Download Progressive Muscle Metaboreflex Activation Gradually Decreases 1

Articles in PresS. Am J Physiol Heart Circ Physiol (December 4, 2009). doi:10.1152/ajpheart.00908.2009
1
Progressive Muscle Metaboreflex Activation Gradually Decreases
2
Spontaneous Heart Rate Baroreflex Sensitivity During Dynamic Exercise
3
4
Javier A. Sala-Mercado1,3, Masashi Ichinose1,4,5, Matthew Coutsos1, Zhenhua
5
Li1,7, Dominic Fano1, Tomoko Ichinose1,6, Elizabeth Dawe2 and Donal S.
6
O'Leary1
7
Departments of Physiology1, Surgical Research Services2& Cardiovascular
8
Research Institute3, Wayne State University School of Medicine, Detroit,
9
Michigan, USA
10
Human Integrative Physiology Laboratory4, School of Business Administration,
11
Meiji University, Tokyo, Japan
12
Laboratory for Applied Human Physiology5, Faculty of Human Development,
13
Kobe University, Kobe, Japan
14
Laboratory for Human Performance Research6, Osaka International University,
15
Osaka, Japan
16
Department of Cardiology7, Qilu Hospital of Shandong University, Shandong,
17
China
18
Direct Correspondence to:
19
Donal S. O’Leary, Ph.D.
20
Department of Physiology
21
Wayne State University School of Medicine
22
540 East Canfield Ave.
23
Detroit, MI 48201
24
(313) 577-5494 Fax
25
(313) 577-1540 Phone
26
[email protected]
27
28
Running Head: Muscle-metaboreflex modulation of baroreflex sensitivity.
29
30
Key Words: Exercise reflexes, Pressor response, Arterial baroreflex sensitivity.
31
Copyright © 2009 by the American Physiological Society.
2
32
33
ABSTRACT
Ischemia of active skeletal muscle elicits a pressor response termed the
34
muscle metaboreflex. We tested the hypothesis that in normal dogs during
35
dynamic exercise, graded muscle metaboreflex activation (MMA) would
36
progressively attenuate spontaneous heart rate baroreflex sensitivity (SBRS).
37
The animals were chronically instrumented to measure heart rate (HR), cardiac
38
output (CO), mean and systolic arterial pressure (MAP,SAP) and left ventricular
39
systolic pressures (LVSP) at rest and during mild or moderate treadmill exercise
40
before and during progressive MMA [via graded reductions of hindlimb blood
41
flow (HLBF)]. SBRS (slopes of the linear relationships (LRs) between HR and
42
LVSP or SAP during spontaneous sequences of ≥ 3 consecutive beats when HR
43
changed inversely vs. pressure) decreased during mild exercise from the resting
44
values (-5.56 ± 0.86 vs. -2.67 ± 0.50 bpm/mmHg, P <0.05) and in addition these
45
LRs were shifted upwards. Progressive MMA gradually and linearly increased
46
MAP, CO, and HR and linearly decreased SBRS and shifted LRs upward and
47
rightward to higher heart rates and pressures denoting baroreflex resetting.
48
Moderate exercise caused a substantial reduction in SBRS (-1.57 ± 0.38
49
bpm/mmHg, P <0.05) and both an upward and rightward resetting. Gradual
3
50
MMA at this higher workload also caused significant progressive increases in
51
MAP, CO and HR and progressive decreases in SBRS and the LRs were shifted
52
to higher MAP and HR. Our results demonstrate that gradual MMA during mild
53
and moderate dynamic exercise progressively decreases SBRS. In addition,
54
baroreflex control of HR is progressively reset to higher blood pressure and HR
55
in proportion to the extent of MMA.
4
56
57
INTRODUCTION
Whole body dynamic exercise can elicit profound changes in autonomic
58
activity.
Two negative feedback reflexes implicated in mediating these
59
responses are the arterial baroreflex and the muscle metaboreflex, which
60
negates perturbations in arterial pressure and blood flow to active skeletal
61
muscle, respectively (34-36). The arterial baroreflex operates via modulation of
62
both cardiac and peripheral vascular function, but does so with markedly
63
different time courses. The buffering of rapid (seconds) changes in arterial
64
pressure occurs via rapid, parasympathetically induced changes in heart rate
65
which usually elicits proportional changes in cardiac output (CO).
66
showed that virtually all of the initial compensatory responses to transient
67
activation of the carotid sinus baroreceptors are due to reflex changes in cardiac
68
output (25). In contrast, as the baroreflex perturbation is maintained past the
69
initial few seconds, most of the reflex changes in arterial pressure now occur via
70
changes in the peripheral vasculature (25; 27).
Ogoh et al.
71
This time-dependant difference in baroreflex mechanisms extends from
72
rest through heavy whole body dynamic exercise as the baroreflex is
73
progressively reset to a higher pressure as workload rises (5; 6; 20; 32).
5
74
Activation of skeletal muscle afferents may be a key factor involved in this
75
resetting (8; 11; 13; 17; 28; 30; 33). Recently, several groups have investigated
76
baroreflex control of heart rate using the spontaneous baroreflex technique (3; 4;
77
15; 26; 37; 48). This technique takes advantage of spontaneously occurring
78
fluctuations in arterial pressure and the resultant baroreflex-mediated changes in
79
heart rate.
80
parasympathetic activity (10; 12).
81
baroreflex sensitivity (HR-SBRS) technique our group has recently observed that
82
during dynamic exercise, muscle metaboreflex activation (MMA) causes not only
83
resetting of the arterial baroreflex but also a decrease in HR-SBRS (40). In our
84
study we activated the muscle metaboreflex via imposing a set decrease in
85
skeletal muscle blood flow to the hindlimbs in running dogs (~50% during mild
86
exercise and ~30% during moderate exercise).
