Laboratory Studies
Inability of Dorsal Spinal Rhizotomy to Prevent
Renal Wrap Hypertension in Rats
PAN JING-YUN, VERNON S. BISHOP, NANCY A. B A L L , AND JOSEPH R. HAYWOOD
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SUMMARY Renal hypertension has been shown to be prevented and reversed by renal denervation.
It has been postulated that the afferent nerves from the kidney are responsible for mediating the
hypertensive stimulus that activates the sympathetic nervous system and increases arterial pressure.
This study was designed to directly test the hypothesis that the afferent renal nerves are necessary for
the development and maintenance of renal hypertension. In the first experiment, dorsal spinal
rhizotomies or sham rhizotomies were performed in rats between T9 and LI, through which afferent
renal nerves have been shown to traverse. After the one-kidney, one-wrap procedure, the increase in
systolic arterial pressure and water intake was similar in the two groups of rats. To determine whether
the removal of afferent renal nerves reversed the hypertensive process, animals with established renal
hypertension were subjected to dorsal rhizotomy or the sham-rhizotomy procedure. Again, there was
no significant effect on systolic arterial pressure and water intake. Although combined dorsal and
ventral rhizotomy and subdiaphragmatic vagotomy did not affect the onset of hypertension, spinal
transaction at the level of C8 effectively prevented the rise in arterial pressure. Although efferent
neural mechanisms contribute to the hypertensive process, these studies suggest that afferent renal
nerves are not directly involved in the development and maintenance of one-kidney, one-wrap renal
hypertension. (Hypertension 7: 722-728, 1985)
KEY WORDS • one-kidney, one-wrap renal hypertension
sympathetic nervous system
C
renal afferent nerves
these forms of renal hypertension.7 8 More recent studies in rats have indicated that renal denervation in twokidney, one clip and one-kidney, one clip, as well as
one-kidney, figure-8 wrap Grollman renal hypertension delays the onset of high blood pressure and reverses the severity of the established hypertension.9""
In fact, complete and irreversible kidney denervation
by renal autotransplantation has been shown to delay
for at least 9 weeks the onset of one-kidney, figure-8
wrap Grollman hypertension.14 Finally, it has been
observed that deoxycorticosterone (DOCA)-salt hypertension also is delayed by renal denervation.15
The mechanisms by which renal denervation delays
the development of experimental hypertension remain
unknown. Elevated efferent sympathetic nervous system activity has been implicated in the etiology of
DOCA-salt hypertension,16 spontaneous hypertension,17 and renal hypertension.9 18-19 It has been suggested that increased renal sympathetic tone in DOCAsalt15 hypertension and the SHR1 facilitates sodium
retention and is necessary for the development of hypertension. On the other hand, the importance of the
renal afferent nerves in the etiology of two-kidney
and one-kidney renal hypertension has been suggested
by Brody20 and recently emphasized by Katholi et al. l0
ONSIDERABLE attention recently has been
focused on the importance of the renal nerves
in the etiology of experimental hypertension.
Sectioning of the renal nerves in the abdomen has been
reported to delay the development of hypertension in
spontaneously hypertensive rats (SHR),1"1 New Zealand genetically hypertensive rats,4 and aortic baroreceptor denervated animals.5 Successive bilateral renal
denervation every 3 weeks has prevented 30 to 40% of
the expected progressive elevation of arterial pressure
in aging SHR. 6 There has been some question as to
whether the renal nerves are necessary for renal artery
stenosis-induced hypertension. Early studies using
dogs suggested that renal denervation has no effect on
From the Department of Pharmacology. The University of Texas
Health Science Center at San Antonio. San Antonio. Texas.
Supported by awards from the National Institutes of Health including HL 26993 and HL 12415.
Dr. Pan is a visiting scientist from the Department of Physiology,
Zhong Shan Medical College. Gaungzhou, the People's Republic
of China.
Address for reprints. Joseph R. Haywood. Ph.D., Department of
Pharmacology, The University of Texas Health Science Center at
San Antonio, San Antonio, Texas 78284.
Received July 25, 1983; accepted January 15, 1985.
722
AFFERENT RENAL NERVES AND RENAL HYPERTENSION/Pfln et al.
