Download Spinal Sympathetic Cardiocardiac Reflexes

Spinal Sympathetic Cardiocardiac
Reflexes
By Alberto Malliani, D. Fred Peterson, Vernon S. Bishop,
and Arthur M. Brown
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
ABSTRACT
We studied the reflex changes in myocardial contractility elicited by
electrical stimulation of afferent cardiac sympathetic nerve fibers or chemical
stimulation of their cardiac endings. Veratridine injected directly into the left
coronary artery was the chemical stimulus. The maximum rate of rise of left
ventricular pressure, dP/dt max, was used as an index of myocardial
contractility. The stimuli evoked increases in dP/dt max in vagotomized cats
with or without spinal transection (Cl). Electrical stimulation provoked the
same effect in vagotomized dogs. Increases in dP/dt max occurred which were
independent of changes in heart rate, preload, or afterload. They were reflex in
nature since they were abolished by section of the upper thoracic sympathetic
rami or cardiac sympathetic nerves. These results are the first demonstration of
a cardiocardiac reflex which can be mediated entirely by the spinal cord.
Electrical stimulation in vagotomized cats and dogs also produced a reflex
increase in arterial blood pressure partly due to sympathetic vasoconstriction.
KEY WORDS
dP/dt max
cardiac sympathetic nerves
afterload
coronary circulation
• We have previously presented electrophysiological evidence that stimuli restricted
to the heart, such as transient changes in
coronary blood flow or pressure, produce
sympathetic reflexes mediated solely by the
spinal cord (1, 2). Even though the sympathetic nerves from which we recorded are known
to contribute substantially to the efferent
innervation of the heart (3, 4 ) , reflex changes
in heart rate or systemic arterial blood
pressure were not identified. Despite this, it
seemed possible that another index of cardiac
performance which was not measured, namely
myocardial contractility, might be reflexly
myocardial contractility
heart rate
spinal cardiac reflexes
preload
veratridine
cats
dogs
altered. The purpose of the present experiments was to determine if such an alteration
could occur. Changes in coronary flow or
pressure were not used as stimuli since these
events can directly affect myocardial contractility (5, 6). Instead, we resorted to electrical
stimulation of afferent sympathetic fibers
arising from the heart or to chemical stimulation of their endings in the heart. We found
that such stimulation elicited a reflex increase
in myocardial contractility due to a cardiocardiac reflex which could be integrated entirely
by the spinal cord.
Methods
EXPERIMENTS IN CATS
From the Departments of Physiology and Medicine,
University of Utah, Salt Lake City, Utah 84112, the
Department of Pharmacology, University of Texas,
San Antonio, Texas 78229, and Istituto di Ricerche
Cardiovascolari, Universita di Milano, Centra
Ricerche Cardiovascolari, C.N.R., 20122 Milano,
Italy.
This work was supported by U. S. Public Health
Service Grants IROI HE 10977-05, HE 13480-01, and
HE 12415-01, and C.N.R. Dr. Brown is an
Established Investigator of the American Heart
Association.
Received September 17, 1971. Accepted for
publication November 23, 1971.
158
Thirty cats were anesthetized by intraperitoneal injection of pentobarbital sodium,
35 mg/kg. The trachea was cannulated and
positive pressure respiration was begun. The
pump was set so as to provide an arterial Pco2 of
30-35 mm Hg, which is normal for cats in Salt
Lake City (elevation 4,200 feet) (2). The animals
were paralyzed with gallamine triethiodide
(Flaxedil), 2 mg/kg. 1 Bilateral cervical vagoto1
The guidelines of the American Physiological
Society regarding anesthetized, curarized animals
were adhered to.