87
decreases in skeletal muscle blood flow were clearly sufficient to activate the
88
muscle metaboreflex, previous studies using this or similar preparations have
89
shown that the magnitude of the metaboreflex pressor response is proportional
90
to the extent of decrease in skeletal muscle blood flow (14; 43; 49). When the
91
metaboreflex is activated, quite linear increases in arterial pressure, heart rate,
These rapid baroreflex responses occur solely via changes in
Employing this spontaneous heart rate
While these imposed
6
92
and cardiac output occur with progressive further decreases in skeletal muscle
93
blood flow. Whether resetting of the baroreflex and decreases in HR-SBRS
94
occur proportionately with progressive MMA is unknown.
95
whether there is a threshold level of MMA for effects on the baroreflex, whether
96
the effects on the baroreflex saturate at a certain level of MMA, and whether
97
there are differential effects of MMA on baroreflex resetting vs. the effects on
98
reduced HR-SBRS. The purpose of the present study was to directly address
99
these questions in normal dogs during mild and moderate dynamic exercise. We
100
hypothesized that graded MMA would progressively reset the arterial baroreflex
101
and attenuate HR-SBRS in direct proportion to the extent of MMA.
Also unknown is
102
103
MATERIALS AND METHODS
104
Experiments were performed on seven adult, mongrel dogs (weight
105
~20-25 kg) of either gender (four males, three females).
The protocols
106
employed in the present study were reviewed and approved by the Wayne State
107
University Animal Investigation Committee and conform with the United States
108
National Institute of Health guide lines.
109
Surgical Preparation and Procedures
7
110
Upon arrival to the laboratory, all animals were accustomed to human
111
handling and during ~10 sessions individually trained to comfortably run freely
112
on a motor-driven treadmill at different speeds.
113
successfully trained to run on the treadmill, two surgical procedures were
114
performed on each animal (left thoracotomy & left flank abdominal surgery
115
separated by at least 10 days).
116
Once the animals were
Prior to each surgery, for tranquilization, the animals received an
117
intramuscular injection of acepromazine (0.2 mg/kg).
118
anesthetized with sodium thiopental (25 mg/kg, i.v.). Following endotracheal
119
intubation, anesthesia was maintained with isoflurane gas (1-3%). Prior to the
120
surgery, the animals received: cefazolin, (antibiotic, 500 mg, intravenously),
121
carprofen (analgesic, 2.0 mg/kg intravenously), buprenorphine (analgesic, 0.1
122
mg/kg intramuscularly), and a 72 hour trans-dermal fentanyl patch was applied
123
(analgesic, dose 125-175 µg per hour). In addition, before the left thoracotomy,
124
selective
125
hydrochloride (2.0 mg/kg).
126
received a second intravenous dose of cefazolin (500 mg i.v.) and antibiotics
127
were continued for the length of the experimental protocol at an oral dose of
intercostal
nerve
blocks
were
performed
The dogs were
with
bupivacaine
Following each surgical procedure, the dogs
8
128
cephalexin 30 mg/kg/12hrs to prevent infections. Moreover, after each surgical
129
procedure, for the following 12 hours buprenorphine and acepromazine were
130
administered (0.05 mg/kg, and 0.5 mg/kg respectively i.v.) as needed to control
131
any type of discomfort.
132
mg/kg/day) for ten days.
133
In the first surgical procedure under sterile conditions, a left thoracotomy (fourth
134
intercostal space) was performed. A fully implantable telemetered blood
135
pressure transducer (Model PAD-70, Data Sciences International) was placed
136
subcutaneously 10 cm caudal to the thoracotomy incision. Its catheter was
137
tunneled into the thoracic cavity through the 7th intercostal space and located
138
inside the left ventricle for measuring left ventricular pressure (LVP). In order to
139
measure CO a 20-mm blood flow transducer (Transonic Systems Inc.) was
140
placed around the ascending aorta. For studies unrelated to the present
141
investigation, three stainless steel ventricular pacing electrodes (O-Flexon,
142
Ethicon Inc.) were sutured to the right ventricular free wall, vascular occluders
143
were placed on the superior and inferior venous cava and two pairs of
144
sonomicrometry crystals were placed on the left ventricular endocardium. The
145
pericardium was re-approximated loosely and the chest was closed in layers.
Thereafter, carprofen was administered orally (4
9
146
After at least 10 days (recovery period) a second surgical procedure (left
147
abdominal retroperitoneal surgery) was performed on each dog. A 10-mm
148
blood flow transducer (Transonic Systems Inc.) was placed on the terminal aorta
149
for measuring hindlimb blood flow (HLBF). All side branches between the iliac
150
arteries and the flow probe were ligated and severed and two 10-mm vascular
151
occluders (DocXS Biomedical Products) were placed on the terminal aorta distal
152
to the flow probe in order for us to reduce flow to the hindlimbs during the
153
experients (via partial external inflation) and elicit the muscle metaboreflex.
154
addition, a catheter was placed in a lumbar side branch of the aorta above the
155
flow probe and occluders to monitor arterial pressure. All flow probe cables,
156
pacing wires, vascular occluder tubings’, and the aortic catheter were tunneled
157
subcutaneously and exteriorized between the scapulae at the end of its
158
corresponding surgical procedure.
159
Experimental procedures
160
All experiments were performed individually and after the animals had fully
161
recovered from the surgeries and were alert, active, afebrile, and of good
162
appetite. After the animals had fully recovered from the instrumentation and
163
before an experiment for data collection was performed every animal was
In
10
164
re-familiarized (~5 times) to run on the motor-driven treadmill. Before each
165
experiment, one animal was brought to the laboratory and allowed to roam freely
166
for ~20 minutes. The animal was then directed to the treadmill. The CO and
167
HLBF probes were connected to a flow meter (Transonic Systems Inc.). The
168
arterial catheter was connected to a pressure transducer (Transpac IV, Abbott
169
Laboratories), the LVP telemetered signal was calibrated and heart rate (HR)
170
was computed by a cardiotachometer triggered by the CO signal.
