| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 1999;100:299-304.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Novel Therapeutic Strategy Against Central Baroreflex Failure
A Bionic Baroreflex System
From the Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Osaka, Japan (T. Sato, T.K., T. Shishido, M.S., K.S.); and the Department of Biomedical Engineering, Vanderbilt University, Nashville, Tenn (J.A.).
Correspondence to Takayuki Sato, MD, Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan. E-mail tacsato{at}ri.ncvc.go.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Central baroreflex failure in Shy-Drager syndrome and traumatic spinal cord injuries results in severe orthostatic hypotension and often confines the patient to the bed. We proposed a novel therapeutic strategy against central baroreflex failure: implementation of an artificial feedback control system able automatically to regulate sympathetic vasomotor tone, that is, a bionic baroreflex system (BBS). With the use of a rat model of central baroreflex failure, we developed the BBS and tested its efficacy.
Methods and Results—Our prototype BBS for the rat consisted of a pressure sensor placed into the aortic arch, stimulation electrodes implanted into the greater splanchnic nerve, and a computer-driven neural stimulator. By a white noise approach for system identification, we first estimated the dynamic properties underlying the normal baroreflex control of systemic arterial pressure (SAP) and then determined how the BBS computer should operate in real time as the artificial vasomotor center to mimic the dynamic properties of the native baroreflex. The open-loop transfer function of the artificial vasomotor center was identified as a high-pass filter with a corner frequency of 0.1 Hz. We evaluated the performance of the BBS in response to rapid-progressive hypotension secondary to sudden sympathetic withdrawal evoked by the local imposition of a pressure step on carotid sinus baroreceptors in 16 anesthetized rats. Without the BBS, SAP rapidly fell by 49±8 mm Hg in 10 seconds. With the BBS placed on-line with real-time execution, the SAP fall was suppressed by 22±6 mm Hg at the nadir and by 16±5 mm Hg at the plateau. These effects were statistically indistinguishable from those of the native baroreflex system.
Conclusions—These results suggest the feasibility of a BBS approach for central baroreflex failure.
Key Words: baroreceptors • nervous system • reflex • blood pressure
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The sympathetic limb of the arterial baroreflex is the most important negative feedback control system functioning physiologically to attenuate the effects of rapid daily perturbations in arterial pressure.1 2 3 4 The change in posture from lying to standing, for example, is associated with a fall in blood pressure sensed by arterial baroreceptors located within the walls of the aortic arch and internal carotid arteries. This fall in pressure is neurally encoded and relayed through afferent pathways to a brain stem vasomotor center that processes the incoming signals, then through activation of efferent sympathetic pathways immediately causes an appropriate degree of compensatory vasoconstriction. Without such compensation, the simple act of standing would cause the arterial pressure responsible for perfusing the brain to inevitably fall, resulting potentially in loss of consciousness. In short, the arterial baroreflex is essential to the buffering of variations in perfusion pressure to the head and upper body during postural tilting.4
Patients with neurological disorders such as Shy-Drager syndrome,5 6 7 8 baroreceptor deafferentation,9 10 and traumatic spinal cord injuries11 12 have central baroreflex failure and a severely impaired quality of life as a consequence. In Shy-Drager syndrome, idiopathic neurodegeneration affects the vasomotor center in the brain stem; however, peripheral sympathetic neurons are assumed to be relatively spared and able to release norepinephrine in response to excitatory outflow. Iatrogenic baroreceptor deafferentation could be induced by irradiation and surgical resection of head and neck tumors. In spinal cord injuries, sympathetic traffic to preganglionic neurons can be interrupted permanently. In either case, peripheral sympathetic neurons have the potential ability to release norepinephrine in response to direct electrical stimuli. Unfortunately, although various interventions such as salt loading,13 14 cardiac pacing,15 16 and adrenergic agonists17 18 have been attempted to treat orthostatic hypotension, most patients nevertheless remain bedridden for a long time. The reason for this unfortunate outcome is that such interventions can neither restore nor reproduce the functioning of the native vasomotor center. We proposed a novel therapeutic strategy against central baroreflex failure that has its basis in bionics and neurocardiology: functional replacement of the vasomotor center with a bionic baroreflex system (BBS). In the present study, we developed the BBS and tested its efficacy in a rat model of central baroreflex failure.