Circulation Research, Vol. XXX, February 1972
159
SPINAL CARDIOCARDIAC REFLEXES
2000
80
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
I min
0.2 sec
FIGURE 1
Effects of stimulating afferent cardiac sympathetic
nerve fibers in vagotomized cats. A: On the left at
faster paper speed are, from top to bottom, control
records of dP/dt (mm Hg/sec), left ventricular pressure measured simultaneously with the tip-transducer
and the catheter-manometer systems (mm Ug, calibration for catheter-manometer system only), aortic
pressure (mm Hg), and ECG. The tip-transducer trace
has a faster rise time and, on the tape playback, more
amplification than the catheter-manometer trace. See
text for fuller discussion of the left ventricular pressure traces. On the right, at slower paper speed,
the tip-transducer pressure has been omitted for
simplification. Nerve stimulation is indicated by the
artifact on the ECC record. B: Same as A except
the inferior cardiac nerve was cut. Nerve stimulation
did not change dP/dt max.
mies were done in each experiment. In 15
experiments, the spinal cord was transected at
CL
Pressure Measurements.—The chest was opened
through a transverse incision in the fifth
left interspace, and the upper four to five ribs
were removed. An incision was made in the left
atrial appendage and a saline-filled catheter with
a strain gauge in its tip (Statham SF1) was
Circulation Research, Vol. XXX, February 1972
introduced into the atrium and passed forward
into the left ventricle. This catheter was
connected to a Statham P23dB manometer. The
tip transducer had a frequency response extending to 2 kHz (7), whereas the cathetermanometer system had a damping ratio of 0.20
and a flat ( ± 5%) frequency response of 7-10 Hz
as calculated by the response to a step input of
pressure (8). The tip transducer drifted slowly in
an unpredictable manner throughout the experiment, although its sensitivity was unchanged.
Therefore, absolute pressure values were obtained
from the catheter-manometer system. In some
experiments, a short length (about 8 cm) of stiff,
wide-bore polyethylene tubing connected to a
Statham P23dB manometer was inserted into the
left ventricle, the root of the aorta, or both. This
catheter-manometer system had a damping ratio
of 0.25 and a flat (±5%) frequency response of
60-75 Hz (8). It gave values of left ventricular
end-diastolic pressure that were identical to those
obtained using the system with the lower
frequency response.
The output of the tip transducer was differentiated to give the maximum rate of rise of left
ventricular pressure, dP/dt max, by a passive RC
network with a time constant of 1 msec. The
differentiator was linear over a range of frequencies of 1 to 500 Hz.
One polyethylene catheter was inserted into a
femoral vein, and another was inserted into a
femoral artery and passed retrograde to the aorta.
The latter was connected to a Statham P23dB
manometer, and the catheter-manometer system
had a flat (±5%) frequency response of 15-20
Hz.
All pressures and the ECG were recorded on a
Honeywell 1508 Visicorder and an Ampex FR
1300 tape recorder.
Pressures and heart rates were measured for
10-20 cardiac cycles during control experiments,
and maximum responses and average values were
calculated.
Nerve Stimulation.—Small branches of nerves
which arose from the heart and projected to the
left stellate ganglion were dissected and cut, care
being taken to preserve the inferior cardiac nerve
(Fig. 1 of ref. 9). A Grass S4 stimulator was used
to stimulate the central end of one of the cut
nerves. The pulses were generally 5—10 v, 2-5
msec at a frequency of 15 Hz. The peripheral cut
end of the nerve was also stimulated, and in all
cases dP/dt max was increased, indicating that
the nerve ran to the heart.
Nerve Recording.—Efferent nervous discharge
was recorded from single units in filaments
dissected out of the third left thoracic ramus
communicans. The methods of recording have
been described (2).