171
recorded on analog to digital recording systems for subsequent offline analyses.
172
For a given experimental session, data were collected at rest and then at a
173
randomly selected workload (mild exercise: 3.2 km h-1, 0% grade elevation or
174
moderate exercise: 6.4 km h-1, 10% grade elevation which causes CO to
175
increase to ~ 40 and 70% of maximal levels (1)). Every animal successfully
176
performed both experimental protocols (mild exercise & moderate exercise) on
177
different days as only one workload was performed per experimental day. All
178
animals ran freely with only positive verbal encouragement. Steady-state data
179
were recorded at rest while the animal was standing on the treadmill, during
180
exercise (at either mild or moderate workload) with unrestricted blood flow to the
181
hindlimbs and after graded reductions of HLBF (via partial inflations of the
All data were
11
182
terminal aortic occluders) in order to elicit gradual metaboreflex activation. Each
183
level of reduction in hindlimb perfusion was maintained until all parameters
184
reached steady state (3-5 min).
185
Data analysis
186
Beat-to-beat CO, HLBF, heart rate (HR), mean arterial pressure (MAP)
187
and LVP, were continuously collected during each experiment. Stroke volume
188
(SV) was calculated as CO/HR. As previously stated, data were recorded for 3
189
to 5 steady state minutes at standing rest, free-flow exercise (mild or moderate)
190
and at each level of HLBF (each reduction) so that each period spanned multiple
191
respiratory cycles. Since left ventricular systolic pressure (LVSP) is virtually
192
identical to systolic pressure in the aortic arch, we used LVSP as the input to the
193
arterial baroreflex.
194
assessed by analysing the beat-to-beat relationship between HR and LVSP as
195
previously described (40). Briefly, the beat-to-beat time series of LVSP and HR
196
were searched for three or more consecutive beats in which the LVSP and HR of
197
the following beat changed in opposite direction (i.e., -HR/+LVSP and
198
+HR/-LVSP).
199
linear regression was applied to each individual sequence and only those
Spontaneous baroreflex control of HR was dynamically
These sequences were identified as baroreflex sequences. A
12
200
sequences in which r2 was > 0.85 were accepted and subsequently a slope was
201
calculated.
202
averaging all slopes computed within a given test period, was calculated and
203
taken as a measure of spontaneous baroreflex sensitivity for that period.
204
Sinoaortic baroreflex denervation virtually abolishes baroreflex sensitivity
205
assessed via this method indicating that these spontaneous reciprocal HR
206
changes that occur as a result of changes in arterial pressure are mediated by
207
the baroreflex (3; 16).
The mean slope of the LVSP-HR relationship, obtained by
208
The nonlinear patterns of the hemodynamic and HR-SBRS responses to
209
graded reductions in HLBF were analyzed by plotting the variable (e.g., MAP)
210
versus HLBF during free-flow exercise and at each level of partial vascular
211
occlusion as shown in figure 1. As described in detail previously (44; 45; 49),
212
during mild exercise initial reductions in hindlimb perfusion do not elicit
213
metaboreflex responses; however, once hindlimb perfusion is reduced below a
214
threshold level, a pressor response occurs. The threshold was approximated
215
as the intersection between two regression lines, the initial response line in
216
which no reflex responses occurred during the initial reductions in hindlimb
217
perfusion and the pressor response line in which further reductions in hindlimb
13
218
perfusion elicited a reflex pressor response. During moderate exercise, often
219
no apparent threshold exists and the initial reduction in hindlimb perfusion elicits
220
reflex responses.
221
ascribed as the free-flow value of hindlimb perfusion.
222
Statistical analysis
If no threshold was apparent, then the threshold was
223
Utilizing the averaged responses for each animal, statistical analyses
224
were performed with Systat software (Systat 11.0). An α-level of P < 0.05 was
225
set to determine statistical significance.
226
repeated measures was used for comparing hemodynamic data obtained at rest
227
and during exercise under free-flow conditions, at threshold and at maximal
228
levels of HLBF reduction during mild and moderate workloads. If a significant
229
interaction term was found, a Test for Simple Effects post hoc analysis
230
(C-Matrix) was performed to determine significant group mean differences. We
231
compared the slope of the linear regression line between HR-SBRS and HLBF
232
after threshold between mild and moderate exercise using a paired t-test. Data
233
are expressed as mean ± SE.
234
RESULTS
One-way Analysis of Variance for
14
235
Figure 2 shows data from one animal during both protocols (mild and
236
moderate exercise). From rest to mild exercise, the relationship between HR
237
and LVSP was shifted upwards and the linear relationship was less steep which
238
represents a decrease in SBRS.
