AMERICAN *JOURNAL. OF PHYSIOLOGV Vol. 228, No. 5, May 1975. Print&
in U.S.A.
of carotid
Modulation b y sciatic MAMORU Department Department
KWMADA,
nerve KUMADA, of Neurology, of Biomedical
sinus
baroreceptw
stimulation KAZUO Laboratory Engineering,
NOGAMI,
AND KIICHI SAGAWA Cornell University Medical College, Nezv York City School of Medicine, Johns Hopkins University, Baltimore, Maryland
of Neurobiology,
MAMORU,
KAZUO NOGAMI, AND KII~HI SAGAWA. sinus baroreccptur rejhx by sciatic nerve stimulation. Am. J. Physiol. 228(5) : 1535-1541. 1975.-In anesthetized, immobilized, and vagotomized cats we analyzed the effect of sciatic nerve stimulation (SNS) on the relationships between intrasinus pressure (ISP) and arterial pressure (AP) and between ISP and heart rate (HR). At each of seven ISP levels between 60 and 240 mmHg, AP and HR before and 20 s after the onset of SNS were plotted against ISP to obtain the ISP-AP and ISP-HR relationships before and during SM. SNS caused increases in AP, HR, and total peripheral resistance (TPR) and a decrease in cardiac output (CO). SNS raised the equilibrium pressure (the value of AP at which AP equaled ISP), but it significantly (P < 0.005) decreased the slope (or gain) of the ISP-AP relationship at ISP’s between 90 and 150 mmHg. SNS also significantly (P < 0.05) diminished the gain of ISP-HR relationship at ISP’s between 120 and 210 mmI-Ig. Modulation of the gain of ISP-AP relationship was ascribable to that of CO but not of TPR. We
of carotid
Modulation
conclude tivity
that in vagotomized
of AP
and
HR
responses
reflex, and 2) the inhibition by modulation
of the reflex
arterial
pressure;
resistance;
gain;
cats I) SNS attenuates
the sensi-
in the
carotid sinus baroreceptor of the reflex AP response was caused CO response.
heart rate; cardiac equilibrium pressure
reflex
output;
total
peripheral
ELECTRICAL STIMULATION Of SOme Somatic afferent Ilel-veS with certain stimulus parameters elicits a rise in arterial pressure and tachycardia (7, 8, 14). Johansson (7) termed this response the somatic pressor response. There is evidence between the somatic pressor indicating the interaction response and the carotid sinus baroreceptor reflex. First, the sympathetic discharges evoked by stimulation of somatic afferents were inhibited by stimulation of the carotid sinus nerve (9), and the discharges of the cardiac parasympathetic nerve evoked by stimulation of the carotid sinus nerve were in turn eliminated by stimulation of the somatic efferents (5, 6). Second, Johansson (7) demonstrated that occlusion of the common carotid artery modified responses of the arterial pressure and renal resistance to somatic nerve stimulation. Such interactions are not surprising at all, since both somatic nerve stimulation and the baroreceptor reflex involve the sympathetic (4, 9) and cardiac parasympathetic nerves (5, 6, 14). In the present study we attempted to clarify quantitatively the modulatory eflect of sciatic nerve stimulation on the carotid sinus baroreceptor reflex. We analyzed,
10021;
and
21205
before and during sciatic nerve stimulation, the relations between isolated intrasinus pressure (BP; input) and various cardiovascular variables such as arterial pressure, heart rate, cardiac output, and total peripheral resistance. As in our previous study (1 Z), we characterized the modulatory effect of sciatic nerve stimulation in terms of two important quantities associated with the input-output relation of the carotid sinus baroreceptor reflex, i.e., the open-loop gain (abbreviated as “gain”) and the equilibrium pressure. The former is the slope of the curve relating isolated and controlled ISP to various cardiovascular variables. The latter is the value of arterial pressure at which arterial pressure equals ISP. To our knowledge, there has been only one study which analyzed the modulatory effect of sciatic nerve stimulation on the ISP-arterial pressure relationship (22). In this study, however, ISP was varied over a relatively narrow range (about 85-145 mmHg), and only the response of arterial pressure was investigated. We considered that a more extensive analysis was necessary to delineate quantitative aspects of the modulation. The central questions we attempted to answer may be summarized as follows: I) Does sciatic nerve stimulation modulate the control of arterial pressure by the carotid sinus baroreceptor reflex? If it does, how is the modulation characterized in terms of the input-output relation curve, gain, and equilibrium pressure? 2) Does sciatic nerve stimulation modulate the reflex control. of heart rate, cardiac output, and total peripheral resistance uniformly or differently? If it does in different manners, how are the modulations of those variables related to that of the reflex control of arterial pressure? We are aware that sciatic nerve stimulation can cause either a pressor or a depressor response, depending on stimulation parameters (7). In this paper, however, sciatic nerve stimulation denotes, unless otherwise specified, only such stimulation that elicits a pressor response. Likewise, the sciatic pressor response signifies a pressor response on stimulating the sciatic nerve, METHODS
Animals and anesthesia. Results were obtained from 27 adult cats of either sex weighing between 2 and 4 kg. The animal was anesthetized by an intravenous injection of alpha-chloralose (60 mg/kg) and urethan (500 mg/kg) after induction with chloroform. After tracheal cannula1535
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
1536 tion, the animal was immobilized with intraperitoneal injection of Flaxedil (20 mg initial dose) and placed on positive-pressure respiration. The vagus nerves were severed in the neck so that the compensatory effect of the aortic baroreceptor reflex and the potential complications medireceptors could be elimiated by other cardiopulmonary nated. Isolation of carotid sinus. With the method detailed in our previous paper (1 l), the right and left carotid sinuses were isolated by ligating the internal carotid and occipital arteries and all other visible vessels. Lingual arteries were cannulated and connected to a servo-controlled pressure sou rce. In order to assure supply of the arterial blood to the carotid sinuses when the experi ment was not being conducted, the external and common carotid arteries were occluded with bulldog clamps only during the experimental ITIll.
Measurements of cardiovascular variables. The following variables were measured : phasic and mean cardiovascular arterial pressures (AP’s), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR). Phasic and mean AP’s were measured from the femoral artery. HR was determined by a tachometer triggered by the AP pulse CO (minus coronary flow) was measured via an electromagnetic flow transducer attached to the root of the ascending aorta after thoracotomy. The transducer (Narco BioSystems, Inc., C series) was connected with an electroflowmeter (Narco Physiometric Electromagnetic magnetic Flowmeter System). To assure a correct zero base line for the CO signal, the phasic flow signal was continuously displayed on an oscilloscope and was manually adjusted such that the Aow signal during the diastolic period would correspond to electrical zero. TPR was calculated as AP/CO by an analog divider circuit and recorded with ISP, AP’s, HR, and CO on a chart recorder (Fig. 1). Sciatic nerve stimulation. Either right or left sciatic nerve was exposed near the hip joint and cut, and one of the several nerve strand .s surround ed by a common sheath was separated from the whole nerve trunk. The central cut end of the separated nerve strand was further unsheathed, placed on a pair of platinum wire electrodes, and maintained in a pool of warmed paraffin oil enclosed by a skin flap. The nerve was stimulated by a 20-s train of rectangular pulses, having a frequency of 70 Hz and a duration of 2 ms, delivered by a constant-current stimulator (Nuclear-Chicago model 7 15O)* The stimulating current was adjusted such that, when the carotid sinus was communicating with the systemic artery, the sciatic pressor response would be between 10 and 70 mmHg (usually between 10 and 250 ~-IA). Experimental design. In every experimental run, ISP was varied between 60 and 240 mmHg in steps of 30 mmHg. At each ISP the sciatic nerve was stimulated for 20 s, since all the cardiovascular variables observed in this study reached new steady states within this length of time (Fig. 1). The relationship between isolated and controlled IS9 (input) and each cardiovascular variable (output) was determined 5 s before and 20 s after the onset of sciatic nerve stimulation. Modulatory effect of sciatic nerve stimulation on the carotid sinus baroreceptor reflex was characterized by alterations of the input-output relations by nerve stimulation.