MALLIANI, PETERSON, BISHOP, BROWN
160
TABLE
Effects of Sliviulaling Afferent Cardiac Sympathetic Fibers and Their Cardiac Endings in the Cat
Group
No. cats
1
2
3
3
2
2
5
5
3
4
5
6
No. trials
9
5
7
3
6
5
„ , Control
1692
1530
2182
2030
1586
1170
±
±
±
±
±
±
54
28
87
288
209
248
dP/dt max (mm Hg/sec)
Stimulated
1935 ± 84
1580 ± 41
2401 ± 131
2032 ± 291
2008 ± 253
1180 =•= 251
Mean^difference
243
50
219
2
422
10
± 72*
± 16
± 66*
± 3
± 94*
± 6
Control
AoSP (mm Hg)
Stimulate
163 *t 11
159 =it 14
123 =i>= 8
113 ± 3
90 =i= 7
7 6 =>
=
8
167 =•= 1'
161 ± 1
126 =<= 8
112 =fc 1
97 =»= 8
77 =t 7
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
Group 1 = electrical stimulation of afferent cardiac sympathetic fibers in vagotomized cats; group 3 = electrical stimul
tion of afferent cardiac sympathetic fibers in spinal vagotomized cats; group 5 = intracoronary injection of veratridine (1/ig) in spinal vagotomized cats; groups 2, 4, and 6 are repetitions of groups 1, 3, and 5, respectively, but in group 2 the 1<
inferior cardiac nerve was sectioned and in groups 4 and 6 T1-T4 left rami were cut. AoSP = aortic systolic pressure; Aol
aortic diastolic pressure; LVP = left ventricular pressure; LVEDP = left ventricular end-diastolic pressure; dP/dt max
maximum rate of rise of left ventricular pressure. Values are means =*= SE. Measurements in the columns labeled Stimulat
were made when dP/dt max was clearly increased.
•P < 0.005.
Coronary Perfusion.—The main left coronary
artery was perfused according to the method of
Brown (10). Veratridine, 1-10 fig in 0.1-0.2 ml
of saline, was injected into the perfusion tubing
using a calibrated Hamilton microsyringe (eight
experiments). Similar injections were made into
the root of the aorta and femoral vein.
EXPERIMENTS IN DOGS
Thoracotomies were performed on 12 mongrel
dogs, weighing 18-27 kg, anesthetized with
sodium pentobarbital, 30 mg/kg. Bilateral cervical vagotomies were performed in each experiment. A stab incision was made through the
anterior wall of the left ventricle and a
sonomicrometer was implanted across the greatest
internal transverse diameter of the left ventricle.
The sonomicrometer has a theoretical resolution
of 0.25 wavelengths which corresponds to 0.07
mm at 5 X 106 Hz. The frequency response of 20
Hz is more than adequate (11, 12).
Through a second incision in the anterior left
ventricular wall approximately 2 cm above the
apex, a Microsystems model 1017 solid-state
pressure transducer was also implanted within the
left ventricle. These gauges have a natural
frequency in excess of 3 kHz (13). Changes in
sensitivity in vitro and in vivo were negligible but
some zero drift could occur. The zero drift was
corrected by setting the left ventricular enddiastolic pressure equal to the left atrial pressure
at the beginning of each experiment. This latter
pressure was measured using a polyvinyl catheter
inserted into the left atrium through the left atrial
appendage. The catheter was connected with a
Statham P23dB manometer. Arterial pressure was
measured through a catheter in the aorta
connected to a Statham P23G6 manometer. The
frequency response of these two catheter-manometer systems was better than 30 Hz.
Aortic flow was measured with an electromagnetic flow probe (Zepeda Instruments) placed
around the ascending aorta. The late diastolic
level of aortic flow was used as the zero-flow
reference point. Flow probes were calibrated in
vitro prior to implantation, and subsequently the
calibration was verified at autopsy; in all cases the
two calibrations varied by less than 5%.
Results
The control values of dP/dt max were
generally lower in the cat than the dog
(compare Tables 1 and 2). The measurements
in the dog experiments are in agreement with
those of others (14). We have disregarded the
maximum rate of fall in left ventricular
pressure since its meaning cannot be interpreted.