239
aorta and imposed reductions in hindlimb blood flow, no metaboreflex pressor
240
response was engaged and there was little change in the HR-LVSP relationship
241
and hence HR-SBRS remained essentially constant. However, once HLBF
242
was reduced below the metaboreflex threshold, HR and blood pressure
243
increased. With the generation of the pressor response, there was a
244
progressive shifting of the HR-LVSP relationship upwards and to the right and
245
the slope progressively flattened. This resulted in a quite linear relationship
246
between HR-SBRS and HLBF as the metaboreflex became progressively more
247
engaged. Similar responses were observed during moderate exercise with
248
even more pronounced falls in HR-SBRS to ~ 20% of resting levels at maximal
249
metaboreflex activation. At both workloads, the decrease in the strength of
250
HR-SBRS was linearly related to the reduction in hindlimb blood flow over the
251
entire range of metaboreflex activation. As we have previously shown (40),
252
neither exercise nor metaboreflex activation affected the number of SBRS
With the initial partial occlusion of the terminal
15
253
occurances observed per minute (Rest-8.3 ± 1.8; mild exercise – 8.5 ± 1.3; mild
254
exercise+MMA – 10.3 ± 1.8; moderate exercise – 8.3 ± 1.0; moderate exercise +
255
MMA – 9.5 ± 2.2, ANOVA P > 0.05)
256
Figure 3 shows HR, SV, CO, MAP, LVSP and HR-SBRS at rest, during
257
mild and moderate exercise without any imposed reductions in HLBF (free flow),
258
at threshold and ~ maximum activation of the muscle metaboreflex. As
259
expected and in agreement with previous studies (41; 42) from rest to mild
260
exercise while MAP and LVSP did not change significantly, we observed
261
increases in HR and SV (as a result in CO), and also a rise in hindlimb blood flow.
262
Thus, the increase in CO is offset by a rise in total vascular conductance due to
263
the active vasodilation in the exercising skeletal muscles, resulting in little
264
change in MAP. In addition, a substantial decrease in HR-SBRS occurred
265
when compared with standing rest. Muscle metaboreflex activation at this
266
workload generated a progressive rise in MAP and LVSP, a significant
267
tachycardia, a small rise in SV, and thus, CO substantially increased.
268
Moreover, muscle metaboreflex activation during mild exercise caused
269
considerable changes in HR-SBRS with a pattern very similar to the changes
270
induced in most other hemodynamic parameters. That is, a clear threshold
16
271
existed for the effects on HR-SBRS and the changes progressed linearly with
272
progressive reductions in HLBF and did not saturate despite marked reductions
273
in HLBF which were the maximal we could impose and obtain steady-state data.
274
Similar results were observed during moderate exercise with the exception that
275
the prevailing level of HLBF was much closer to metaboreflex threshold (and no
276
threshold was observed in some experiments). Again, the pattern of the
277
changes HR-SBRS with metaboreflex activation mirrored those that occurred in
278
most hemodynamic parameters (e.g. HR, CO, MAP, LVSP). Table 1 shows the
279
average slope (of all animals) of the linear regression line during mild and
280
moderate exercise between HLBF and HR-SBRS. The average slope after
281
muscle metaboreflex threshold during mild exercise was ~ -4.15 meaning that
282
for every l/min decrease in HLBF beyond metaboreflex threshold, HR-SBRS
283
decreased 4.15 bpm/mmHg. The high value of the correlation coefficient
284
indicates a very close linear relationship between these two variables.
285
Moreover, although the slope was significantly reduced during moderate
286
exercise, there was still a very close relationship between HLBF and HR-SBRS
287
as shown by a high correlation coefficient value in this condition.
17
288
To compare whether the effects of muscle metaboreflex activation on
289
spontaneous baroreflex control of heart rate occurred concurrently with the
290
effects of the muscle metaboreflex on the other hemodynamic parameters, we
291
compared the HLBF at metaboreflex threshold which is separately calculated for
292
each of the variables. Figure 4 shows that at either workload, there was no
293
significant difference in hindlimb blood flow at the calculated MMA threshold for
294
HR-SBRS, HR, CO, LVSP and MAP, indicating that the muscle metaboreflex
295
modulates the heart, blood pressure and the baroreflex in concert.
296
for each experiment, the relationship between HR-SBRS and LVSP beyond
297
metaboreflex threshold was also quite linear at both workloads (Figure 5). On
298
average, HR-SBRS decreased ~10% for every 10 mmHg increase in LVSP
299
during steady-state metaboreflex activation at both workloads.
In addition,
300
301
DISCUSSION
302
To our knowledge, this is the first study to show that 1) graded muscle
303
metaboreflex activation during dynamic exercise not only progressively resets
304
the arterial baroreflex operating point, but also gradually decreases spontaneous
305
heart rate baroreflex sensitivity in direct proportion to the extent of muscle
306
metaboreflex activation; 2) the metaboreflex threshold level of hindlimb blood
18
307
flow for effects on HR-SBRS were not different between the hemodynamic
308
parameters and the arterial baroreflex, and the effects of the muscle
309
metaboreflex on HR-SBRS occurred proportionately with the reflex effects on
310
the hemodynamic parameters such as HR, CO and MAP; 3) the effects of
311
MMA on HR-SBRS occur progressively with graded metaboreflex activation and
312
do not saturate over a wide range of MMA; and 4) the effects of MMA on
313
baroreflex resetting were coincident with the effects on reduced HR-SBRS.
314
Feedback reflexes responsible for autonomic modulation during whole
315
body dynamic exercise. Overall, in addition to the feed-forward role of central
316
command, two negative feedback reflexes likely responsible for the autonomic
317
modulation during dynamic exercise are the arterial baroreflex and reflexes
318
arising from activation of skeletal muscle afferents (mechano-sensitive and
319
metabo-sensitive). A fall in skeletal muscle oxygen delivery and flow leads to
320
accumulation of metabolic by-products within the active muscle that stimulate
321
group III and IV afferent neurons, which evokes reflex changes in autonomic
322
nerve activity and release of vasoactive hormones; termed the muscle
323
metaboreflex.
324
cause peripheral vasoconstriction, which in turn raises mean arterial pressure.
This reflex can trigger a significant increase in CO and/or also
19
325
The arterial baroreflex is the primary short-term regulator of arterial blood
326
pressure by altering peripheral vasoconstriction and cardiac output, via
327
adjustments of sympathetic and parasympathetic nerve activity (38).