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Renal catecholamines have been shown to be absent in
one-kidney, figure-8 wrap hypertensive rats.21 Renal
denervation in one-kidney, one-clip rats resulted in a
decrease in hypothalamic norepinephrine content, returned plasma norepinephrine to control levels, and
caused a reduced depressor response to ganglionic
blockade. 9 - n These observations led to the hypothesis
that clipping the renal artery or wrapping the kidney
caused an increase in renal afferent nerve signals that
triggered an increase in peripheral sympathetic efferent activity and thus resulted in renal hypertension. As
renal denervation severed both renal afferent and efferent fibers, no direct experimental evidence has indicated whether the renal hypertensive process involved
renal afferent nerves, efferent nerves, or both.
It has been reported that the major projections of
renal afferent fibers to the spinal cord are directed
ipsilaterally through the ninth thoracic to the first lumbar spinal dorsal roots in rats by using the methods of
horseradish peroxidase" and the fluorescent dye true
blue. 24 •" Therefore, renal afferent denervation can be
approached by selective section of these dorsal spinal
roots in rats. In addition, efferent nerves have in some
instances been shown to traverse through the ventral
roots.26 For this reason, the present study employed
dorsal and combined dorsal and ventral rhizotomy to
determine whether renal afferent nerves contribute to
the development and maintenance of one-kidney, onewrap renal hypertension; and whether renal afferent
denervation resulted in a functional decrease in the
contribution of the sympathetic nervous system to arterial pressure.
Methods
Male Sprague-Dawley rats weighing 290 to 330 g
were individually housed in wire cages in a room with
constant temperature (approximately 22 °C) and a 12hour light, 12-hour dark cycle. All animals were maintained on rat chow and tap water ad libitum.
723
to LI were also severed. All spinal rhizotomized and
sham-operated rats were allowed at least 10 days to
recover from the operation.
Spinal Transection
Rats for spinal transection were anesthetized with
chloral hydrate (1 mg/kg). An incision was made from
the base of the skull to the level of T4. The prominent
second thoracic spinous process of the second thoracic
vertebrae was used for anatomical orientation. The
major strap muscles were separated with forceps, and
the paraspinous musculature was scraped from the vertebral laminae from C6 to T l . The vertebral laminae at
C7 was removed with small bone scissors, and the dura
at C8 was exposed and removed. The spinal cord at C8
was transected with small scissors.
Arterial and Venous Catheterization
Each animal was prepared with femoral artery and
vein catheters for the direct measurement of arterial
pressure and drug injection. While the rats were anesthetized with methoxyflurane, a heparin-filled Tygon
catheter with a Teflon tip was inserted into the lower
abdominal aorta through the left femoral artery. Polyethylene tubing (PE-50) was placed in the left femoral
vein. All catheters were exteriorized in the dorsal midcervical region of the neck. One day later, arterial
pressure was monitored in the conscious rats with an
Ailtech (MS20) pressure transducer (Ailtech Associates, Inc., Deerfield, IL, USA) with a Beckman Dynograph Recorder (Beckman Instruments, Inc., Fullerton, CA, USA). Heart rate was obtained from the
arterial pressure pulse with a cardiotachometer. A 30minute to 60-minute baseline mean arterial pressure
and heart rate were obtained for each rat. To assess the
contribution of the sympathetic nervous system to arterial pressure in one-kidney Grollman hypertension,
hexamethonium bromide (25 mg/kg i.v.) and atropine
sulfate (0.4 mg/kg i.v.) were sequentially administered in each rat. Arterial pressure and heart rate were
recorded for 10 minutes after each injection.
Spinal Rhizotomy
Dorsal spinal rhizotomy was performed while the
rats were under sodium pentobarbital anesthesia (50
mg/kg i.p.). The vertebrae attached to the 13 ribs were
used for anatomical orientation, and a midline, dorsal
longitudinal incision was made over the spine. The
paraspinous musculature was scraped from vertebral
laminae, and muscles attached to the left transverse
processes from T9 to LI were sectioned. Then, the left
vertebral laminae from T9 to LI, inclusive, were removed with small bone scissors. Under a dissecting
microscope, the dura was opened directly over the left
dorsal root entry zone from T9 to L1 and the left dorsal
roots were cut near their zone of entry by angled microscissors. Overlying muscles and connective tissue
were sutured, and the skin was closed with 4-0 silk.