In two experiments, we passed the tip
transducer from the femoral artery to the root
of the aorta as well as from the left atrium
into the left ventricle. We measured the time
interval between the initial deflection of the
QRS complex of the ECG and the upstroke of
aortic systolic pressure, which indicated opening of the aortic valve. This latter point
corresponded to the point at which the rapid
upstroke of ventricular pressure measured
with the transducer became abruptly more
rounded (Figs. 1 and 2). Using this latter
Circulation Research, Vol. XXX,
February 1972
SPINAL CARDIOCARDIAC
AoDP (mm Hg)
Control
Stimulated
!4
10
r
3
)0
>6
19
±
±
±
±
11
12
7
2
± 6
± 2
124
123
74
60
56
39
± 10
± 10
± 7
± 3
=*= 13
± 2
161
REFLEXES
LVP/max (mm Hg)
Stimulated
Control
165
160
126
114
92
SO
± 12
± 14
± S
± 3
=*= 8
± 14
171 =fc 11
163 ± 14
130 ± 9
114 ± 2
97 ± 8
83 ± 7
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
criterion, dP/dt max was always attained
before the aortic valve opened in the present
experiments.
We have already reported that electrical
stimulation of afferent cardiac sympathetic
fibers in cats elicits substantial and prompt
increases in arterial pressure which are
due to sympathetic vasoconstriction and are
abolished by blocking doses of phenoxybenzamine (9). These increases in arterial pressure would have complicated the interpretation of changes in dP/dt max. Therefore, in
the present experiments, they were reduced
and delayed in onset by doses of phenoxybenzamine hydrochloride, 0.5 mg/kg, that partially blocked alpha-receptors. In spinal (Cl)
vagotomized cats and in vagotomized dogs,
the changes in arterial pressure were smaller
and more delayed in onset; hence in these
experiments phenoxybenzamine was not required.
Effects of Electrical Stimulation of Afferent
Cardiac Sympathetic Fibers in Vagotomized
Cats.—When a substantial increase in dP/dt
max was clearly attained, there were slight
increases in aortic systolic and peak left
ventricular pressures, but there were no
changes in aortic diastolic and left ventricular
end-diastolic pressures and heart rate (Table
1, group 1, and Fig. 1A). At this time,
increases in dP/dt max were almost completely independent of changes in afterload,
preload, or heart rate. Stimulation was stopped as the rising dP/dt max approached its
plateau; aortic pressures continued to rise for
some 20 seconds thereafter (Fig. 1A, right).
The tip-transducer trace represented the left
ventricular pressure pulse more accurately
Circulation Research, Vol. XXX, February 1972
LVEDP (mm Hg)
Control
Stimulated
2.5
1.9
2.2
1.3
1.8
1.1
±
±
±
±
±
±
0.3
0.6
0.3
1.0
1.0
0.4
3.0
2.0
2.2
1.3
1.0
0.5
± 0.4
± 0.6
=* 0.3
± 1.0
± 0.3
± 0.2
Heart rate (beats/min)
Stimulated
Control
217
211
196
183
194
181
±
±
±
±
±
±
11
16
13
16
13
4
217
211
195
184
194
182
±
±
±
±
±
±
11
16
13
15
13
4
than the catheter-manometer record. Hence, it
was essential for the derivation of dP/dt. The
end-diastolic pressures on both records were
the same when there was no drift on the tiptransducer record, and the peak left ventricular pressure measured with the cathetermanometer system equaled the aortic systolic
pressure. Thus, the catheter-manometer system accurately described the range of left
ventricular pressures. The tip-transducer measurements were readily calibrated from the
catheter-manometer measurements.
Section of the left inferior cardiac nerve,
which was the main efferent limb of the reflex,
did not significantly alter control measurements, but the increase in dP/dt max during
stimulation was greatly reduced (Table 1,
group 2, and Fig. IB). A smaller increase in
aortic pressure persisted, and its onset was
delayed. The increase in dP/dt max was
subsequently abolished by right stellectomy
although the increase in aortic pressure was
reduced but still present. This increase was
eliminated in two cats following the intravenous injection of full blocking doses of
phenoxybenzamine, 5 mg/kg (9).