Usually more than one experimental run was conducted on an individual cat. All the data from repeated runs within a single animal were averaged to obtain a pair of inputoutput relationships for each cardiovascular variable, one before and another during sciatic nerve stimulation. The averaged data were then used for the statistical analysis of the difference before and during sciatic nerve stimulation* The data on CO and TPR were expressed in each experimental run as the percent of those values when ISP was set at 60 mmHg and the sciatic nerve was not stimulated. REStiLTS
Pattern of curdiovuscular responses to sciatic nerve stimuhtion. The rise in arterial pressure following the 20-s stimulation of the sciatic nerve was associated with increases in TPR and HR (Fig. 1) CO usually decreased during sciatic nerve stimulation at ISP’s between 60 and 150 mmHg, but remained unchanged at BP’s above that range. These cardiovascular variables reached new steady levels within 20 s after the onset of sciatic nerve stimulation. Modulation of reflex control of urterialpressura. At each of seven fixed ISP’s between 60 and 240 mmHg, an elevation of AP was brought about by sciatic nerve stimulation However, the magnitude of the pressor response was dependent on ISP. As ISP was set to 90, 120, and then to 150 mmHg, the elevation became gradually increased, whereas at ISP’s above 150 mmHg, the elevation remained virtually the same (Fig. 2, A and B). Because of this dependency of the pressor response on ISP, the slope or the gain of the ISP-AP relation was significantly decreased (Y < 0.005) by sciatic nerve stimulation over the ISP region between 90 and 150 mmHg (Fig. 2C). On the other hand, the gain was not significantly altered at ISP’s between 150 and 240 mmHg. It is thus concluded that, over the ISP range between 90 and 150 mmHg, sciatic nerve stimulation inhibited the control of AP by the carotid sinus baroreceptor reflex. We have previously demonstrated (12) that the ISP-AP relationship could be approximated by a sigmoid curve. In order to analyze more quantitatively the modulatory effects of the sciatic nerve stimulation on the reflex control of AP, we calculated the best-fit sigmoid curve for the ISP-AP relation of Fig. 2A by the method detailed elsewhere (12). The mean square error between the observed data and the best-fit curve was 1 mmHg before and during sciatic nerve stimulationWe then calculated, as in our previous study (1 Z), the following values (characteristic values) that characterized the best-fit curve: a) the maximum reflex gain (the maximum value of the slope of the fitted ISP-AP curve), b) peak ISP (ISP at which the maximum gain was attained), c) threshold ISP (arbitrarily defined as an ISP in the left half of the ISP-gain curve at which the gain decreased to 5 % of the maximum value), d) saturation ISP (arbitrarily defined as an ISP in the right half of the ISP-gain curve at which the gain decreased to 5 % of the maximum value), e) maximum and minimum AP’s (estimated by extrapolating ISP to low and high extremes, respectively), f) range of’ISP-dependent AP (difference between maximum and minimum AP’s), and g) equilibrium pressure (see second introductory paragraph for definition).
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
SCIATIC
NERVE
STIMULATION
AZ\JD
A
B
CAROTID
SINUS
c
REFLEX
D
1537
E
F
G
480
lntrasinus pressure (mm Hgl
--_-
- ----
0
Arterial pressure (mm Hgl
r”
dAdI/rI,I,,, FIG. 1. Cardiovascular responses to sciatic nerve stimulation. Right sciatic nerve was stimulated for 20 s as indicated by a thick line in 7th tracing from top. Amplitude of pulse was 40 PA, duration 2 ms, and the frequency 70 Hz. ISP was maintained at 60 mmHg in A, 90 mmHg in B, 120 mmHg in C, 150 mmHg in D, 180 mmHg in E, 2 10 mmHg in 12, and 240 mmHg in G. Sample records were arranged in sequential order. CO (5th tracing from top) was obtained by passing ascending aortic flow signal (4th tracing from top) through a low-pass filter with a time constant of 1 s.
Ii 0
Mean AP (mm Hg)
Ascending n-
Cardiac
output
-
-
-
--
-
O-
JotaI peripheral resistance
--a
/f--l
-a-
O-me
Sciatic stimulation
--F
-__I
_--I
I 30 set
120 240 17
Heart rate (beats I mi nl
------
TABLE 1. charac~er~dc uahes during control jxriod and during I) LP-AP relationshljl of Fig. between LW and gain of ‘rejlex
0.8 j
]
j
\
!
60
90
120
150
180
1
1
210
240
a r/l Q, 0.6 F
90 120 INTRASINUS
ml 150 -- 180 -' 210 PRESSURE (mm Hg)
-60>O INTRASINUS
PRESSURE
(mm
Hg)
2. Relationship between ISP (abscissa) and ,AP (A) or gain of reflex control of AP (C) before and during sciatic nerve stimulation (ordinate). Relationship between ISP and difference in AP between control value and value during sciatic nerve stimulation is shown by B. In this and subsequent figures, solid line connecting the filled circles represents relationship during prestimulus period, whereas broken line connecting open circles represents relationship at end of 20-s stimulation of sciatic nerve. Data were obtained from 27 cats and mean and standard error of mean were plotted in ordinate. In this and subsequent figures, asterisks attached on upper right corner of open circles signify that difference between control value during stimulation is statistically significant (P < 0.05).
__
,__
-. - -
M.aximum gain Peak ISP, mmHg Threshold ISP, mmHg Saturation ISP, mmHg Maximum AP, mmHg Minimum AP, mmHg Range of ISP-dependent AP, mmI-Ig Equilibrium pressure, mmHg - .- _...-.___ _.- - --For definition of characteristic
Of the fdow~ng kuo curues scialic nerve stimulation. ZA, and 2) relationship AP control of Fig. 2C Control
-- ------~-
Sciatic Nerve
Stimulation --
0.81 139 41 236 164 83 81
0.62 141 40 242 190 125 65
130
151
value,
see text.
FIG.
As summarized in Table 1, the following results were obtained from the fitted curve. I) Sciatic nerve stimulation elevated the equilibrium pressure from 130 to 151 mrnHg, 2) Maximum and Ininimuln AP’s were both increased by However, the increase in the sciatic nerve stimulation. minimum AP was greater than that in the maximum AP (42 VS~ 26 mmHg). As a consequence, the range of ISP-
dependent AP was diminished by sciatic nerve stimulation (from 81 to 65 mmHg). 3) The maximum gain was diminished by sciatic nerve stimulation from 0.80 to 0.62 changes in the (a 23 % fali). 4) Th ere were no marked peak ISP, saturation ISP, and threshold ISP. sciatic nerve stimulation elevated the In summary, equilibrium pressure and decreased the gain of the ISP-AP relation over the ISP range between 90 and 150 mmHg. Application of the curve litting to the experimental data further indicated that sciatic nerve stimulation elevated the maximum and minimum AP’s, but narrowed the range of ISP-dependent AP, Modulation of reflex confrol ojr heart rate. At every ISP examined, the sciatic pressor response was attended by tachycardia (Fig. 1 and 4A). Since the vagus nerves had been severed in the preparation, this tachycardia was mediated by the sympathoadrenergic c system. The tachycardia at
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
1538
KUMADA,
various ISP’s was not uniform but was greater at higher BP’s (Fig. 4, A and B). Thus, the gain of the ISP-HR relationship was significantly diminished over the ISP region between 120 and 210 mmHg (P < 0.05, Fig. 4C). It was thus demonstrated that sciatic nerve stimulation inhibited the reflex control of HR as part of the reflex control of AP. The same curve-fitting method used for AP was applied to the ISP-HR relationship of Fig. 4A and the relationship between ISP and the gain of reflex HR control shown by Fig. 4-C. As illustrated by Fig. 5A, the mean square error between the best-fit curve and the experimental data was 0 beat/min during the control period and 1 beat/min during sciatic nerve stimulation. As summarized in Table 2, sciatic nerve stimulation raised the minimum HR from 2 17 to 228 beats/min while maintaining the maximum HR virtually the same (234 vs. 236 beats/min). Therefore, the range of ISP-dependent HR was narrowed by sciatic nerve stimulation (from 17 to 8 beats/min). It was also found that sciatic nerve stimulation shifted the threshold ISP toward a higher ISP region (from 50 to 78 mmHg) and the saturation ISP toward the opposite direction (from 277 to 235 mmHg). In other words, sciatic nerve stimulation narrowed the range of ISP over which the reflex control of HR was These characteristic values derived from the operative. curve fitting again demonstrated that sciatic nerve stimulation inhibited the reflex control of HR. 20ar
*
NOGAMI,
l
230
3. Best-fit curve for ISP-AP between ISP and gain of reflex legend to Fig. 2 for explanation figure.
FIG.