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Framework for BBS Development
A simplified diagram representing characteristics of the native baroreflex system is provided in Figure 1A
. The vasomotor center responsively
modifies its command over sympathetic vasomotor nerve activity
according to changes in arterial pressure sensed by
arterial baroreceptors. Efferent sympathetic nerve activity
in turn governs the functional properties of various effectors, such as
resistive and capacitive vessels, which exert direct influence over
systemic arterial pressure (SAP). With the BBS (Figure 1B), by contrast, changes in SAP are sensed by a pressure
transducer in the aortic arch and fed into a computer functioning as an
artificial vasomotor center. On the basis of measured changes in SAP,
the artificial vasomotor center executes real-time operations that
determine the frequency of electrical stimulation (STM) necessary for
compensatory adjustment of SAP to the desired level and then commands
an electrical stimulator to deliver a stimulus of the same frequency to
a sympathetic vasomotor nerve. To enable the BBS to effectively mimic
the functioning of the native baroreflex system, it is necessary
quantitatively to identify the operating rule that underlies native
baroreflex function and to implant it into the BBS. Therefore we first
analyzed under open-loop conditions the input-output relation
characterizing native baroreflex function
(Hnative) by using a white noise identification
method.19 20 Next, we identified the open-loop transfer
function (HSTM
SAP) from STM to SAP. Finally,
we determined the open-loop transfer function required for the
artificial vasomotor center of the BBS, that is,
HSAPSTM, by a simple process of division,
Hnative/HSTMSAP. The
transfer function HSAPSTM represents
the operating rule characterizing quantitatively the dynamics of how
the artificial vasomotor center should operate in its stimulation of
the sympathetic vasomotor nerve to mimic the native baroreflex.
|
Animals and Surgical Procedures
The care of animals was in strict accordance with the guiding
principles of the Physiological Society of Japan. A
total of 16 male Sprague-Dawley rats weighing 280 to 350 g were
used. The rat was first placed in a glass jar, where it breathed a
mixture of 2% halothane (Fluothane, Takeda Pharmaceuticals) in
oxygen-enriched air for 5 to 10 minutes. After induction
anesthesia, an endotracheal tube was introduced orally and
the rat was ventilated artificially by a volume-controlled rodent
respirator (model 683, Harvard Apparatus). In accordance
with Ono et al,21 anesthesia was maintained
through the use of 1.2% halothane during surgical procedures and 0.6%
halothane during data recording. Pancuronium bromide (0.8
mg · kg-1 ·
h-1 IV) was administered to eliminate
spontaneous muscle activity. Arterial blood gases were
monitored with a blood gas analyzer (IL-13064, Instrumentation
Laboratory). Polyethylene tubing (PE-10, Becton Dickinson) was inserted
into the right femoral vein. For the prevention of dehydration during
experiments, physiological saline was continuously
infused at a rate of 5 mL · kg-1 ·
h-1 with a syringe pump (CFV-3200, Nihon
Kohden). For measurement of SAP, a 2F catheter-tipped
micromanometer (SPC-320, Millar Instruments) was
placed in the aortic arch through the right femoral artery.
To open the feedback loop of the native baroreflex system, we isolated both carotid sinuses from the systemic circulation by our previous method.22 We cut the vagal and aortic depressor nerves bilaterally. Two short sections of polyethylene tubing (PE-50) were placed into both carotid sinuses and connected to a fluid-filled transducer (DX-200, Viggo-Spectramed) and to a servo-controlled pump system based on an electromagnetic shaker and linear power amplifier (ARB-126, AR Brown).