328
addition, it is well known that the baroreflex control of heart rate and blood
329
pressure is reset during exercise. One known mechanism responsible for this
330
baroreflex resetting during exercise is the feedback from skeletal muscle
331
afferents.
332
feedback from the skeletal muscles modulate the arterial baroreflex function (19;
333
28; 46).
334
(HR-SBRS) technique to study the interaction between these two reflexes, our
335
group has recently observed that during mild and moderate dynamic exercise,
336
muscle metaboreflex activation causes not only resetting of the arterial
337
baroreflex but also a decrease in HR-SBRS (40). In that study, MMA was
338
obtained via a one step reduction in HLBF (~50% and ~70% of exercising blood
339
flow level for mild and moderate workload respectively). However, it remained
340
unknown whether the muscle metaboreflex affects the arterial baroreflex in
341
similar fashion as the cardiovascular effects of the metaboreflex on
342
hemodynamic parameters. Previous studies from our and other laboratories
In
In animal and human studies, it has been shown that neural
Employing the spontaneous heart rate baroreflex sensitivity
20
343
have shown that the stimulus-response relationship between O2 delivery or
344
blood flow to active skeletal muscle is quite linear once beyond threshold and no
345
saturation occurs at sub-maximal workloads over a wide range of metaboreflex
346
activation (14; 43; 49). The question remained whether the effects of MMA on
347
HR-SBRS would show a similar trend and we found that this was the case.
348
Progressive MMA caused progressive increases in HR and MAP and
349
progressively reset the HR-LVSP relationship upwards and to the right with a
350
decrease in baroreflex HR sensitivity as indexed by the spontaneous method.
351
The effects of MMA on HR-SBRS were quite linear when analyzed both as the
352
relationship between the imposed reductions in HLBF and HR-SBRS and the
353
metaboreflex-induced increases in LVSP vs. HR-SBRS.
354
muscle metaboreflex became apparent at the same threshold level of HLBF as
355
all other hemodynamic parameters and no saturation of the effects of MMA on
356
HR-SBRS was evident over the range of MMA employed (which reflected the
357
largest activation of the muscle metaboreflex we could obtain in which
358
steady-state could be achieved with the animal freely exercising on the treadmill).
359
Thus, the present study shows that the muscle metaboreflex control of cardiac
360
function at either mild or moderate exercise is induced and progresses linearly in
The effects of the
21
361
concert with baroreflex modulation as HLBF at the threshold for HR-SRBRS, CO,
362
MAP, LVSP and HR were not different and all responded linearly with further
363
reductions in HLBF.
364
Muscle metaboreflex and baroreflex interaction. It is highly likely that
365
muscle metaboreflex and baroreflex interaction occurs centrally.
Previous
366
studies have shown that central modulation of the baroreflex circuitry may be
367
responsible for mediating resetting of the baroreflex during exercise (7; 8; 11; 17;
368
19; 30). Among the different possible central sites that are part of the central
369
baroreflex arc, the nucleus tractus solitarii (NTS) is a region where an interaction
370
between these two reflexes can take place, for this nucleus apart for being
371
known for participating in many viscerosensory systems receives inputs from
372
both the baroreceptor afferents and spinal somato-sensory input, and contains a
373
complex network of excitatory and inhibitory interneurons (2). Indeed, neural
374
feedback from skeletal muscle afferents have been shown to activate a
375
GABAergic mechanism within the NTS which reduces the rapid bradycardic
376
responses to transient excitability of baroreceptor activation (18; 31).
377
different or additional possible central site for this reflexes interaction is the
378
rostral ventrolateral medulla, for it has been shown that skeletal muscle afferents
A
22
379
can cause direct excitation of sympathetic premotor neurons in this brain stem
380
region (22; 29; 47).
381
baroreflex interaction is that muscle metaboreflex-induced increase in plasma
382
norepinephrine attenuates baroreflex modulation of HR (21) as it has been
383
previously shown that MMA elicits a rise in plasma norepinephrine and that high
384
plasma norepinephrine concentration attenuates parasympathetic control of HR
385
(9; 23). However, it is still uncertain if more central regions are involved as well
386
as the cellular mechanisms responsible for the interaction.
Another possibility for the muscle metaboreflex and
387
Limitations of the study. Our approach to evaluate the arterial baroreflex
388
control of HR based on spontaneous fluctuations in blood pressure and HR has
389
advantages and disadvantages, which have been previously described in detail
390
(39; 40). Briefly, the spontaneous baroreflex technique enables a qualitative and
391
quantitative estimate of the baroreceptor-cardiac response relationships during
392
spontaneous blood pressure fluctuations without the necessity of any
393
mechanical or pharmacological intervention. Sympatho-stimulatory reflexes by
394
stretch of cardiac chambers after phenylephrine-induced increase of afterload or
395
a direct β-adrenergic stimulation at the sinus node level by high doses of the
396
drug may affect baroreflex sensitivity determination. Alternatively, the autonomic
23
397
mechanisms mediating these rapid baroreflex-induced changes in HR are likely
398
only parasympathetic in nature (24; 26) and in addition this approach only
399
examines the baroreflex sensitivity over a relatively modest range of pressure,
400
which therefore does not allow the calculation of the entire sigmoidal baroreflex
401
stimulus-response relationship. It is possible if not likely that at least a portion
402
of the reduction in HR-SBRS with exercise and metaboreflex activation stemmed
403
from a shift in the operating point of the baroreflex from the high slope section
404
near the middle of the stimulus-response relationship towards a flatter part of the
405
sigmoid curve (33). Previous studies have shown that HR-SBRS is virtually
406
abolished after arterial baroreceptor denervation, which shows the reflex nature
407
of the HR responses (3; 16).