Effects of Electrical Stimulation of Afferent
Cardiac Sympathetic Fibers in Spinal Vagotomized Cats.—When the increase in dP/dt
max due to stimulation reached its plateau,
aortic systolic and peak left ventricular
pressures were only slightly elevated. There
were no changes in aortic diastolic and left
ventricular end-diastolic pressures or heart
rate (Table 1, group 3, and Fig. 2). Section of
the first four left thoracic rami (T1-T4)
abolished the response (Table 1, group 4).
This ruled out the existence of functional
MALLIANI, PETERSON, BISHOP, BROWN
162
1-2000
50
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
0.2 sec
FIGURE 2
Effects of stimulating afferent cardiac sympathetic fibers in spinal vagotomized cats. Left:
control record containing from top to bottom dP/dt (mm Hg/sec), tip-transducer record of left
ventricular pressure (mm Hg), aortic pressure (mm Hg), and ECG. Right: Record obtained
during the peak response to 15 seconds of stimulation. Artifacts on the dP/dt and ECG
traces were introduced by nerve stimulation. The increase in dP/dt max was much greater
than the increases in aortic systolic and peak left ventricular pressures. Heart rate and aortic
diastolic pressures were unchanged.
connections, either direct or synaptically
mediated by the stellate ganglion, between
the nerve being stimulated and the efferent
cardiac sympathetic nerves. The effects were
therefore reflex in nature.
A shortcoming of the experiments was that
in addition to afferent cardiac sympathetic
fibers (2) other noncardiac afferent fibers
were probably being stimulated. To restrict
the stimulus to nerve endings within the heart,
we injected veratridine directly into the left
coronary artery.
Effects of the Intracoronary Injection of
Veratriddne in Spinal Vagotomized Cats.—
When the increase in dP/dt max following the
intracoronary injection of veratridine was at
its plateau, slight elevations of aortic systolic
and peak left ventricular pressures also
occurred (Table 1, group 5, and Fig. 3A).
Aortic diastolic and left ventricular enddiastolic pressures and heart rate were unaffected. Section of left T1-T4 rami prevented
the response in these cats (Table 1, group 6,
and Fig. 3B). When the dose of veratridine
was subsequently doubled, a smaller rise in
dP/dt max was evoked. This was then abolished by right stellectomy.
Control injections of similar doses of
veratridine into the femoral vein or root of the
aorta were without effect. Likewise, intracoronary injection of equivalent volumes of saline
were ineffective.
Effects of the Intracoronary Injection of
Veratridine on Afferent and Efferent Nervous
Discharge in T3.—We have previously reported an increased discharge in afferent
cardiac sympathetic fibers following the intracoronary injection of veratridine (2). A reflex
increase in the neural discharge of two
preganglionic units in one cat was noted at
this time (2). We have confirmed and
extended this finding in four additional cats
(Fig. 4) and now have recorded increased
efferent discharge in six units in five cats. The
Circulation Research, Vol. XXX,
February 1972
SPINAL CARDIOCARDIAC REFLEXES
163
I-2OOO
I min
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
FIGURE 3
Effects of injection of 2 iig of veratridine into the coronary perfusion circuit (at brief interruption in bottom traces) in spinal vagotomized cats. A = before and B = after section of
left T1—T4 rami. Traces from top to bottom are dP/dt (mm Hg/sec), left ventricular pressure (mm Hg), coronary arterial pressure (mm Hg), and aortic pressure (mm Hg). Calibration values are the same in A and B. Coronary flow was 7 ml/min making coronary arterial
pressure higher than aortic pressure. The time required for the drug to circulate from the
injection site to the tip of the cannula was about 15 seconds. The rise in dP/dt max was
much greater than the rise in aortic pressure in A.
1 1 11
1
1 11
1
1 1
1
\\
-140
-105
-70
-90
:70
-50
L
30
I SEC
FIGURE 4
Effects of the injection of 1 ng of veratridine into the coronary perfusion circuit (signal,
bottom trace) on the discharge of a single efferent preganglionic fiber dissected from the
white ramus of T3. Record from top to bottom shows the electroneurogram (smaller deflections are ECG artifacts), coronary arterial pressure (mm Hg), aortic pressure (mm Hg), and
signal mark. The time that elapsed between drug injection and its appearance at the end of
the coronary cannula was about 10 seconds. Spinal vagotomized cat.