According to earlier findings that the abdominal splanchnic vascular bed innervated by the greater splanchnic nerve23 is a major effector mechanism for the arterial baroreflex in animals24 25 26 and humans,11 12 we selected this nerve as the sympathetic vasomotor nerve interface for the BBS. The left greater splanchnic nerve was identified, separated free, and cut at the level of the diaphragm with a retroperitoneal approach through a left flank incision. A pair of Teflon-coated platinum wires (7720, A-M Systems) was looped around and fixed on the distal end of the nerve. The implantation site of the wires was embedded in silicone rubber (Sil-Gel 604, Wacker). The free ends of the wires were connected to an isolated constant-voltage stimulator (SS-202J and SEN-7203, Nihon Kohden) controlled with a personal computer (PC-9801RA21, NEC). An analog-to-digital converter (AD12-16D98H, Contec) was built into the computer. Finally, the flank incision was closed in layers.
Data Recording for Estimation of
Hnative
To estimate the open-loop transfer function
Hnative, we randomly altered carotid sinus
pressure (CSP) between 100 to 120 mm Hg with a white bandwidth up
to 2 Hz by using the servo-controlled pump system. While the random
perturbation was given for an hour, the electrical signals of CSP and
SAP were first low-pass filtered with antialiasing filters having a
cutoff frequency of 50 Hz (-3 dB) and an attenuation slope of -80
dB · decade-1 (ASIP-0260L, Canopus) and
then digitized at a rate of 100 Hz by means of the analog-to-digital
converter.
Data Recording for Estimation of HSTMSAP
To estimate the open-loop transfer function
HSTMSAP, we randomly changed STM between 0 to
10 Hz with a white bandwidth up to 2 Hz while CSP was kept at a
constant pressure of 120 mm Hg. The pulse width of the stimulus
was fixed at 2 ms. The stimulation voltage was adjusted for each animal
to produce a pressor response of 40 mm Hg at 10 Hz. This resulted
in an average amplitude of 4.8±0.5 V (mean±SD). While the random
perturbation was given for 1 hour, STM and SAP were digitized at a rate
of 100 Hz.
Estimation of Transfer Function
The transfer function Hxy from input
x to output y was estimated with a fast Fourier
transform algorithm.19 20 The digitized data of
x and y were resampled at 2 Hz after a moving
average to avoid aliasing. The time series of each datum was divided
into 50 segments of 256 points each, with 128 points of overlap between
segments. The length of each segment was 128 seconds in duration. To
suppress spectral leakage, we applied a Hann window to each segment and
then computed the raw autospectra of x and y and
the raw cross-spectrum between the two. To reduce an error in
estimating the spectrum, we calculated the ensemble average of 50 raw
spectra. Finally, we computed the transfer function over the frequency
range of 0.008 to 1 Hz with a resolution bandwidth of 0.008 Hz as
follows:
 |
y is, in general, a complex quantity
and is therefore expressible in polar form as
 |
y| and 
xy
are the gain and phase of the transfer function, respectively. The
squared coherence function, a measure of linear dependence between
x and y, was estimated with the following
equation:
 |
Implantation of HSAPSTM Into BBS
The open-loop transfer function required for the artificial
vasomotor center, HSAPSTM, was determined by a
simple process of division,
Hnative/HSTMSAP. To make
the BBS computer operate in real time as the artificial vasomotor
center, we programmed the computer to automatically calculate
instantaneous STM in response to instantaneous SAP change according to
a convolution algorithm:19 20
 |
STM.
Efficacy of BBS
We evaluated the performance of the BBS in response to
rapid progressive hypotension secondary to sudden sympathetic
withdrawal. Sympathetic withdrawal was evoked by the imposition on
carotid sinus baroreceptors of a pressure step from 110 to 140
mm Hg. The pressure step was maintained for 30 seconds. The sudden
sympathetic withdrawal would be expected to produce relatively rapid
and progressive hypotension similar to orthostatic
hypotension in central baroreflex failure. While being in real time fed
into the BBS computer, SAP was recorded during the on-line
real-time execution of the BBS. SAP was also recorded while the BBS
was inactivated. For reference, we estimated the SAP
response under the closed-loop condition of the native baroreflex from
Hnative.