tion See this
B
r
240
PRESStiRE
Imt;~ I@)
2
0.15
---
c ‘F -.g
0.10
---
0 l
2i u
relation of Fig. control of AP of closed and
SAGAWA
Modulation of reflex controlof cardiac output and total peripheral resistance. In this series of experiments in 10 cats, modulation of the reflex control of AP was correlated to those of CO and TPR. These 10 experiments could be considered as since sciatic nerve stimulation raised the representative, equilibrium pressure and decreased the gain of the ISP-AP relationship at ISP’s between 90 and 150 mmHg (Fig. 6, A and C). Sciatic nerve stimulation brought about an increase in TPR at every ISP examined and a decrease in CO at BP’s between 60 and 150 mmHg (Fig* 6, D, E, G, and H). Thus, the rise in the equilibrium pressure on sciatic nerve stimulation was exclusively the result of an increase in TPR. However, as shown below, the decrease in the gain of the reflex AP control was the result of a change in the CO response. Before sciatic nerve stimulation, CO remained virtually the same, as ISP was altered between 60 and 240 mmHg (Fig. 6G). Th e g ain of the reflex CO response was thus near zero (Fig. 61). Sciatic nerve stimulation diminished CO at BP’s between 60 and 150 mmHg, but the decrease in CO was attenuated as ISP was increased (Fig. 6H)* Consequently, the BP-CO relation during sciatic nerve stimulation showed that CO increased wi;h ISP (Fig. 6G). The average gain of the reflex CO control was thus significantly altered (P < 0.025) by sciatic nerve stimulation at ISP’s between 90 and 150 mmHg, and this alteration contributed to the decrease in the gain of the reflex AP control. On the other hand, the gain of the reflex TPR response within the same ISP range was not significantly altered (P < 0.4) by sciatic nerve stimulation. In summary, the elevation of the equilibrium pressure 0.20
INTRASINUS
AND
/
_
60
90
120
150
180
210
240
INTRASIWIS
FIG. 5. Best-fit tion between ISP See legend to Fig. figure.
curve for ISP-HR and gain of reflex 2 for explanation
0
”
l
l \
\
\
:/
\
::;
0
120
l
\ A,
/’ ,4’
60 90 PRESSURE (mm HgI
relation control of closed
\
// ,’
z 0.05 --. 3
2A (A) or relaof Fig. 2C (B). open circles in
I--,
\
\
I
’
h,
150
180
210
of Fig. 4A (A) of HR of Fig. and open circles
1
240
or rela4C (B). in this
2. Characteristic values Of the following two curves during control period and during sciatic nerve stimulation. I) LW-HR relationship of Fig. 4A, and 2) relationship between ISP and gain of reflex HR control of Fig.4 C TABLE
L210LI
12
a
60
1 90
1 120
] 150
0 180
210
, 240
0.20 I --
1
c
B
--lo-r 90
120
INTAASINUS
150
180
210
PRES SURE (mm Hg)
Control
240
60
120
150
I~TRASINUSPRESSURE
1x0
210 '-240 (mm~g)
FIG. 4. ISP-HR relation (A) and relation between ISP and gain of reflex control of HR (C) before (a) and after 20 s of sciatic nerve stimulation (0). Relationship between ISP and difference in HR between control value and value during sciatic nerve stimulation is shown in B. Mean and SE of 16 sets of experimental data are shown.
Maximum gain, beats/min mmHg Peak ISP, mmHg Threshold ISP, mmHg Saturation ISP, mmHg Maximum HR, beats/min Minimum HR, beats/min Range of ISP-dependent beats/min
per
HR,
0.14 156 50 277 234 217 17
Sciatic
Nerve
Stimulation
0.09 163 78 235 236 228 8
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
SCIATIC
NERVE
STIMULATION
AND
1
1
I
I
I
I
1
60
90
120
150
180
210
240
CAROTID
e
SINUS
0
LL60
1539
REFLEX
1 120I 150I 180I 210I
90
1
240
s z-
,’ pv-L
-* .
90
120
150
180
210
240
t
60
90
120
150
180
210
240
120
150
180
210
240
120
150
180
210
240
F
I
60
90
I
120
I
1
I
1
,150
180
210
240
1
I
I
I
1
60
90
120
150
180
INTRASINUS
6. Relationships between ISP and following variables: AP or CO (G) and gain of reflex control of AP (C), TPR TPR m or CO (I). Illustration B, J3, or H denotes, respectively, relation-
FIG.
(4, (F),
by sciatic nerve stimulation was attributable to the response of TPR, whereas the decrease in the gain of the reflex AP control was the result of the modified response of CO. DXSCUSSIQN
The present study demonstrated an inhibitory effect of sciatic nerve stimulation on the reflex control of AP and HR. The inhibition of the reflex AP response was seen over the ISP range between 90 and 150 mmHg and was due to the alteration in the ISP-CO relation. Within the same ISP changes were found in the gain of range, no significant the reflex TPR control. Thus, the different behavior of CO before and during sciatic nerve stimulation was the key factor in the modulation of the reflex AP response. Sciatic nerve stimulation significantly diminished CO at BP’s between 60 and 150 mmHg. This decrease in CO appears to be a result of an increased afterload on the left ventricle (i.e., aortic pressure) rather than diminished cardiac contractility, since I) the decrease in CO by sciatic nerve stimulation was attenuated as AP was decreased on elevating ISP, and 2) a concomitant increase in HR indicates an enhanced activity of the cardiac sympathetic nerve and/or adrenal secretion, both of which should augment the cardiac contractility. In the isolated and supthe aortic pressure ported heart of the cat, increasing
PRESSURE
I
210
t
240
60
90
(mmlig)
ship between ISP and difference in AP, TPR, or CO between control value and value during sciatic nerve stimulation. l , 0 Variables before and after 20 s of sciatic nerve stimulation, respectively.