Circulation Research, Vol. XXX, February 1972
164
MALLIANI, PETERSON, BISHOP, BROWN
TABLE 2
Effects of Electrical Stimulation of Afferent Cardiac Sympathetic Fibers in Vagolomized Dogs
Control
dP/dt max (mm Hg/sec)
AoSP (mm Hg)
AoDP (mm Hg)
Hit (beats/min)
LVP max (mm Hg)
LVEDP (mm Hg)
Mean CO (ml/min kg"1)
ED diam (mm)
ES diam (mm)
2084
103
78
112
119
3.1
103
30.0
24.2
± 284
=t 11
± 10
± 3
± 12
± 0.8
± 17
=*= 8.0
± 8.0
Stimulated
Mean difference
2354 ± 292
270 ± 81*
8 * 5t
7.0 * 3t
111
86
112
129
3.4
118
=fc 12
* 10
± 3
=*= 12
=*= 0.9
± 26
28.2 =t 8.1
24.6 =•= 8.5
0
10
0.3
10
0.2
0.42
- 3t
± 0.3
=*= 6.0
± 0.2
± 0.83
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
Values are means =<= SE; each value represents 50 measurements in six dogs. In the column
labeled Stimulated, values are peak effects. AoSP = aortic systolic pressure; AoDP = aortic
diastolic pressure; HR = heart rate; LVP = left ventricular pressure; LVEDP = left ventricular
end-diastolic pressure; CO = cardiac output; ED diam = end-diastolic diameter; ES diam =
end-systolic diameter.
*P < 0.001.
fP < 0.01.
%P < 0.05.
response was abolished by prior section of
both ansa subclaviae and inferior cardiac
nerves.
Effects of Electrical Stimulation of Afferent
Cardiac Sympathetic Fibers in Vagotomized
Dogs.—In the dog, dP/dt max has been
shown to be a reliable index of myocardial
contractility when changes in heart rate,
preload, or afterload are minimized (14). Its
usefulness in the cat has not been so clearly
established, although it seems reasonable to
assume that the same considerations apply in
this species as in the dog. Therefore, we
repeated the experiments in dogs. In addition,
we were able to measure aortic flow and left
ventricular internal diameter.
Stimulation elicited a significant increase in
dP/dt max, peak left ventricular pressure, and
arterial systolic and diastolic pressures (Table
2, Fig. 5). Mean cardiac output and stroke
volume increased slightly, but left ventricular
end-diastolic pressure and heart rate were
unchanged. Neither end-systolic nor enddiastolic internal left ventricular diameters
were altered significantly. However, the rate
of change of internal diameter increased
significantly (P < 0.01) from an average of
30.8 ±1.1 to 33.6 ±1.0 (SD) mm/sec.
The latency before onset of the increase in
dP/dt max was 12.5 ±3.8 seconds, whereas
23.6 ± 10.5 seconds elapsed before arterial
pressure began to rise (P < 0.05, 50 trials, six
dogs). In one experiment, phenoxybenzamine,
5 mg/kg, did not affect the latency or
magnitude of the response of dP/dt max but
delayed the onset and reduced the magnitude
of the rise in arterial pressure.
The response was abolished in four experiments by cutting T1-T4 left rami. In two
experiments, section of the left major cardiac
nerves prevented the rise in dP/dt max and
had only a small effect on the increase in
arterial pressure. The aorta was constricted in
these animals to increase arterial pressure to
levels generally attained during nerve stimulation. In all cases, left ventricular end-systolic
and end-diastolic internal diameters and peak
left ventricular and left ventricular end-diastolic pressures increased significantly as the
arterial pressure was elevated. In contrast to
the nerve stimulation experiments, a very
small increase in dP/dt max (4%) was noted.