Statistical Analysis
The SAP responses to the sudden sympathetic withdrawal were
analyzed by a mixed model of ANOVA. A post hoc analysis
for multiple comparisons was performed by a Scheffé procedure.
Differences were considered significant at P<0.05. Values
are expressed as mean±SD.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Shown in Figure 2
is a
representative example of a process for determining the
operating rule of the artificial vasomotor center. The SAP response to
random CSP perturbation appeared to be sluggish and opposite (Figure 2A). Clearly, the estimated transfer function indicated low-pass
dynamic characteristics for Hnative (Figure 2B). The gain spectrum reveals a steady-state (lowest frequency)
gain of 
2 that is fairly constant up to 0.1 Hz. Toward higher
frequencies, the gain decreased rapidly as a function of frequency. The
phase spectrum shows that the input-output relation was out of phase at
steady state and that the phase delay increased with frequency. The
squared coherence values were found to be close to unity, indicating
that the input-output relation was governed by nearly linear dynamics
and that the transfer function well described the input-output relation
in the frequency domain. Because the closed-loop gain4 is
given by 1/(1+|Hnative|), the native baroreflex system
in this case would be expected at steady state to suppress the effect
of an external disturbance in pressure to one-third the
magnitude of the disturbance after a significant transient
response. The SAP response to random electrical stimulation of the
greater splanchnic nerve also seemed to be sluggish (Figure 2C).
Similar to Hnative, the transfer function
HSTMSAP had low-pass characteristics with a
corner frequency of 0.1 Hz (Figure 2D). Across the higher range
of frequencies, however, its rate of gain attenuation was faster than
that of Hnative. The transfer function
HSAPSTM was determined by
Hnative/HSTMSAP.
HSAPSTM is a high-pass filter with a corner
frequency of 0.1 Hz that essentially compensates for the relatively
faster gain attenuation in HSTMSAP as compared
with Hnative (Figure 2E). The phase
spectrum indicates that the input-output relation was out of phase at
steady state.
|
The significance of our investigation is most readily suggested by a
representative example in Figure 3A, where we evaluated the
performance of the BBS in response to rapid progressive
hypotension secondary to sudden sympathetic withdrawal. Sensing the
rapid fall in SAP, the BBS automatically computed STM and appropriately
stimulated the sympathetic nerve to prevent SAP from falling >25% in
10 seconds. Figures 3B and 3C summarize results obtained for 16
rats, demonstrating effectiveness of BBS performance in
buffering SAP fall in response to sympathetic withdrawal. With normal
operation of the native baroreflex prevented and without bionic
compensation (no baroreflex), SAP fell by 49±8 mm Hg in 10
seconds in response to sympathetic withdrawal. However, with the BBS
placed on-line with real-time execution (bionic baroreflex), the SAP
fall was suppressed by 22±6 mm Hg at the nadir and by 16±5
mm Hg at the plateau. These effects were statistically
indistinguishable from those of the native baroreflex system.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present results indicate that with the use of the BBS, we have been able to reproduce the dynamic functioning of the native baroreflex control of SAP. The fact that our BBS could mimic the native baroreflex would suggest the importance of our framework in developing the BBS and a new therapeutic strategy against central baroreflex failure.
System Identification by White Noise Approach
To develop an artificial device for functional replacement
of a physiological system, we should clarify and
identify its function quantitatively. Therefore we described the native
arterial baroreflex control of SAP in terms of system
physiology by using the white noise technique. Compared with the
traditional approach of testing dynamic properties of the
physiological system with step and sine wave
stimuli, the white noise approach has definite advantages as
follows.19 First, if a step stimulus is applied, we learn
the response of the system to this step and have little notion of the
response of the system to any other type of stimulus. If a sinusoidal
pulse is applied, then we know the response of the system to such a
stimulus and little else. The same applies for any other specific
waveform. In the white noise approach, the system is tested with every
possible stimulus. The white noise stimulus is a very rich stimulus. It
should be emphasized that the white noise method is perfectly suited to
the analysis of linear systems. As shown in Figures 2B
and 2D, high coherence values close to unity indicate the validity of
our method for system identification. Second, the identification of the
physiological system through the white noise
technique is largely unaffected by the types of contaminating noise
usually present in such a system. Our study provides the first and
quantitative description of the dynamic properties of the
arterial baroreflex control in rats.