approximately above 150 mmHg resulted in a decrease in CO (20). In our preparation, in which the sympathoadrenal system was intact, a decrease in CO was observed when AP exceeded around 150-l 75 mmHg (Fig. 6G). However, for the following reason, a neural mechanism was also likely to be involved in the modulation of the BP-CO relationship by sciatic nerve stimulation. As mentioned earlier, inhibition was present in the reflex HR response. Since vagus nerves were severed in the preparation, the observed inhibition must be due to a modulation in the HR control through the sympathoadrenal system. It may be that the sensitivity of the cardiac sympathetic nerve to a change in the carotid sinus afferent signals was reduced during sciatic nerve stimulation. In this series of experiments, the efferent cardiac parasympathetic nerve was eliminated as a result of bilateral cervical vagotomy. It is unlikely, however, that the lack of the efferent cardiac parasympathetic nerve would significantly affect the modulatory effect of sciatic nerve stimulation on the reflex AP control at BP’s between 90 and 150 mmHg. In cats anesthetized by chloralose and urethan, Kunze (13) demonstrated that the efferent cardiac parasympathetic fibers were silent when AP (Le., input to carotid sinus and aortic arch baroreceptors) was below 140-150 mmHg. c In other words, at ISP’s below 140-150
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
1540 mmHg, the efferent cardiac parasympathetic fibers would not participate in the carotid sinus baroreceptor reflex. Thus, at ISP’s between 90 and 150 mmHg, the presence or absence of the efferent cardiac parasympathetic nerve would not make significant difference as far as the reflex control of AP, CO, and TPR is concerned. In a series of experiments in seven dogs, Ulmar (22) did not find a significant change in the slope of the ISP-AP relationship on stimulating the sciatic nerve. There are two possible explanations on the discrepancies between Ulmar’s results and our studies: I) in Ulmar’s experiment the vagus nerves were left intact. Therefore, aortic nerves and possibly the afferents from the cardiopulmonary area must have attenuated the effect of sciatic nerve stimulation on AP. Further, the range of variations of AP in Ulmar’s studies was below 125 mmHg during the control period and below 140 mmHg during the sciatic pressor response. These values are considerably lower than those in our experiment and others (18, 19, 2 1) Within this range of AP, the heart would be able to maintain its output by the Frank-Starling’s mechanism despite the variation in the afterload in the sciatic pressor response (15). 2) In Ulmar’s analysis of the data, the gains before and during sciatic nerve stimulation were calculated over different ranges of ISP. Further, Ulmar fitted his data on the ISP-AP relationship to a single straight line, despite an obvious inflection in that relationship (e.g., at the ISP of around 100-I 10 mmHg in Fig. 1 of ref. 22). Since the ISP-AP relation was nonlinear, the gain should have been compared over the same ISP region before and during sciatic nerve stimulation. It has been known that stimulation of certain areas within the hypothalamus and mesencephalon elicits a pressor response (defense response: DR) which is accompanied by various autonomic reactions (l-3). Both DR and the sciatic pressor response (SW increase AP and elevate the equilibrium pressure; their modulatory efiects on the carotid sinus baroreceptor reflex may look similar
KUMADA,
NOGAMI,
AND
SAGAWA
comparison of the present in these respects. However, results with our previous findings (10, 12) reveals that the two modulations are quite different in the following aspects: 1) DR increases the gain of the reflex AP control at ISP’s between 150 and 240 mmHg, whereas SPR decreases the gain at ISP’s between 90 and 150 mmHg. 2) In DR, TPR is responsible for the modulation of the reflex AP control, whereas in SPR, CO is responsible for the modulation. 3) DR expands the operating range of the reflex AP response toward a higher ISP region, whereas SPR does not alter the operating range of the reflex control of AP. 4) In DR, the gain of the reflex HR control was increased, whereas in SPR, it was decreased. By virtue of the sigmoidal curve fitting with the data and an analysis of the characteristics of the fitted curve, we could define the pattern of the modulation of the carotid sinus baroreceptor reflex by sciatic nerve stimulation which is distinct from the modulation by the hypothalamic and mesencephalic defense mechanisms. Finally, the interaction between the sciatic pressor response and the carotid sinus baroreceptor reflex would take place under natural behavioral conditions. The SOmatic pressor response is elicited by stimulating the unmyelinated (or group 1V) component of the afferent nerve (7, 16). Possibly involved in the somatic pressor response are myelinated group 11 and 111 fibers of muscle and cutaneous afferents (17). Therefore, natural stimuli to nociceptors and possibly thermoreceptors will initiate the sciatic pressor response which modulates the reflex control of the cardiovascular system by the carotid sinus baroreceptor reflex in the manner disclosed by the present analysis.
HL
This investigation 14529, HL 15434,
Present address Osaka, Japan. Received
for
publication
of
was
supported
HL
16834, Nogami
and NS 03346. : KANEBO,
26 August
1974..
K.
by
Public
Health Ltd.,
Service
Grants
Miyakojimaku,
REFERENCES 1. ABRAHAMS, V. C., S. M. HILTON, AND A. ZBROZYNA. Active muscle vasodilation produced by stimulation of the brain stem: its significance in the defence reactions. J. Physiol., London 154: 491513, 1960. 2. ABRAHAMS, V. C., S. M. HILTON, AND A. ZBRO~YNA. The role of active muscle vasodilation in the alerting stage of the defence reaction. J. Physiol., London 171: 189-209, 1964. B. FOLKOW, P. H. KYLSTRA, B. LISANDER, 3. DJOJOSUGITO, A. M., AND R. S. TUT’~LE. Differentiated interaction between the hypothalamic defence reaction and baroreceptor reflexes. I. Effects on heart rate and regional ilow resistance. Acta PhysioL. &and. 78 : 376-385, 1970. 4. HEYMANS, C,, AND E. NEIL. Rt$exogen~c Areas of the Cardzovascular System. Boston: Little, Brown, 1958. 5. IRIUCHIJIMA, J., AND M. KUMADA, Efferent cardiac vagal discharge of the dog in response to electrical stimulation of sensory nerve. Japan. J. Physiol. 13 : 599-605, 1963. 6. IRIUCHIJIMA, J., AND M. KUMADA. Activity of single vagal fibers efferent to the heart. f@m. J. Physiol. 14 : 479-487, 1964. 7. J OHANSSON, B. Circulatory responses to stimulation of somatic afferents. Acta physiol. &and. 57, Suppl. 198 : l-91, 1962. 8. KATZ, S., AND J. H. PERRYMAN. Respiratory and blood pressure responses to stimulation of peripheral afferent nerves. Am. J. Physiol. 208 : 993-999, 1965.
9. KOIZWMI,
K., H. SELLER, A. KAUFMAN, AND C. McC, BROOKS. of sympathetic discharges and their relation to baroreand respiratory activities. Brain Res. 27: 281-294, 1971. 10. KUMADA, M., AND K. SAGAWA. Modulation of carotid sinus baroreceptor reflex by central gray stimulation. S. Physiol. Sot. Jufian 36: 147-148, 1974. 11. KUMADA, h/l., R. M. SCHMIDT, K. SAGAWA, AND K. S. TAN. Carotid sinus reflex in response to hemorrhage. Am. J. Pfzysiol. 219: 1373-1379, 1970. 12. KUMADA, h/l., I,. P. SCHRAMM, R. A. ALTMANSBERGER, AND K. SAGAWA. Modulation of carotid sinus baroreceptor reflex by hypothalamic defense response. Am. J. Physiol. 228 : 34-45, 1975. 13. KUNZS, D. L. Reflex discharge patterns of cardiac vagal efferent fibers. J. Physiol., London 222 : l-15, 1972. 14. QUEST, J. A., AND G, L. GEBBER. Modulation of baroreceptor reflexes by somatic afferent nerve stimulation. Am. J. Physio2. 222: 1251-1259, 1972. 15. SAGAWA, K. Analysis of the ventricular pumping capacity as a function of input and output pressure loads. In: Physical Basis of Circulatory T>ansport: Regulation and Exchange, edited by E. B. Reeve and A. C. Guyton. Philadelphia: Saunders, 1967, p. 141-149. 16. SATO, A. Spinal and medullary reflex components of the somatosympathetic reflex discharges evoked by stimulation of the group IV somatic afferent. Brain Res. 51: 307-318, 1973. Pattern ceptor
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
SCIATIC
NERVE
STIMULATION
17. SATO, A., AND R. F. SCHMIDT.
18.
19.
20.