The sham-operated rats underwent the same operation,
except that the left dorsal roots from T9 to L1 were not
sectioned. The dorsal and ventral rhizotomized rats
received the same operation, but ventral roots from T9
Verification of Renal Afferent Denervation
The spinal cords of all animals that underwent dorsal
rhizotomy, combined dorsal and ventral rhizotomy,
and spinal section were visually inspected. Only the
animals in which complete rhizotomy between T9 and
LI or spinal section was observed were included in the
data.
To further assess renal afferent denervation, a midline laparotomy was performed with the rats under
sodium pentobarbital anesthesia. A miniature flow
probe was placed on the superior mesenteric artery to
record the blood flow with a pulsed Doppler flowmeter. Arterial pressure was monitored through the
femoral artery. The left renal nerves were dissected
from surrounding tissue and severed distally. The central end of the renal nerves was placed on a bipolar
stimulating electrode and stimulated with a frequency
of 16 Hz at 8 V. In sham-operated rats (/! = 3), the
responses to electrical stimulation of the central end
724
HYPERTENSION
were characterized by increased vascular resistance
(+ 11.0 ± 1.8%) of the superior mesenteric artery.
The response to stimulation of the left renal nerves in
dorsal rhizotomized rats (n = 4) was not observed
( - 0 . 5 ± 2.3%).
Experiment 1
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To determine the effect of dorsal rhizotomy on the
onset and maintenance of one-kidney, one-wrap renal
hypertension, six dorsal rhizotomized rats and six
sham-rhizotomized animals were studied for 4 weeks.
During the first week, body weight and systolic arterial
pressure (by the nonheating, photoelectric cell method) were measured three times for average control
values. Daily water intake measurements were taken to
determine baseline fluid intake. At the end of the
week, all the animals were subjected to one-kidney,
figure-8 wrap procedure described by Grollman27 during the same operation. Systolic arterial pressure and
body weight, measured 3 times each week, and daily
determinations of water intake were continued over the
next 4 weeks.
At the end of the study, each animal was catheterized for a direct measurement of arterial pressure and
heart rate. In addition, the functional sympathetic
component contributing to blood pressure was assessed by administering atropine sulfate (0.4 mg/kg
i.v.) and hexamethonium bromide (25 mg/kg i.v.).
Experiment 2
Renal afferent denervation was performed in animals with established one-kidney, one-wrap renal hypertension to determine its importance in the maintenance of elevated arterial pressure. After measurement
of control systolic arterial pressure, body weight, and
water intake, all animals were subjected to the
one-kidney, one-wrap hypertensive procedure. Three
weeks later, when systolic arterial pressure had
reached a plateau, four animals underwent dorsal rhizotomy and four animals underwent sham rhizotomy.
Systolic pressure, body weight, and water intake measurements were continued for 2 weeks after operation.
The conscious animals were then catheterized for the
determination of resting arterial pressure and heart
rate. The functional sympathetic nervous system contribution to arterial pressure was assessed with the use
of ganglionic blockade.
Experiment 3
To determine the role of afferent nerves passing
through the ventral spinal roots and the sympathetic
nervous system in the early phase of one-kidney, onewrap renal hypertension, four groups of animals were
studied during the first week of renal hypertension.
The first group of rats (/; = 9) was sham-rhizotomized;
the second group of animals (/; = 9) received dorsal
rhizotomy, the third group of rats (n = 6) underwent
both ventral and dorsal rhizotomy, and the final group
of animals underwent spinal transection at C8. One
week postwrap, all animals were catheterized and direct arterial pressure and heart rate measurements were
made while the animals were conscious.
VOL 7, No
5, SEPTEMBER-OCTOBER
1985
Experiment 4
To eliminate the possibility of afferent nerves from
the kidney traversing the vagus to activate the hypertensive process, subdiaphragmatic vagotomy (n = 5)
or sham vagotomy (/; = 5) was performed. After an
initial weight loss the animals resumed normal eating
behavior, and body weight returned to preoperative
levels. Both groups of rats were then subjected to the
renal wrap procedure. Systolic arterial pressure was
followed for 14 days. At the end of that period, the
animals were prepared with femoral artery and vein
catheters for direct recording of blood pressure while
conscious.
Statistics
Comparisons of the two groups of animals in Experiments 1, 2, and 4 were made by two-way analysis
of variance for repeated measures.28 Significant
changes within each group were determined by oneway analysis of variance for repeated measures and
multiple range test using the mean square error from
the overall two-way analysis of variance. Differences
between groups were detected with a modified t test.