Dynamic Characteristics of BBS
As shown in Figure 2E, the artificial vasomotor center of
the BBS had a high-pass or derivative nature. Although the dynamic
characteristics from CSP to sympathetic vasomotor nerve activity in
rats have never been analyzed in the frequency domain, our
previous study27 characterized the transfer functions from
CSP to sympathetic nerve activity (mechanoneural arc) and from
sympathetic nerve activity to SAP (neuromechanical arc) in rabbits. The
high-pass characteristics of the mechanoneural arc up to 1 Hz
compensated for the low-pass characteristics of the neuromechanical arc
and thus we speculated that the native baroreflex would be optimized
and achieve its quickness and stability. Whereas effector organs in the
BBS were limited to the abdominal vascular bed innervated
by the greater splanchnic nerve, the high-pass characteristics of the
mechanoneural arc in the BBS, that is,
HSAPSTM, would contribute toward compensating
for the relatively sluggish response of the neuromechanical arc in the
BBS, that is, HSTMSAP.
Clinical Implications
Two important challenges accompany the prospect of future
development of the BBS for central baroreflex failure: (1) Hardware
for clinical use is required, that is, a pressure sensor, an electrical
stimulator, and stimulating electrodes. (2) A standardized software
paradigm prescribing precisely how the bionic vasomotor center should
determine STM in response to changes in SAP must be established.
Fortunately, certain difficulties posed by these challenges have been
addressed in other areas of clinical practice to some degree and may be
readily adaptable for use with the BBS. For example, a
tonometer28 has been developed as a noninvasive continuous
monitor of SAP. Implantable pulse generators such as cardiac pacemakers
can serve as permanent electrical stimulators. Also, implantable wire
leads for nerve stimulation29 30 and epidural catheters
for percutaneous spinal stimulation31 32
have been approved for the long-term treatment of some neurological
disorders and for long-term therapy of pain control. Finally, inasmuch
as our present study establishes a solid framework for the
necessary software development to implement the approach, we
enthusiastically affirm not only that we can but that we should develop
the BBS as a new therapeutic modality for treatment of severe
orthostatic intolerance in central baroreflex failure such
as Shy-Drager syndrome, baroreceptor deafferentation, and traumatic
spinal cord injuries.
Study Limitations
In the present study, for the sake of simplicity, we cut
the vagal nerves bilaterally to exclude the vagally mediated effect on
the arterial baroreflex. The dynamic properties of the
arterial baroreflex may be different from the present
results when vagally mediated effects are present. Anesthetic
agents used in the present study could also affect the dynamic
properties of arterial baroreflex control of SAP. Although
we used a linear approach for estimating the dynamic properties of
arterial baroreflex, the nonlinear nature of the
arterial baroreflex system such as threshold and saturation
phenomena4 20 22 has been well known. Therefore our
results should be interpreted carefully. However, the fact that the
present framework enabled us to restore arterial
baroreflex function suggests that the linear approximation of the
central baroreflex arc is reasonable, at least under our experimental
conditions.
The vasomotor center of the arterial baroreflex33 is affected by higher-order centers such as the limbic-hypothalamic systems and receives various afferents from the periphery such as sympathetic afferent cardiac and splanchnic fibers.34 35 In the present study, we ignored these components. Thus further investigation concerning the effects of these components on the arterial baroreceptor reflex is needed for clarifying the native baroreflex and developing the truly "bionic" baroreflex system.