AND
CAROTID
Somatosympathetic fibers, central pathways, discharge characteristics. 53: 916-947, 1973, SCHER, A. M., AND A. C. YOUNG. Servoanalysis reflex effects on peripheral resistance. Circulation 162, 1963. SCHMIDT, I
in U.S.A.
of carotid
Modulation b y sciatic MAMORU Department Department
KWMADA,
nerve KUMADA, of Neurology, of Biomedical
sinus
baroreceptw
stimulation KAZUO Laboratory Engineering,
NOGAMI,
AND KIICHI SAGAWA Cornell University Medical College, Nezv York City School of Medicine, Johns Hopkins University, Baltimore, Maryland
of Neurobiology,
MAMORU,
KAZUO NOGAMI, AND KII~HI SAGAWA. sinus baroreccptur rejhx by sciatic nerve stimulation. Am. J. Physiol. 228(5) : 1535-1541. 1975.-In anesthetized, immobilized, and vagotomized cats we analyzed the effect of sciatic nerve stimulation (SNS) on the relationships between intrasinus pressure (ISP) and arterial pressure (AP) and between ISP and heart rate (HR). At each of seven ISP levels between 60 and 240 mmHg, AP and HR before and 20 s after the onset of SNS were plotted against ISP to obtain the ISP-AP and ISP-HR relationships before and during SM. SNS caused increases in AP, HR, and total peripheral resistance (TPR) and a decrease in cardiac output (CO). SNS raised the equilibrium pressure (the value of AP at which AP equaled ISP), but it significantly (P < 0.005) decreased the slope (or gain) of the ISP-AP relationship at ISP’s between 90 and 150 mmHg. SNS also significantly (P < 0.05) diminished the gain of ISP-HR relationship at ISP’s between 120 and 210 mmI-Ig. Modulation of the gain of ISP-AP relationship was ascribable to that of CO but not of TPR. We
of carotid
Modulation
conclude tivity
that in vagotomized
of AP
and
HR
responses
reflex, and 2) the inhibition by modulation
of the reflex
arterial
pressure;
resistance;
gain;
cats I) SNS attenuates
the sensi-
in the
carotid sinus baroreceptor of the reflex AP response was caused CO response.
heart rate; cardiac equilibrium pressure
reflex
output;
total
peripheral
ELECTRICAL STIMULATION Of SOme Somatic afferent Ilel-veS with certain stimulus parameters elicits a rise in arterial pressure and tachycardia (7, 8, 14). Johansson (7) termed this response the somatic pressor response. There is evidence between the somatic pressor indicating the interaction response and the carotid sinus baroreceptor reflex. First, the sympathetic discharges evoked by stimulation of somatic afferents were inhibited by stimulation of the carotid sinus nerve (9), and the discharges of the cardiac parasympathetic nerve evoked by stimulation of the carotid sinus nerve were in turn eliminated by stimulation of the somatic efferents (5, 6). Second, Johansson (7) demonstrated that occlusion of the common carotid artery modified responses of the arterial pressure and renal resistance to somatic nerve stimulation. Such interactions are not surprising at all, since both somatic nerve stimulation and the baroreceptor reflex involve the sympathetic (4, 9) and cardiac parasympathetic nerves (5, 6, 14). In the present study we attempted to clarify quantitatively the modulatory eflect of sciatic nerve stimulation on the carotid sinus baroreceptor reflex. We analyzed,
10021;
and
21205
before and during sciatic nerve stimulation, the relations between isolated intrasinus pressure (BP; input) and various cardiovascular variables such as arterial pressure, heart rate, cardiac output, and total peripheral resistance. As in our previous study (1 Z), we characterized the modulatory effect of sciatic nerve stimulation in terms of two important quantities associated with the input-output relation of the carotid sinus baroreceptor reflex, i.e., the open-loop gain (abbreviated as “gain”) and the equilibrium pressure. The former is the slope of the curve relating isolated and controlled ISP to various cardiovascular variables. The latter is the value of arterial pressure at which arterial pressure equals ISP. To our knowledge, there has been only one study which analyzed the modulatory effect of sciatic nerve stimulation on the ISP-arterial pressure relationship (22). In this study, however, ISP was varied over a relatively narrow range (about 85-145 mmHg), and only the response of arterial pressure was investigated. We considered that a more extensive analysis was necessary to delineate quantitative aspects of the modulation. The central questions we attempted to answer may be summarized as follows: I) Does sciatic nerve stimulation modulate the control of arterial pressure by the carotid sinus baroreceptor reflex? If it does, how is the modulation characterized in terms of the input-output relation curve, gain, and equilibrium pressure? 2) Does sciatic nerve stimulation modulate the reflex control. of heart rate, cardiac output, and total peripheral resistance uniformly or differently? If it does in different manners, how are the modulations of those variables related to that of the reflex control of arterial pressure? We are aware that sciatic nerve stimulation can cause either a pressor or a depressor response, depending on stimulation parameters (7). In this paper, however, sciatic nerve stimulation denotes, unless otherwise specified, only such stimulation that elicits a pressor response. Likewise, the sciatic pressor response signifies a pressor response on stimulating the sciatic nerve, METHODS
Animals and anesthesia. Results were obtained from 27 adult cats of either sex weighing between 2 and 4 kg. The animal was anesthetized by an intravenous injection of alpha-chloralose (60 mg/kg) and urethan (500 mg/kg) after induction with chloroform. After tracheal cannula1535
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
1536 tion, the animal was immobilized with intraperitoneal injection of Flaxedil (20 mg initial dose) and placed on positive-pressure respiration. The vagus nerves were severed in the neck so that the compensatory effect of the aortic baroreceptor reflex and the potential complications medireceptors could be elimiated by other cardiopulmonary nated. Isolation of carotid sinus. With the method detailed in our previous paper (1 l), the right and left carotid sinuses were isolated by ligating the internal carotid and occipital arteries and all other visible vessels. Lingual arteries were cannulated and connected to a servo-controlled pressure sou rce. In order to assure supply of the arterial blood to the carotid sinuses when the experi ment was not being conducted, the external and common carotid arteries were occluded with bulldog clamps only during the experimental ITIll.
Measurements of cardiovascular variables. The following variables were measured : phasic and mean cardiovascular arterial pressures (AP’s), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR). Phasic and mean AP’s were measured from the femoral artery. HR was determined by a tachometer triggered by the AP pulse CO (minus coronary flow) was measured via an electromagnetic flow transducer attached to the root of the ascending aorta after thoracotomy. The transducer (Narco BioSystems, Inc., C series) was connected with an electroflowmeter (Narco Physiometric Electromagnetic magnetic Flowmeter System). To assure a correct zero base line for the CO signal, the phasic flow signal was continuously displayed on an oscilloscope and was manually adjusted such that the Aow signal during the diastolic period would correspond to electrical zero. TPR was calculated as AP/CO by an analog divider circuit and recorded with ISP, AP’s, HR, and CO on a chart recorder (Fig. 1). Sciatic nerve stimulation. Either right or left sciatic nerve was exposed near the hip joint and cut, and one of the several nerve strand .s surround ed by a common sheath was separated from the whole nerve trunk. The central cut end of the separated nerve strand was further unsheathed, placed on a pair of platinum wire electrodes, and maintained in a pool of warmed paraffin oil enclosed by a skin flap. The nerve was stimulated by a 20-s train of rectangular pulses, having a frequency of 70 Hz and a duration of 2 ms, delivered by a constant-current stimulator (Nuclear-Chicago model 7 15O)* The stimulating current was adjusted such that, when the carotid sinus was communicating with the systemic artery, the sciatic pressor response would be between 10 and 70 mmHg (usually between 10 and 250 ~-IA). Experimental design. In every experimental run, ISP was varied between 60 and 240 mmHg in steps of 30 mmHg. At each ISP the sciatic nerve was stimulated for 20 s, since all the cardiovascular variables observed in this study reached new steady states within this length of time (Fig. 1). The relationship between isolated and controlled IS9 (input) and each cardiovascular variable (output) was determined 5 s before and 20 s after the onset of sciatic nerve stimulation. Modulatory effect of sciatic nerve stimulation on the carotid sinus baroreceptor reflex was characterized by alterations of the input-output relations by nerve stimulation.