Differences in resting direct arterial pressures between
two groups were analyzed by Student's / test. Arterial
pressure differences in Experiment 3 were analyzed by
one-way analysis of variance. Significance was taken
a s p < 0.05.
Results
Experiment 1
The effects of dorsal rhizotomy on the development
and maintenance of one-kidney, one-wrap renal hypertension are shown in Figure 1. The renal wrap procedure resulted in a progressive, significant rise in systolic arterial pressure in both the dorsal rhizotomized and
sham-rhizotomized animals (p < 0.05). Systolic arterial pressure reached a plateau of 187 ± 7 mm Hg in
the rhizotomized animals and 179 ± 7 mm Hg in the
sham-rhizotomized animals by Day II. At no time
during the 4-week course of hypertension were there
any differences in systolic arterial pressure between
the two groups of rats. Changes in water intake and
body weight were also similar in the two groups
of animals through the course of hypertension (see
Figure 1).
Resting mean arterial pressure obtained from indwelling arterial catheters was also similar in both
groups of animals. The mean arterial pressure of the
sham-rhizotomized animals was 141 ± 4 mm Hg,
while the mean arterial pressure of the dorsal rhizotomized animals was 148 ± 7 mm Hg. Baseline heart
rate values were 387 ± 11 beats/minute and 407 ± 22
beats/minute in the sham-rhizotomized and dorsal rhizotomized rats respectively. As shown in Figure 2,
total ganglionic blockade produced an equivalent decrease in mean arterial pressure in both groups of rats.
Although the sympathetic nervous system contribution
to arterial pressure was similar in the two groups of
rats, the increased arterial pressure may have been
maintained in the dorsal rhizotomized animals by an-
AFFERENT RENAL NERVES AND RENAL HYPERTENSION/Pa// el al.
other pressor system. As the vasopressin antagonist
has been shown to lower arterial pressure in renal
wrap hypertensive rats,^ the vascular antagonist
d(CH2)5Tyr(Me)AVP was administered after ganglionic blockade. Equivalent decreases in arterial pressure were observed in the two groups of rats (— 19.8
± 2.0 mm Hg in sham-operated rats and —22.0 ± 5.1
mm Hg in renal wrapped rats).
•
• Sham Rhizotomy (n * 6)
0---0 Dorsal Rhizotomy ln^6)
1 p<O.OS from Control
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Control
Time (days)
FIGURE I. The effect of previous dorsal rhizotomy and sham
rhizolomy is shown for the time course of systolic arterial pressure, water intake, and body weight following the one-kidnew
one-wrap procedure. Significant increases in arterial pressure
and water intake occurred in both groups of rats when compared with the prewrap control period (p < 0.05). There were
no differences between the dorsal rhizotomized and shamrhizotomized rats.
Experiment 2
Figure 3 shows the effect of renal hypertension and
sham rhizotomy or dorsal rhizotomy on systolic arterial pressure, water intake, and body weight. After the
induction of renal hypertension, systolic arterial pressure in the two groups of rats showed a progressive rise
that approached a plateau of 204 mm Hg in both groups
of animals. Subsequent to sham rhizotomy or dorsal
rhizotomy, the arterial pressure of both groups of rats
fell during the first 2 days after operation. Arterial
pressure then increased in both groups of rats. There
were no differences in systolic arterial pressure between the two groups of animals at any time after the
rhizotomy procedure. In addition, there were no differences in water intake or body weight between the two
groups of rats throughout the study.
Direct measurement of arterial pressure and heart
rate showed that there was no significant difference in
baseline mean arterial pressure in the two groups of
animals (159 ± 8 mm Hg in the dorsal rhizotomized
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FIOURF. 2. The resting mean arterial pressure (MAP) and the
change in mean arterial pressure produced by ganglionic
blockade with hexamethonium bromide and atropine sulfate are
shown for sham-rhizolomized and dorsal rhizotomized rats
There was no significant difference in the resting blood pressure
or the ganglionic blockade response in the two groups of rats.
Control
FIGURE 3. Changes in systolic arterial pressure, water intake, and body weight resulting from the one-kidney, one-wrap
procedure are shown before and after dorsal rhizotomy or sham
rhizotomy. Arterial pressure and water intake remained significantly elevated following the rhizotomy procedure fp < 0.05).