408
Conclusions: In conclusion, MMA during mild and moderate dynamic
409
exercise progressively resets the arterial baroreflex to higher blood pressure and
410
HR in direct proportion to the extent of MMA. As the muscle metaboreflex is
411
engaged, it simultaneously resets and progressively depresses HR-SBRS in
412
concert with the increases in heart rate, cardiac output and arterial blood
413
pressure. Thus, the central interactions occur concurrently with the efferent
414
responses. The fall in SBRS with metaboreflex activation indicates that the
24
415
ability of the baroreflex to rapidly respond to perturbations in arterial pressure via
416
changes in HR progressively decreases as muscle ischemia ensues. This may
417
be particularly important in during exercise in patients with claudication and in
418
other patients with high sympathetic activity such as those with heart failure and
419
hypertension.
420
421
ACKNOWLEDGEMENTS
422
The authors thank Jody Helme-Day, and Erin Krengel, for expert
423
technical assistance and care of the animals. This research was supported by
424
National Heart, Lung, and Blood Institute Grant HL-55473.
425
25
426
Table 1: All animal’s average slope of the linear regression lines between HLBF
427
and HR-SBRS during mild and moderate exercise. The high correlation
428
coefficient denotes the close linear relationship between the two variables.
429
Figure 1: Example of the nonlinear pattern of one’s animal hemodynamic (mean
430
arterial pressure) response to graded reductions in hindlimb blood flow.
431
Figure 2: Panels A and C: Prevailing Heart rate (HR) and left ventricular systolic
432
pressure (LVSP) with corresponding mean slopes at rest (dark squares dotted
433
lines), during free flow exercise (dark triangles dashed lines) and during exercise
434
+ hindlimb blood flow (HLBF) step reductions (empty circles solid lines) in one
435
animal. Panels B and D show in the same animal the heart rate spontaneous
436
baroreflex sensitivity level (HR-SBRS) during free flow exercise (dark triangles
437
dashed lines) and during exercise + HLBF step reductions (empty circles solid
438
lines).
439
Figure 3: Average heart rate (HR), stroke volume (SV), cardiac output (CO),
440
mean arterial pressure (MAP), left ventricular systolic pressure (LVSP) and heart
441
rate spontaneous baroreflex sensitivity (HR-SBRS) at rest (triangles), during
442
mild (solid circles) and moderate (empty circles) exercise without any imposed
443
reductions in HLBF (free flow), at threshold and ~ maximum activation of the
26
444
muscle metaboreflex (maximal possible hindlimb blood flow reduction). An *
445
indicate a significant increase from rest to mild or moderate exercise (P < 0.05),
446
while † indicates a significant increase from mild or moderate exercise threshold
447
to ~ maximum activation of the muscle metaboreflex (P < 0.05)
448
Figure 4: Hindlimb blood flows at metaboreflex threshold for heart rate
449
spontaneous baroreflex sensitivity (HR-SBRS), heart rate (HR), cardiac output
450
(CO), left ventricular systolic pressure (LVSP) and mean arterial pressure (MAP).
451
Grey bars: mild exercise, black bars: moderate exercise. Note that no statistical
452
difference was found.
453
Figure 5: Relationship between heart rate spontaneous baroreflex sensitivity
454
(HR-SBRS) and left ventricular systolic pressure (LVSP) beyond metaboreflex
455
threshold for each experiment at mild (left panel) and moderate (right panel)
456
workloads. The thick black solid line represents the average of the slopes and
457
intercepts of the individual lines.
458
27
459
460
461
462
463
464
465
466
467
468
469
Table 1. Average slope of the linear regressions lines between HLBF and HR-SBRS during mild and moderate exercise.
Mild exercise
Moderate exercise
HR-SBRS/HLBF
(bpm/mmHg/l/min)
-4.15 ± 1.09
-1.12 ± 0.29 *
Correlation coefficient
-0.98 ± 0.01
-0.96 ± 0.01
Values are means ± SE. HR-SBRS - spontaneous baroreflex sensitivity, HLBF - Hindlimb blood flow. * P<0.05
Mild vs. Moderate exercise.
28
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
Figure 1
29
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
Figure 2
30
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
Figure 3
31
552
553
554
555
Figure 4
32
556
557
558
559
560
561
Figure 5
33
562
563
564
References
565
1. Augustyniak RA, Collins HL, Ansorge EJ, Rossi NF and O'Leary DS.
566
Severe exercise alters the strength and mechanisms of the muscle
567
metaboreflex. American Journal of Physiology-Heart and Circulatory
568
Physiology 280: H1645-H1652, 2001.
569
2. Barraco RA. Nucleus of the solitary tract. Boca Raton: CRC Press, 1993.
570
3. Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A and
571
Mancia G. Evaluation of baroreceptor reflex by blood pressure monitoring
572
in unanesthetized cats. Am J Physiol Heart Circ Physiol 254: H377-H383,
573
1988.
574
4. Burger HR, Chandler MP, Rodenbaugh DW and Dicarlo SE. Dynamic
575
exercise shifts the operating point and reduces the gain of the arterial
576
baroreflex in rats. American Journal of Physiology-Regulatory Integrative
577
and Comparative Physiology 44: R2043-R2048, 1998.
34
578
5. Coote JH and Dodds WN. The baroreceptor reflex and the cardiovascular
579
changes associated with sustained muscular contraction in the cat.
580
Pflugers Arch 363: 167-173, 1976.
581
6. Dicarlo SE and Bishop VS. Onset of exercise shifts operating point of
582
arterial baroreflex to higher pressures. Am J Physiol 262: H303-H307,
583
1992.
584
7. Fadel PJ, Ogoh S, Watenpaugh DE, Wasmund W, Olivencia-Yurvati A,
585
Smith ML and Raven PB. Carotid baroreflex regulation of sympathetic
586
nerve activity during dynamic exercise in humans. American Journal of
587
Physiology-Heart and Circulatory Physiology 280: H1383-H1390, 2001.