Discussion
The increase in left ventricular dP/dt max
that we have described either represents a
neurally mediated increase in myocardial
contractility or is the consequence of a change
Circulation Research, Vol. XXX,
February 1972
SPINAL CARDIOCARDIAC REFLEXES
165
WAAAA
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
1 sac
JV/WIAJ
0.5 min
18
1 sec
FIGURE 5
Effects of stimulating afferent cardiac sympathetic fibers in the vagotomized dog. Left: Control record taken at fast paper speed. Right: Peak effect of nerve stimulation at fast paper
speed. Middle: Response to nerve stimulation (S) at slow paper speed. The record from top
to bottom shows the greatest left ventricular internal transverse diameter (mm), left ventricular pressure (mm Hg), dP/dt (mm Hg/sec), aortic pressure (mm Hg), and ECG.
in heart rate, preload, or afterload (14-17).
Since in our experiments neither heart rate nor
preload changed, we need only consider the
possible contribution of an increase in afterload, i.e., arterial pressure. The following
findings may be used to support the idea that
this contribution was negligible and that the
rise in dP/dt max represented a true augmentation of myocardial contractility due to a
spinal sympathetic reflex. (1) In spinal cats,
electrical and chemical stimuli produced no
change in arterial diastolic pressure, and the
small increase in arterial systolic pressure
which occurred was detectable only when
dP/dt max had already reached its peak value.
(2) In vagotomized dogs, the increase in
Circulation Research, Vol. XXX, February 1972
dP/dt max began with a latency that was
about half of that for the increase in arterial
pressure. In vagotomized cats, the increase
was clearly established when the changes in
arterial pressure were still small. (3) In these
experiments, section of the left inferior cardiac
nerve greatly reduced or prevented the
increase in dP/dt max, but the rise in arterial
pressure, although smaller and further delayed
in onset, nevertheless persisted. (4) In the
dog, equivalent increases in arterial pressure
produced mechanically had very little effect
ondP/dtmax (14).
The increases in myocardial contractility
and arterial pressure were reflexly evoked
since there were no direct connection among
166
MALLIANI, PETERSON, BISHOP, BROWN
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
the afferent fibers which were stimulated and
the efferent limbs of the nervous pathway. We
consider this reflex to have at least two
components: (1) an increase in myocardial
contractility due to increased cardiac sympathetic drive and (2) an increase in arterial
pressure due to sympathetic vasoconstriction
and to the reflex increase in myocardial
contractility. The reflex sympathetic vasoconstriction is probably similar to that already
reported (9). However, we do not interpret
these results to indicate that spinal sympathetic reflexes are excitatory only. In this regard,
we were limited by the artificial nature of the
stimuli we used. It is possible that more
physiological stimulation of the cardiac endings might also reflexly inhibit the sympathetic
outflow in spinal vagotomized cats (18).
We have already reported that physiological
and pathophysiological alterations in the
activity of cardiac receptors initiate spinal
sympathetic reflexes which may participate in
the neural control of circulation. However,
since the evidence was electrophysiological,
the target organs to which the reflexly
modulated sympathetic activity was directed
were not identified. Therefore, the argument
in favor of spinal sympathetic cardiocardiac
reflexes was not conclusive (1, 2, 18). Now, by
establishing the heart as a target organ, we
have definitely proved the existence of a spinal
neural circuit mediating cardiocardiac reflexes
which subserve changes in myocardial contractility.
References
coronary circulation of the heart. In Circulation Proceedings, Harvey Tercentenary Congress. Oxford, Blackwell, 1958, p 168.
6. BACANER, M.B., LIOY, F., AND VISSCHER, M.B.:
Coronary blood flow, oxygen delivery rate and
cardiac performance. J Physiol (Lond)
216:111-127, 1971.