In summary, we proposed a novel therapeutic strategy against central baroreflex failure with the BBS. Our prototype of the BBS consisted of a pressure sensor, stimulation electrodes implanted into a peripheral sympathetic nerve, and a computer-driven neural stimulator. In rats, we first estimated the dynamic properties underlying the normal baroreflex control of arterial pressure. We then determined how the BBS computer should operate as the artificial vasomotor center to mimic the native baroreflex. The BBS could indeed reproduce the native baroreflex in a model of central baroreflex failure.
|
Acknowledgments |
|---|
This study was supported by a grant-in-aid for developmental scientific research (09770051) from the Ministry of Education, Science, Sports, and Culture of Japan, by a health sciences research grant for advanced medical technology from the Ministry of Health and Welfare of Japan, a grant for ground research for space utilization from NASDA and Japan Space Forum, a grant for medical and pharmaceutical research from the Mochida Memorial Foundation, and by a grant for research on hypertension and autonomic nervous system from the Kimura Memorial Heart Foundation/Pfizer Pharmaceuticals Inc. Dr Alexander was also supported in part by a National Institute of Neurological Disorders and Stroke grant (5U01 NS33460).
Received October 26, 1998; revision received March 26, 1999; accepted April 9, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Schmidt RM, Kumada M, Sagawa K. Cardiac output and total peripheral resistance in carotid sinus reflex. Am J Physiol. 1971;221:480–487.
2. Guyton AC, Coleman TG, Granger HJ. Circulation: overall regulation. Ann Rev Physiol. 1972;34:13–46.[Medline] [Order article via Infotrieve]
3.
Malliani A, Pagani M, Lombardi F, Cerutti S.
Cardiovascular neural regulation explored in the
frequency domain. Circulation. 1991;84:482–492.
4.
Sato T, Kawada T, Inagaki M, Shishido T, Takaki
H, Sugimachi M, Sunagawa K. New analytic framework for understanding
sympathetic baroreflex control of arterial pressure.
Am J Physiol. 1999;276:H2251–H2261.
5. Shy M, Drager GA. A neurological syndrome associated with orthostatic hypotension: a clinico-pathologic study. Arch Neurol. 1960;3:511–527.
6.
The Consensus Committee of the American Autonomic
Society and the American Academy of Neurology. Consensus statement on
the definition of orthostatic hypotension, pure autonomic
failure, and multiple system atrophy. Neurology. 1996;46:1470.
7.
Schatz IJ. Farewell to the "Shy-Drager syndrome."
Ann Intern Med. 1996;125:74–75.
8.
Goldstein DS, Holmes C, Cannon RO III, Eisenhofer G,
Kopin IJ. Sympathetic cardioneuropathy in dysautonomias.
N Engl J Med. 1997;336:696–702.
9.
Onrot J, Wiley RG, Fogo A, Biaggioni I, Robertson D,
Hollister AS. Neck tumour with syncope due to paroxysmal sympathetic
withdrawal. J Neurol Neurosurg Psychiatry. 1987;50:1063–1066.
10. Lee HT, Brown J, Fee WE Jr. Baroreflex dysfunction after nasopharyngectomy and bilateral carotid isolation. Arch Otolaryngol Head Neck Surg. 1997;123:434–437.
11. Frankel HL, Mathias CJ. Severe hypertension in patients with high spinal cord lesions undergoing electro-ejaculation: management with prostaglandin E2. Paraplegia. 1980;18:293–299.[Medline] [Order article via Infotrieve]
12. Matthews JM, Wheeler GD, Burnham RS, Malone LA, Steadward RD. The effects of surface anaesthesia on the autonomic dysreflexia response during functional electrical stimulation. Spinal Cord. 1997;35:647–651.[Medline] [Order article via Infotrieve]
13. Wilcox CS, Puritz R, Lightman SL, Bannister R, Aminoff MJ. Plasma volume regulation in patients with progressive autonomic failure during changes in salt intake or posture. J Lab Clin Med. 1984;104:331–339.[Medline] [Order article via Infotrieve]
14. Mehlsen J, Boesen F. Substantial effect of acute hydration on blood pressure in patients with autonomic failure. Clin Physiol. 1987;7:243–246.[Medline] [Order article via Infotrieve]
15. Kristinsson A. Programmed atrial pacing for orthostatic hypotension. Acta Med Scand. 1983;214:79–83.[Medline] [Order article via Infotrieve]
16.