588
8. Gallagher KM, Fadel PJ, Smith SA, Norton KH, Querry RG,
589
Olivencia-Yurvati A and Raven PB. Increases in intramuscular pressure
590
raise arterial blood pressure during dynamic exercise. J Appl Physiol 91:
591
2351-2358, 2001.
35
592
9. Hammond RL, Augustyniak RA, Rossi NF, Lapanowski K, Dunbar JC
593
and O'Leary DS. Alteration of humoral and peripheral vascular responses
594
during graded exercise in heart failure. J Appl Physiol 90: 55-61, 2001.
595
10. Iellamo F. Neural mechanisms of cardiovascular regulation during exercise.
596
597
Autonomic Neuroscience-Basic & Clinical 90: 66-75, 2001.
11. Iellamo F, Legramante JM, Raimondi G and Peruzzi G. Baroreflex
598
control of sinus node during dynamic exercise in humans: effects of central
599
command and muscle reflexes. American Journal of Physiolog 272:
600
H1157-H1164, 1997.
601
12. Iellamo F, Sala-Mercado JA, Ichinose M, Hammond RL, Pallante M,
602
Ichinose TK, Stephenson LW and O'Leary DS. Spontaneous baroreflex
603
control of heart rate during exercise and muscle metaboreflex activation in
604
heart failure. Am J Physiol Heart Circ Physiol 293(3): H1929-H1936., 2007.
36
605
13. Kaufman MP, Rybicki KJ, Waldrop TG and Mitchell JH. Effect on arterial
606
pressure of rhythmically contracting the hindlimb muscles of cats. J Appl
607
Physiol 56: 1265-1271, 1984.
608
14. Kim JK, Sala-Mercado JA, Rodriguez J, Scislo TJ and O'Leary DS.
609
Arterial baroreflex alters strength and mechanisms of muscle metaboreflex
610
during dynamic exercise. Am J Physiol Heart Circ Physiol 288:
611
H1374-H1380, 2005.
612
15. Kuo TBJ and Yang CCH. Sleep-Related Changes in Cardiovascular
613
Neural Regulation in Spontaneously Hypertensive Rats. Circulation 112:
614
849-854, 2005.
615
16. Legramante JM, Raimondi G, Massaro M, Cassarino S, Peruzzi G and
616
Iellamo F. Investigating feed-forward neural regulation of circulation from
617
analysis of spontaneous arterial pressure and heart rate fluctuations.
618
Circulation 99: 1760-1766, 1999.
37
619
17. McIlveen SA, Hayes, S.G. and Kaufman MP. Both central command and
620
exercise pressor reflex reset carotid sinus baroreflex. Am J Physiol 280:
621
H1454-H1463, 2001.
622
18. McWilliam PN and Shepheard SL. A GABA-mediated inhibition of
623
neurones in the nucleus tractus solitarius of the cat that respond to
624
electrical stimulation of the carotid sinus nerve. Neurosci Lett 94(3):
625
321-326, 1988.
626
19. McWilliam PN, Yang T and Chen LX. Changes in the baroreceptor reflex
627
at the start of muscle contraction in the decerebrate cat. J Physiol 436:
628
549-558, 1991.
629
20. Melcher A and Donald DE. Maintained ability of carotid baroreflex to
630
regulate arterial pressure during exercise. Am J Physiol 241: H838-H849,
631
1981.
632
633
21. Miyamoto T, Kawada T, Takaki H, Inagaki M, Yanagiya Y, Jin Y,
Sugimachi M and Sunagawa K. High plasma norepinephrine attenuates
38
634
the dynamic heart rate response to vagal stimulation. Am J Physiol Heart
635
Circ Physiol 284: H2412-H2418, 2003.
636
22. Morrison SF and Reis DJ. Reticulospinal vasomotor neurons in the RVL
637
mediate the somatosympathetic reflex. Am J Physiol 256: R1084-R1097,
638
1989.
639
23. Nishiyasu T, Tan N, Morimoto K, Sone R and Murakami N.
640
Cardiovascular and humoral responses to sustained muscle metaboreflex
641
activation in humans. J Appl Physiol 84: 116-122, 1998.
642
24. O'Leary DS and Seamans DP. Effect of exercise on autonomic
643
mechanisms of baroreflex control of heart rate. J Appl Physiol 75:
644
2251-2257, 1993.
645
25. Ogoh S, Fadel PJ, Nissen P, Jans O, Selmer C, Secher NH and Raven
646
PB. Baroreflex-mediated changes in cardiac output and vascular
647
conductance in response to alterations in carotid sinus pressure during
648
exercise in humans. Journal of Physiology-London 550: 317-324, 2003.
39
649
26. Ogoh S, Fisher JP, Dawson EA, White MJ, Secher NH and Raven PB.
650
Autonomic nervous system influence on arterial baroreflex control of heart
651
rate during exercise in humans. J Physiol (Lond) 566: 599-611, 2005.
652
27. Olivier NB and Stephenson RB. Characterization of baroreflex
653
impairment in conscious dogs with pacing-induced heart failure. Am J
654
Physiol 265: R1132-R1140, 1993.
655
28. Potts JT, Hand GA, Li JH and Mitchell JH. Central interaction between
656
carotid baroreceptors and skeletal muscle receptors inhibits
657
sympathoexcitation. J Appl Physiol 84: 1158-1165, 1998.
658
29. Potts JT, Lee SM and Anguelov PI. Tracing of projection neurons from
659
the cervical dorsal horn to the medulla with the anterograde tracer
660
biotinylated dextran amine. Auton Neurosci 98: 64-69, 2002.
