exercise and not the intervening time. This is
suggested because the change in mean arterial pressure (Panel C) and heart rate
(Panel D) to graded colon distension before and after sham exercise were not different.
These data suggest that a single bout of dynamic exercise may be safe therapeutic
approach to reduce the severity of autonomic dysreflexia. *P<0.05, pre-exercise vs.
post-exercise
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Arterial Pressure ( mmHg)
140
120
100
80
60
0
30
60
90
120
150
180
120
150
180
Time (sec)
Heart Rate (bpm)
550
500
450
400
350
300
0
30
60
90
Time (sec)
Figure 1
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Mean Arterial Pressure
(mmHg)
110
105
100
95
90
85
Rest
5
10
15
20
25
30
35
40
25
30
35
40
Time (min)
Heart Rate
(bpm)
550
500
450
400
Rest
5
10
15
20
Time (min)
Figure 2
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A
C
Post-Exercise
30
25
20
*
15
*
10
5
*
0
Post-Sham Exercise
30
25
20
15
10
5
0
10
30
50
80
10
Colon Distension Pressure
(mmHg)
30
50
80
Colon Distension Pressure
(mmHg)
B
D
0
0
∆ Heart Rate
(bpm)
-20
∆ Heart Rate
(bpm)
Pre-Sham Exercise
35
Pre-Exercise
∆ Mean Arterial Pressure
(mmHg)
∆ Mean Arterial Pressure
(mmHg)
35
-40
-20
-40
-60
-60
-80
-80
10
30
50
10
80
30
50
Colon Distension Pressure
(mmHg)
Colon Distension Pressure
(mmHg)
Figure 3
80