7. NOBLE, M.I.M., GABE, I.T., TRENCHARD, D., AND
Guz, A.: Blood pressure in the ascending aorta
of conscious dogs. Cardiovasc Res 1:9-20,
1967
8. FRY, D.L.: Physiologic recording by modern
instruments with particular reference to pressure recording. Physiol Rev 40:753-788,
1960.
9. PETERSON,
11.
12.
13.
BRONK, D.W., FERGUSON, L.K., MARGARIA,
R.,
AND SOLANDT, D.Y.: Activity of the cardiac
sympathetic centers. Am J Physiol 117:237249, 1936.
4.
RANDALL, W.C., MCNALLY, H., COWAN, J.,
CALIGUIRI, L., AND ROHSE, W.G.: Functional
analysis of the cardioaugmentor and cardioaccelerator pathways in the dog. Am J Physiol
191:213-217, 1957.
5. GREGG, D.E.; Regulation of collateral and
Pressor
HORWITZ, L.D., BISHOP, V.S., STONE, H.L., AND
STEGALL, H.F., KARDON, M.B., STONE, H.L., AND
NOBLE, M.I.M., MILNE, E.N.C., GOERKE, R.J.,
CARLSSON, E., DOMENECH, R.J., SAUNDERS,
K.B., AND HOFFMAN, J.I.E.: Left ventricular
filling and diastolic pressure-volume relations
in the conscious dog. Circ Res 24:269-284,
1969.
14.
FURNIVAL,
CM.,
LINDEN,
R.J.,
AND SNOW,
H.M.: Inotropic changes in the left ventricle:
Effect of changes in heart rate, aortic pressure
and end-diastolic pressure. J Physiol (Lond)
211:359-387, 1970.
REEVES, T.J., HEFNER, L.L., JONES, W.B.,
COGHLAN, C , PRIETO, G . , AND CARROLL, J . :
Hemodynamic determinants of the rate of
change in pressure in the left ventricle during
isometric contraction. Am Heart J 60:745-761,
1960.
A: Sympathetic reflex elicited by experimental
coronary occlusion. Am J Physiol 217:703-709,
1969.
3.
A.M.:
BISHOP, V.S.: Portable, simple sonomicrometer. J Appl Physiol 23:289-293, 1967.
15.
tic reflexes initiated by coronary receptors. J
Physiol (Lond) 212:685-705, 1971.
AND BROWN,
STEGALL, H.F.: Continuous measurement of
internal left ventricular diameter. J Appl
Physiol 24:738-740, 1968.
1. MALLIANI, A., SCHWARTZ, P.J., AND ZANCHETTI,
2. BROWN, A., AND MALLIANI, A.: Spinal sympathet-
D.F.,
reflexes produced by stimulation of afferent
cardiac nerve fibers in the cardiac sympathetic
nerves of the cat. Circ Res 28:605-610,
1971.
10. BROWN, A.M.: Motor innervation of the coronary
arteries of the cat. J Physiol (Lond)
198:311-328, 1968.
16.
GLEASON, W.L., AND BRAUNWALD, E.: Studies on
the first derivative of the ventricular pressure
pulse in man. J Clin Invest 41:80-91, 1962.
17. MASON, D.T.: Usefulness and limitations of the
rate of rise of intraventricular pressure
(dP/dt) in the evaluation of myocardial
contractility in man. Am J Cardiol 23:516527, 1969.
18.
MALLIANI, A., PAGANI, M., RECORDATI, G., AND
SCHWARTZ, P.J.: Spinal sympathetic reflexes
elicited by increases in arterial blood pressure.
Am J Physiol 220:128-134, 1971.
Circulation Research, Vol. XXX, February 1972
Spinal Sympathetic Cardiocardiac Reflexes
ALBERTO MALLIANI, D. Fred PETERSON, VERNON S. BISHOP and ARTHUR M.
BROWN
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
Circ Res. 1972;30:158-166
doi: 10.1161/01.RES.30.2.158
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1972 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circres.ahajournals.org/content/30/2/158
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation Research is online at:
http://circres.ahajournals.org//subscriptions/