661
30. Potts JT and Mitchell JH. Rapid resetting of carotid baroreceptor reflex by
662
afferent input from skeletal muscle receptors. American Journal of
663
Physiology-Heart and Circulatory Physiology 44: H2000-H2008, 1998.
40
664
31. Potts JT, Paton JFR, Mitchell JH, Garry MG, Kline G, Anguelov PT and
665
Lee SM. Contraction-sensitive skeletal muscle afferents inhibit arterial
666
baroreceptor signalling in the nucleus of the solitary tract: role of intrinsic
667
GABA interneurons. Neuroscience 119: 201-214, 2003.
668
32. Potts JT, Shi XR and Raven PB. Carotid baroreflex responsiveness
669
during dynamic exercise in humans. Am J Physiol 265: H1928-H1938,
670
1993.
671
672
673
674
675
676
33. Raven PB, Fadel PJ and Ogoh S. Arterial baroreflex resetting during
exercise: a current perspective. Exp Physiol 91: 37-49, 2006.
34. Rowell LB. Reflex control of the circulation during exercise. Int J Sports
Med 13 Suppl 1: S25-S27, 1992.
35. Rowell LB. Human circulation regulation during physical stress. New York:
Oxford University Press, 1986.
41
677
36. Rowell LB and O'Leary DS. Reflex control of the circulation during
678
exercise: chemoreflexes and mechanoreflexes. J Appl Physiol 69: 407-418,
679
1990.
680
37. Ryan S, Ward S, Heneghan C and McNicholas WT. Predictors of
681
Decreased Spontaneous Baroreflex Sensitivity in Obstructive Sleep Apnea
682
Syndrome. Chest 131: 1100-1107, 2007.
683
38. Sagawa K. Baroreflex control of systemic artrial pressure and vascular bed.
684
In: Handbook of Physiology
Section 2: The Cardiovascular System Vol.
685
III Peripheral Circulation Part 2, edited by Shepherd JT, Abboud IM and
686
Greiger SR. Bethesda: American Physiology Society, 1983, p. 453-496.
687
39. Sala-Mercado JA, Ichinose M, Hammond RL, Coutsos M, Ichinose T,
688
Pallante M, Iellamo F and O'Leary DS. Spontaneous baroreflex control of
689
heart rate versus cardiac output: altered coupling in heart failure. Am J
690
Physiol Heart Circ Physiol 294: H1304-H1309, 2008.
42
691
40. Sala-Mercado JA, Ichinose M, Hammond RL, Ichinose TK, Pallante M,
692
Stephenson LW, O'Leary DS and Iellamo F. Muscle Metaboreflex
693
Attenuates Spontaneous Heart Rate Baroreflex Sensitivity During Dynamic
694
Exercise. Am J Physiol Heart Circ Physiol 292(6): H2867-H2873., 2007.
695
41. Sala-Mercado JA, Hammond RL, Kim JK, McDonald PJ, Stephenson
696
LW and O'Leary DS. Heart Failure Attenuates Muscle Metaboreflex
697
Control of Ventricular Contractility During Dynamic Exercise. Am J Physiol
698
Heart Circ Physiol 292(5): H2159-H2166, 2006.
699
42. Sala-Mercado JA, Hammond RL, Kim JK, Rossi NF, Stephenson LW
700
and O'Leary DS. Muscle metaboreflex control of ventricular contractility
701
during dynamic exercise. Am J Physiol Heart Circ Physiol 290: H751-H757,
702
2006.
703
43. Sheriff DD, Augustyniak RA and O'Leary DS. Muscle
704
chemoreflex-induced increases in right atrial pressure. Am J Physiol 275:
705
H767-H775, 1998.
43
706
44. Sheriff DD, O'Leary DS, Scher AM and Rowell LB. Baroreflex attenuates
707
pressor response to graded muscle ischemia in exercising dogs. Am J
708
Physiol 258: H305-H310, 1990.
709
45. Sheriff DD, Wyss CR, Rowell LB and Scher AM. Does inadequate
710
oxygen delivery trigger pressor response to muscle hypoperfusion during
711
exercise? Am J Physiol 253: H1199-H1207, 1987.
712
46. Smith SA, Querry RG, Fadel PJ, Gallagher KM, Strømstad M, Kojiro I,
713
Raven PB and Secher NH. Partial blockade of skeletal muscle
714
somatosensory afferents attenuates baroreflex resetting during exercise in
715
humans. The Journal of Physiology 551: 1013-1021, 2003.
716
47. Stornetta RL, Morrison SF, Ruggiero DA and Reis DJ. Neurons of
717
rostral ventrolateral medulla mediate somatic pressor reflex. Am J Physiol
718
256: R448-R462, 1989.
44
719
48. Waki H, Kasparov S, Katahira K, Shimizu T, Murphy D and Paton JF.
720
Dynamic exercise attenuates spontaneous baroreceptor reflex sensitivity in
721
conscious rats. Exp Physiol 88: 517-526, 2003.
722
49. Wyss CR, Ardell JL, Scher AM and Rowell LB. Cardiovascular
723
responses to graded reductions in hindlimb perfusion in exercising dogs.
724
Am J Physiol 245: H481-H486, 1983.
725
726
27
Figure 1
28
Figure 2
29
Figure 3
30
Figure 4
31
Figure 5
26
Table 1. Average slope of the linear regressions lines between HLBF and HR-SBRS during mild and moderate exercise.
Mild exercise
Moderate exercise
HR-SBRS/HLBF
(bpm/mmHg/l/min)
-4.15 ± 1.09
-1.12 ± 0.29 *
Correlation coefficient
-0.98 ± 0.01
-0.96 ± 0.01
Values are means ± SE. HR-SBRS - spontaneous baroreflex sensitivity, HLBF - Hindlimb blood flow. * P<0.05 Mild
vs. Moderate exercise.