Bannister R, da Costa DF, Hendry WG, Jacobs J, Mathias
CJ. Atrial demand pacing to protect against vagal overactivity in
sympathetic autonomic neuropathy. Brain. 1986;109:345–356.
17.
Kachi T, Iwase S, Mano T, Saito M, Kunimoto M, Sobue I.
Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve
activities in Shy-Drager syndrome. Neurology. 1988;38:1091–1094.
18.
Obara A, Yamashita H, Onodera S, Yahara O, Honda H,
Hasebe N. Effect of xamoterol in Shy-Drager syndrome.
Circulation. 1992;85:606–611.
19. Marmarelis PZ, Marmarelis VZ. Analysis of Physiological Systems: The White-Noise Approach. New York, NY: Plenum; 1978.
20.
Sato T, Kawada T, Shishido T, Miyano H, Inagaki M,
Miyashita H, Sugimachi M, Knuepfer MM, Sunagawa K. Dynamic transduction
properties of in situ baroreceptors of rabbit aortic depressor nerve.
Am J Physiol. 1998;274:H358–H365.
21.
Ono A, Kuwaki T, Kumada M, Fujita T. Differential
central modulation of the baroreflex by salt loading in normotensive
and spontaneously hypertensive rats. Hypertension. 1997;29:808–814.
22.
Sato T, Kawada T, Miyano H, Shishido T, Inagaki M,
Yoshimura R, Tatewaki T, Sugimachi M, Alexander J Jr, Sunagawa K. New
simple methods for isolating baroreceptor regions of carotid sinus and
aortic depressor nerves in rats. Am J Physiol. 1999;276:H326–H332.
23. Gabella G. Autonomic nervous system. In: Paxinos G, ed. The Rat Nervous System. 2nd ed. San Diego, Calif: Academic Press; 1995:81–103.
24.
Shoukas AA, Sagawa K. Control of total systemic
vascular capacity by the carotid sinus baroreceptor reflex. Circ
Res. 1973;33:22–33.
25.
Hainsworth R, Karim F. Responses of abdominal vascular
capacitance in the anaesthetized dog to changes in carotid sinus
pressure. J Physiol (Lond). 1976;262:659–677.
26.
Carneiro JJ, Donald DE. Blood reservoir function of dog
spleen, liver, and intestine. Am J Physiol. 1977;232:H67–H72.
27.
Ikeda Y, Kawada T, Sugimachi M, Kawaguchi O, Shishido
T, Sato T, Miyano H, Matsuura W, Alexander J Jr, Sunagawa K. Neural arc
of baroreflex optimizes dynamic pressure regulation in achieving both
stability and quickness. Am J Physiol. 1996;271:H882–H890.
28.
Sato T, Nishinaga M, Kawamoto A, Ozawa T, Takatsuji H.
Accuracy of a continuous blood pressure monitor based on
arterial tonometry. Hypertension. 1993;21:866–874.
29. Reid SA. Surgical technique for implantation of the neurocybernetic prosthesis. Epilepsia. 1990;31(suppl 2):S38–S39.
30. DeGiorgio C, Handforth A, Schachter S, Uthman B, Naritoku D, Tecoma E, Henry T, Collins S, Vaughn B, Gilmartin R, Labar D, Morris G, Salinsky M, Osorio I, Ristanovic R, Labiner D, Jones J, Murphy J, Ney G, Wheless J, Tarver B, Duffell W Jr, US E05 Vagus Nerve Stimulation Study Group. Vagus nerve stimulation for medically intractable partial-onset seizures: initial report of the United States E05 Study Group. Epilepsia. 1997;38(suppl 6):S133. Abstract.