Usually more than one experimental run was conducted on an individual cat. All the data from repeated runs within a single animal were averaged to obtain a pair of inputoutput relationships for each cardiovascular variable, one before and another during sciatic nerve stimulation. The averaged data were then used for the statistical analysis of the difference before and during sciatic nerve stimulation* The data on CO and TPR were expressed in each experimental run as the percent of those values when ISP was set at 60 mmHg and the sciatic nerve was not stimulated. REStiLTS
Pattern of curdiovuscular responses to sciatic nerve stimuhtion. The rise in arterial pressure following the 20-s stimulation of the sciatic nerve was associated with increases in TPR and HR (Fig. 1) CO usually decreased during sciatic nerve stimulation at ISP’s between 60 and 150 mmHg, but remained unchanged at BP’s above that range. These cardiovascular variables reached new steady levels within 20 s after the onset of sciatic nerve stimulation. Modulation of reflex control of urterialpressura. At each of seven fixed ISP’s between 60 and 240 mmHg, an elevation of AP was brought about by sciatic nerve stimulation However, the magnitude of the pressor response was dependent on ISP. As ISP was set to 90, 120, and then to 150 mmHg, the elevation became gradually increased, whereas at ISP’s above 150 mmHg, the elevation remained virtually the same (Fig. 2, A and B). Because of this dependency of the pressor response on ISP, the slope or the gain of the ISP-AP relation was significantly decreased (Y < 0.005) by sciatic nerve stimulation over the ISP region between 90 and 150 mmHg (Fig. 2C). On the other hand, the gain was not significantly altered at ISP’s between 150 and 240 mmHg. It is thus concluded that, over the ISP range between 90 and 150 mmHg, sciatic nerve stimulation inhibited the control of AP by the carotid sinus baroreceptor reflex. We have previously demonstrated (12) that the ISP-AP relationship could be approximated by a sigmoid curve. In order to analyze more quantitatively the modulatory effects of the sciatic nerve stimulation on the reflex control of AP, we calculated the best-fit sigmoid curve for the ISP-AP relation of Fig. 2A by the method detailed elsewhere (12). The mean square error between the observed data and the best-fit curve was 1 mmHg before and during sciatic nerve stimulationWe then calculated, as in our previous study (1 Z), the following values (characteristic values) that characterized the best-fit curve: a) the maximum reflex gain (the maximum value of the slope of the fitted ISP-AP curve), b) peak ISP (ISP at which the maximum gain was attained), c) threshold ISP (arbitrarily defined as an ISP in the left half of the ISP-gain curve at which the gain decreased to 5 % of the maximum value), d) saturation ISP (arbitrarily defined as an ISP in the right half of the ISP-gain curve at which the gain decreased to 5 % of the maximum value), e) maximum and minimum AP’s (estimated by extrapolating ISP to low and high extremes, respectively), f) range of’ISP-dependent AP (difference between maximum and minimum AP’s), and g) equilibrium pressure (see second introductory paragraph for definition).
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
SCIATIC
NERVE
STIMULATION
AZ\JD
A
B
CAROTID
SINUS
c
REFLEX
D
1537
E
F
G
480
lntrasinus pressure (mm Hgl
--_-
- ----
0
Arterial pressure (mm Hgl
r”
dAdI/rI,I,,, FIG. 1. Cardiovascular responses to sciatic nerve stimulation. Right sciatic nerve was stimulated for 20 s as indicated by a thick line in 7th tracing from top. Amplitude of pulse was 40 PA, duration 2 ms, and the frequency 70 Hz. ISP was maintained at 60 mmHg in A, 90 mmHg in B, 120 mmHg in C, 150 mmHg in D, 180 mmHg in E, 2 10 mmHg in 12, and 240 mmHg in G. Sample records were arranged in sequential order. CO (5th tracing from top) was obtained by passing ascending aortic flow signal (4th tracing from top) through a low-pass filter with a time constant of 1 s.
Ii 0
Mean AP (mm Hg)
Ascending n-
Cardiac
output
-
-
-
--
-
O-
JotaI peripheral resistance
--a
/f--l
-a-
O-me
Sciatic stimulation
--F
-__I
_--I
I 30 set
120 240 17
Heart rate (beats I mi nl
------
TABLE 1. charac~er~dc uahes during control jxriod and during I) LP-AP relationshljl of Fig. between LW and gain of ‘rejlex
0.8 j
]
j
\
!
60
90
120
150
180
1
1
210
240
a r/l Q, 0.6 F
90 120 INTRASINUS
ml 150 -- 180 -' 210 PRESSURE (mm Hg)
-60>O INTRASINUS
PRESSURE
(mm
Hg)
2. Relationship between ISP (abscissa) and ,AP (A) or gain of reflex control of AP (C) before and during sciatic nerve stimulation (ordinate). Relationship between ISP and difference in AP between control value and value during sciatic nerve stimulation is shown by B. In this and subsequent figures, solid line connecting the filled circles represents relationship during prestimulus period, whereas broken line connecting open circles represents relationship at end of 20-s stimulation of sciatic nerve. Data were obtained from 27 cats and mean and standard error of mean were plotted in ordinate. In this and subsequent figures, asterisks attached on upper right corner of open circles signify that difference between control value during stimulation is statistically significant (P < 0.05).
__
,__
-. - -
M.aximum gain Peak ISP, mmHg Threshold ISP, mmHg Saturation ISP, mmHg Maximum AP, mmHg Minimum AP, mmHg Range of ISP-dependent AP, mmI-Ig Equilibrium pressure, mmHg - .- _...-.___ _.- - --For definition of characteristic
Of the fdow~ng kuo curues scialic nerve stimulation. ZA, and 2) relationship AP control of Fig. 2C Control
-- ------~-
Sciatic Nerve
Stimulation --
0.81 139 41 236 164 83 81
0.62 141 40 242 190 125 65
130
151
value,
see text.
FIG.
As summarized in Table 1, the following results were obtained from the fitted curve. I) Sciatic nerve stimulation elevated the equilibrium pressure from 130 to 151 mrnHg, 2) Maximum and Ininimuln AP’s were both increased by However, the increase in the sciatic nerve stimulation. minimum AP was greater than that in the maximum AP (42 VS~ 26 mmHg). As a consequence, the range of ISP-
dependent AP was diminished by sciatic nerve stimulation (from 81 to 65 mmHg). 3) The maximum gain was diminished by sciatic nerve stimulation from 0.80 to 0.62 changes in the (a 23 % fali). 4) Th ere were no marked peak ISP, saturation ISP, and threshold ISP. sciatic nerve stimulation elevated the In summary, equilibrium pressure and decreased the gain of the ISP-AP relation over the ISP range between 90 and 150 mmHg. Application of the curve litting to the experimental data further indicated that sciatic nerve stimulation elevated the maximum and minimum AP’s, but narrowed the range of ISP-dependent AP, Modulation of reflex confrol ojr heart rate. At every ISP examined, the sciatic pressor response was attended by tachycardia (Fig. 1 and 4A). Since the vagus nerves had been severed in the preparation, this tachycardia was mediated by the sympathoadrenergic c system. The tachycardia at
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
1538
KUMADA,
various ISP’s was not uniform but was greater at higher BP’s (Fig. 4, A and B). Thus, the gain of the ISP-HR relationship was significantly diminished over the ISP region between 120 and 210 mmHg (P < 0.05, Fig. 4C). It was thus demonstrated that sciatic nerve stimulation inhibited the reflex control of HR as part of the reflex control of AP. The same curve-fitting method used for AP was applied to the ISP-HR relationship of Fig. 4A and the relationship between ISP and the gain of reflex HR control shown by Fig. 4-C. As illustrated by Fig. 5A, the mean square error between the best-fit curve and the experimental data was 0 beat/min during the control period and 1 beat/min during sciatic nerve stimulation. As summarized in Table 2, sciatic nerve stimulation raised the minimum HR from 2 17 to 228 beats/min while maintaining the maximum HR virtually the same (234 vs. 236 beats/min). Therefore, the range of ISP-dependent HR was narrowed by sciatic nerve stimulation (from 17 to 8 beats/min). It was also found that sciatic nerve stimulation shifted the threshold ISP toward a higher ISP region (from 50 to 78 mmHg) and the saturation ISP toward the opposite direction (from 277 to 235 mmHg). In other words, sciatic nerve stimulation narrowed the range of ISP over which the reflex control of HR was These characteristic values derived from the operative. curve fitting again demonstrated that sciatic nerve stimulation inhibited the reflex control of HR. 20ar
*
NOGAMI,
l
230
3. Best-fit curve for ISP-AP between ISP and gain of reflex legend to Fig. 2 for explanation figure.
FIG.