31. Shimoji K, Kitamura H, Ikezono E, Shimizu H, Okamoto K, Iwakura Y. Spinal hypalgesia and analgesia by low-frequency electrical stimulation in the epidural space. Anesthesiology. 1974;41:91–94.[Medline] [Order article via Infotrieve]
32.
Shimoji K, Hokari T, Kano T, Tomita M, Kimura R,
Watanabe S, Endoh H, Fukuda S, Fujiwara N, Aida S. Management of
intractable pain with percutaneous epidural spinal cord
stimulation: differences in pain-relieving effects among diseases and
sites of pain. Anesth Analg. 1993;77:110–116.
33. Kumada M, Terui N, Kuwaki T. Arterial baroreceptor reflex: its central and peripheral neural mechanisms. Prog Neurobiol. 1990;35:331–361.[Medline] [Order article via Infotrieve]
34.
Malliani A, Recordati, Schwartz PJ. Nervous
activity of afferent cardiac sympathetic fibres with atrial and
ventricular endings. J Physiol (Lond). 1973;229:457–469.
35. Kostreva DR, Hopp FA, Kampine JP. Depressor responses to stimulation of sympathetic afferents in monkeys and dogs. Am J Physiol. 1981;240:R23–R28.We proposed a novel therapeutic strategy against central baroreflex failure: implementation of an artificial feedback control system able automatically to regulate sympathetic vasomotor tone, that is, a bionic baroreflex system (BBS). Our prototype BBS consisted of a pressure sensor, stimulation electrodes implanted into a peripheral sympathetic nerve, and a computer-driven neural stimulator. In rats, we first estimated the dynamic properties underlying the normal baroreflex control of arterial pressure. We then determined how the BBS computer should operate as the artificial vasomotor center to mimic the native baroreflex. The BBS could indeed reproduce the native baroreflex in a model of central baroreflex failure.
This article has been cited by other articles:
 |
|
 |
|
  F. Yamasaki, T. Ushida, T. Yokoyama, M. Ando, K. Yamashita, and T. Sato Artificial Baroreflex: Clinical Application of a Bionic Baroreflex System Circulation, February 7, 2006; 113(5): 634 - 639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yamamoto, T. Kawada, A. Kamiya, H. Takaki, M. Sugimachi, and K. Sunagawa Static interaction between muscle mechanoreflex and arterial baroreflex in determining efferent sympathetic nerve activity Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1604 - H1609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hemingway, K. Franco, and E. Chmelik Shy-Drager Syndrome: Multisystem Atrophy With Comorbid Depression Psychosomatics, February 1, 2005; 46(1): 73 - 76. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yanagiya, T. Sato, T. Kawada, M. Inagaki, T. Tatewaki, C. Zheng, A. Kamiya, H. Takaki, M. Sugimachi, and K. Sunagawa Bionic epidural stimulation restores arterial pressure regulation during orthostasis J Appl Physiol, September 1, 2004; 97(3): 984 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kawada, K. Uemura, K. Kashihara, A. Kamiya, M. Sugimachi, and K. Sunagawa A derivative-sigmoidal model reproduces operating point-dependent baroreflex neural arc transfer characteristics Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2272 - H2279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sato, T. Kawada, M. Inagaki, T. Shishido, M. Sugimachi, and K. Sunagawa Dynamics of sympathetic baroreflex control of arterial pressure in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R262 - R270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sato, T. Kawada, M. Sugimachi, and K. Sunagawa Bionic Technology Revitalizes Native Baroreflex Function in Rats With Baroreflex Failure Circulation, August 6, 2002; 106(6): 730 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ketch, I. Biaggioni, R. Robertson, and D. Robertson Four Faces of Baroreflex Failure: Hypertensive Crisis, Volatile Hypertension, Orthostatic Tachycardia, and Malignant Vagotonia Circulation, May 28, 2002; 105(21): 2518 - 2523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kawada, T. Shishido, M. Inagaki, T. Tatewaki, C. Zheng, Y. Yanagiya, M. Sugimachi, and K. Sunagawa Differential dynamic baroreflex regulation of cardiac and renal sympathetic nerve activities Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1581 - H1590. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||