tion See this
B
r
240
PRESStiRE
Imt;~ I@)
2
0.15
---
c ‘F -.g
0.10
---
0 l
2i u
relation of Fig. control of AP of closed and
SAGAWA
Modulation of reflex controlof cardiac output and total peripheral resistance. In this series of experiments in 10 cats, modulation of the reflex control of AP was correlated to those of CO and TPR. These 10 experiments could be considered as since sciatic nerve stimulation raised the representative, equilibrium pressure and decreased the gain of the ISP-AP relationship at ISP’s between 90 and 150 mmHg (Fig. 6, A and C). Sciatic nerve stimulation brought about an increase in TPR at every ISP examined and a decrease in CO at BP’s between 60 and 150 mmHg (Fig* 6, D, E, G, and H). Thus, the rise in the equilibrium pressure on sciatic nerve stimulation was exclusively the result of an increase in TPR. However, as shown below, the decrease in the gain of the reflex AP control was the result of a change in the CO response. Before sciatic nerve stimulation, CO remained virtually the same, as ISP was altered between 60 and 240 mmHg (Fig. 6G). Th e g ain of the reflex CO response was thus near zero (Fig. 61). Sciatic nerve stimulation diminished CO at BP’s between 60 and 150 mmHg, but the decrease in CO was attenuated as ISP was increased (Fig. 6H)* Consequently, the BP-CO relation during sciatic nerve stimulation showed that CO increased wi;h ISP (Fig. 6G). The average gain of the reflex CO control was thus significantly altered (P < 0.025) by sciatic nerve stimulation at ISP’s between 90 and 150 mmHg, and this alteration contributed to the decrease in the gain of the reflex AP control. On the other hand, the gain of the reflex TPR response within the same ISP range was not significantly altered (P < 0.4) by sciatic nerve stimulation. In summary, the elevation of the equilibrium pressure 0.20
INTRASINUS
AND
/
_
60
90
120
150
180
210
240
INTRASIWIS
FIG. 5. Best-fit tion between ISP See legend to Fig. figure.
curve for ISP-HR and gain of reflex 2 for explanation
0
”
l
l \
\
\
:/
\
::;
0
120
l
\ A,
/’ ,4’
60 90 PRESSURE (mm HgI
relation control of closed
\
// ,’
z 0.05 --. 3
2A (A) or relaof Fig. 2C (B). open circles in
I--,
\
\
I
’
h,
150
180
210
of Fig. 4A (A) of HR of Fig. and open circles
1
240
or rela4C (B). in this
2. Characteristic values Of the following two curves during control period and during sciatic nerve stimulation. I) LW-HR relationship of Fig. 4A, and 2) relationship between ISP and gain of reflex HR control of Fig.4 C TABLE
L210LI
12
a
60
1 90
1 120
] 150
0 180
210
, 240
0.20 I --
1
c
B
--lo-r 90
120
INTAASINUS
150
180
210
PRES SURE (mm Hg)
Control
240
60
120
150
I~TRASINUSPRESSURE
1x0
210 '-240 (mm~g)
FIG. 4. ISP-HR relation (A) and relation between ISP and gain of reflex control of HR (C) before (a) and after 20 s of sciatic nerve stimulation (0). Relationship between ISP and difference in HR between control value and value during sciatic nerve stimulation is shown in B. Mean and SE of 16 sets of experimental data are shown.
Maximum gain, beats/min mmHg Peak ISP, mmHg Threshold ISP, mmHg Saturation ISP, mmHg Maximum HR, beats/min Minimum HR, beats/min Range of ISP-dependent beats/min
per
HR,
0.14 156 50 277 234 217 17
Sciatic
Nerve
Stimulation
0.09 163 78 235 236 228 8
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
SCIATIC
NERVE
STIMULATION
AND
1
1
I
I
I
I
1
60
90
120
150
180
210
240
CAROTID
e
SINUS
0
LL60
1539
REFLEX
1 120I 150I 180I 210I
90
1
240
s z-
,’ pv-L
-* .
90
120
150
180
210
240
t
60
90
120
150
180
210
240
120
150
180
210
240
120
150
180
210
240
F
I
60
90
I
120
I
1
I
1
,150
180
210
240
1
I
I
I
1
60
90
120
150
180
INTRASINUS
6. Relationships between ISP and following variables: AP or CO (G) and gain of reflex control of AP (C), TPR TPR m or CO (I). Illustration B, J3, or H denotes, respectively, relation-
FIG.
(4, (F),
by sciatic nerve stimulation was attributable to the response of TPR, whereas the decrease in the gain of the reflex AP control was the result of the modified response of CO. DXSCUSSIQN
The present study demonstrated an inhibitory effect of sciatic nerve stimulation on the reflex control of AP and HR. The inhibition of the reflex AP response was seen over the ISP range between 90 and 150 mmHg and was due to the alteration in the ISP-CO relation. Within the same ISP changes were found in the gain of range, no significant the reflex TPR control. Thus, the different behavior of CO before and during sciatic nerve stimulation was the key factor in the modulation of the reflex AP response. Sciatic nerve stimulation significantly diminished CO at BP’s between 60 and 150 mmHg. This decrease in CO appears to be a result of an increased afterload on the left ventricle (i.e., aortic pressure) rather than diminished cardiac contractility, since I) the decrease in CO by sciatic nerve stimulation was attenuated as AP was decreased on elevating ISP, and 2) a concomitant increase in HR indicates an enhanced activity of the cardiac sympathetic nerve and/or adrenal secretion, both of which should augment the cardiac contractility. In the isolated and supthe aortic pressure ported heart of the cat, increasing
PRESSURE
I
210
t
240
60
90
(mmlig)
ship between ISP and difference in AP, TPR, or CO between control value and value during sciatic nerve stimulation. l , 0 Variables before and after 20 s of sciatic nerve stimulation, respectively.
approximately above 150 mmHg resulted in a decrease in CO (20). In our preparation, in which the sympathoadrenal system was intact, a decrease in CO was observed when AP exceeded around 150-l 75 mmHg (Fig. 6G). However, for the following reason, a neural mechanism was also likely to be involved in the modulation of the BP-CO relationship by sciatic nerve stimulation. As mentioned earlier, inhibition was present in the reflex HR response. Since vagus nerves were severed in the preparation, the observed inhibition must be due to a modulation in the HR control through the sympathoadrenal system. It may be that the sensitivity of the cardiac sympathetic nerve to a change in the carotid sinus afferent signals was reduced during sciatic nerve stimulation. In this series of experiments, the efferent cardiac parasympathetic nerve was eliminated as a result of bilateral cervical vagotomy. It is unlikely, however, that the lack of the efferent cardiac parasympathetic nerve would significantly affect the modulatory effect of sciatic nerve stimulation on the reflex AP control at BP’s between 90 and 150 mmHg. In cats anesthetized by chloralose and urethan, Kunze (13) demonstrated that the efferent cardiac parasympathetic fibers were silent when AP (Le., input to carotid sinus and aortic arch baroreceptors) was below 140-150 mmHg. c In other words, at ISP’s below 140-150
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
1540 mmHg, the efferent cardiac parasympathetic fibers would not participate in the carotid sinus baroreceptor reflex. Thus, at ISP’s between 90 and 150 mmHg, the presence or absence of the efferent cardiac parasympathetic nerve would not make significant difference as far as the reflex control of AP, CO, and TPR is concerned. In a series of experiments in seven dogs, Ulmar (22) did not find a significant change in the slope of the ISP-AP relationship on stimulating the sciatic nerve. There are two possible explanations on the discrepancies between Ulmar’s results and our studies: I) in Ulmar’s experiment the vagus nerves were left intact. Therefore, aortic nerves and possibly the afferents from the cardiopulmonary area must have attenuated the effect of sciatic nerve stimulation on AP. Further, the range of variations of AP in Ulmar’s studies was below 125 mmHg during the control period and below 140 mmHg during the sciatic pressor response. These values are considerably lower than those in our experiment and others (18, 19, 2 1) Within this range of AP, the heart would be able to maintain its output by the Frank-Starling’s mechanism despite the variation in the afterload in the sciatic pressor response (15). 2) In Ulmar’s analysis of the data, the gains before and during sciatic nerve stimulation were calculated over different ranges of ISP. Further, Ulmar fitted his data on the ISP-AP relationship to a single straight line, despite an obvious inflection in that relationship (e.g., at the ISP of around 100-I 10 mmHg in Fig. 1 of ref. 22). Since the ISP-AP relation was nonlinear, the gain should have been compared over the same ISP region before and during sciatic nerve stimulation. It has been known that stimulation of certain areas within the hypothalamus and mesencephalon elicits a pressor response (defense response: DR) which is accompanied by various autonomic reactions (l-3). Both DR and the sciatic pressor response (SW increase AP and elevate the equilibrium pressure; their modulatory efiects on the carotid sinus baroreceptor reflex may look similar
KUMADA,
NOGAMI,
AND
SAGAWA
comparison of the present in these respects. However, results with our previous findings (10, 12) reveals that the two modulations are quite different in the following aspects: 1) DR increases the gain of the reflex AP control at ISP’s between 150 and 240 mmHg, whereas SPR decreases the gain at ISP’s between 90 and 150 mmHg. 2) In DR, TPR is responsible for the modulation of the reflex AP control, whereas in SPR, CO is responsible for the modulation. 3) DR expands the operating range of the reflex AP response toward a higher ISP region, whereas SPR does not alter the operating range of the reflex control of AP. 4) In DR, the gain of the reflex HR control was increased, whereas in SPR, it was decreased. By virtue of the sigmoidal curve fitting with the data and an analysis of the characteristics of the fitted curve, we could define the pattern of the modulation of the carotid sinus baroreceptor reflex by sciatic nerve stimulation which is distinct from the modulation by the hypothalamic and mesencephalic defense mechanisms. Finally, the interaction between the sciatic pressor response and the carotid sinus baroreceptor reflex would take place under natural behavioral conditions. The SOmatic pressor response is elicited by stimulating the unmyelinated (or group 1V) component of the afferent nerve (7, 16). Possibly involved in the somatic pressor response are myelinated group 11 and 111 fibers of muscle and cutaneous afferents (17). Therefore, natural stimuli to nociceptors and possibly thermoreceptors will initiate the sciatic pressor response which modulates the reflex control of the cardiovascular system by the carotid sinus baroreceptor reflex in the manner disclosed by the present analysis.
HL
This investigation 14529, HL 15434,
Present address Osaka, Japan. Received
for
publication
of
was
supported
HL
16834, Nogami
and NS 03346. : KANEBO,
26 August
1974..
K.
by
Public
Health Ltd.,
Service
Grants
Miyakojimaku,
REFERENCES 1. ABRAHAMS, V. C., S. M. HILTON, AND A. ZBROZYNA. Active muscle vasodilation produced by stimulation of the brain stem: its significance in the defence reactions. J. Physiol., London 154: 491513, 1960. 2. ABRAHAMS, V. C., S. M. HILTON, AND A. ZBRO~YNA. The role of active muscle vasodilation in the alerting stage of the defence reaction. J. Physiol., London 171: 189-209, 1964. B. FOLKOW, P. H. KYLSTRA, B. LISANDER, 3. DJOJOSUGITO, A. M., AND R. S. TUT’~LE. Differentiated interaction between the hypothalamic defence reaction and baroreceptor reflexes. I. Effects on heart rate and regional ilow resistance. Acta PhysioL. &and. 78 : 376-385, 1970. 4. HEYMANS, C,, AND E. NEIL. Rt$exogen~c Areas of the Cardzovascular System. Boston: Little, Brown, 1958. 5. IRIUCHIJIMA, J., AND M. KUMADA, Efferent cardiac vagal discharge of the dog in response to electrical stimulation of sensory nerve. Japan. J. Physiol. 13 : 599-605, 1963. 6. IRIUCHIJIMA, J., AND M. KUMADA. Activity of single vagal fibers efferent to the heart. f@m. J. Physiol. 14 : 479-487, 1964. 7. J OHANSSON, B. Circulatory responses to stimulation of somatic afferents. Acta physiol. &and. 57, Suppl. 198 : l-91, 1962. 8. KATZ, S., AND J. H. PERRYMAN. Respiratory and blood pressure responses to stimulation of peripheral afferent nerves. Am. J. Physiol. 208 : 993-999, 1965.
9. KOIZWMI,
K., H. SELLER, A. KAUFMAN, AND C. McC, BROOKS. of sympathetic discharges and their relation to baroreand respiratory activities. Brain Res. 27: 281-294, 1971. 10. KUMADA, M., AND K. SAGAWA. Modulation of carotid sinus baroreceptor reflex by central gray stimulation. S. Physiol. Sot. Jufian 36: 147-148, 1974. 11. KUMADA, h/l., R. M. SCHMIDT, K. SAGAWA, AND K. S. TAN. Carotid sinus reflex in response to hemorrhage. Am. J. Pfzysiol. 219: 1373-1379, 1970. 12. KUMADA, h/l., I,. P. SCHRAMM, R. A. ALTMANSBERGER, AND K. SAGAWA. Modulation of carotid sinus baroreceptor reflex by hypothalamic defense response. Am. J. Physiol. 228 : 34-45, 1975. 13. KUNZS, D. L. Reflex discharge patterns of cardiac vagal efferent fibers. J. Physiol., London 222 : l-15, 1972. 14. QUEST, J. A., AND G, L. GEBBER. Modulation of baroreceptor reflexes by somatic afferent nerve stimulation. Am. J. Physio2. 222: 1251-1259, 1972. 15. SAGAWA, K. Analysis of the ventricular pumping capacity as a function of input and output pressure loads. In: Physical Basis of Circulatory T>ansport: Regulation and Exchange, edited by E. B. Reeve and A. C. Guyton. Philadelphia: Saunders, 1967, p. 141-149. 16. SATO, A. Spinal and medullary reflex components of the somatosympathetic reflex discharges evoked by stimulation of the group IV somatic afferent. Brain Res. 51: 307-318, 1973. Pattern ceptor
Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
SCIATIC
NERVE
STIMULATION
17. SATO, A., AND R. F. SCHMIDT.
18.
19.
20.
AND
CAROTID
Somatosympathetic fibers, central pathways, discharge characteristics. 53: 916-947, 1973, SCHER, A. M., AND A. C. YOUNG. Servoanalysis reflex effects on peripheral resistance. Circulation 162, 1963. SCHMIDT, I