726
HYPERTENSION
-lO-i
Sham
Rhizotomy
(n = 4)
VOL
7,
No
5,
SEPTEMBER-OCTOBER
1985
170-
Dorsal
Rhizotomy
(n = 4)
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FIGURE 4. The mean arterial pressure (MAP) response to
ganglionic blockade with hexamethonium bromide and atropine
sulfate is shown for sham-rhizotomized and dorsal rhizotomized
rats. There was no difference between the two groups of rats.
Resting mean arterial pressure also was not different between
the two groups of rats.
group and 169 ± 13 mm Hg in the sham-rhizotomized
animals). Heart rates were also not different between
the two groups of rats (394 ± 18 beats/min in rhizotomized animals and 420 ± 15 beats/min in the shamoperated group). Total ganglionic blockade (Figure 4)
produced a significant decrease in mean arterial pressure in both groups of animals (49 ± 10 mm Hg in the
rhizotomized rats and 52 ± 4 mm Hg in the shamrhizotomized animals, p < 0.05), but there was no
significant difference in the decrease in mean arterial
pressure between these two groups of animals.
Experiment 3
The effect of dorsal rhizotomy, dorsal and ventral
rhizotomy, and spinal cord transection at C8 is shown
in Figure 5. The sham-rhizotomized, renal wrapped
animals had a resting mean arterial pressure of 139 ±
4 mm Hg. The mean arterial pressures for the dorsal
rhizotomized animals and dorsal and ventral rhizotomized rats were 141 ± 7 mm Hg and 159 ± 9 mm Hg
respectively. Animals with spinal cord transection at
C8 had a resting mean arterial pressure of 117 ± 3
mm Hg.
Dorsal
Rhizotomy
(n«9)
Dorsal
and Ventral
Rhizotomy
(n-6)
Spinal
Transaction
(n>4)
FIGURE 5. The resting mean arterial pressure in conscious
rats 1 week after the one-kidney, one-wrap procedure is shown
for rats that underwent sham rhizotomy, dorsal rhizotomy, dorsal and ventral rhizotomy and spinal cord transection at C8.
The animals with a cervical transection of the spinal cord had a
significantly lower arterial pressure and were protected against
hypertension (p < 0.05).
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6
8
10
12
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Time (days)
Experiment 4
As shown in Figure 6, there were no differences in
systolic arterial pressure before one-kidney, figure-8
renal wrap in vagotomized or sham-vagotomized rats.
Following the renal wrap procedure, arterial pressure
consistently increased in both groups of animals during
the 2-week period. Direct measurements of arterial
pressure revealed no differences between the vagotomized (152.6 ± 10.8 mm Hg) and the sham-vagoto-
FIGURE 6. Systolic arterial pressure, water intake, and body
weight are shown for subdiaphragmatic vagotomized (n = 5)
and sham-vagotomized (n = 5) rats during a control period and
14 days after one-kidney, figure-8 renal wrap. Arterial pressure
significantly increased to the same extent in both groups of rats,
as indicated byt(p< 0.05). The rise in water intake was less in
the vagotomized rats, while the loss in body weight was greater.
* = significance between groups (p < 0.05).
AFFERENT RENAL NERVES AND RENAL HYPERTENSION/Pan et al.
mized (153.6 ± 10.3 mm Hg) rats; however, the vagotomized rats experienced a blunted increase in water
intake over the 2-week period compared with the
sham-operated rats. In addition, there was a significant
weight loss in the vagotomized rats during the postwrap period (p < 0.05).
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Discussion
Recent studies have demonstrated that peripheral
denervation of a kidney by autotransplantation
(Haywood JR, Patel NP, Corry RD, unpublished observations, 1984) or renal nerve section combined with
phenol9"13 protects an animal against the severity of
renal hypertension. The mechanism through which
denervation of the clipped or wrapped kidney prevents
the onset of high blood pressure is unclear. One line of
reasoning suggested that as no excessive sodium loss
occurred and no decrease in renin-angiotensin system
activity could be detected in renal denervated rats,
efferent neural mechanisms probably were not contributing to the hypertensive process.7 This concept was
reinforced by the observation of Fink and Brody,21
who demonstrated a reduced renal catecholamine
content in the renal wrapped kidney, which indicated
the absence of a functional sympathetic tone to the
kidney. For these reasons, investigators suggested that
afferent nerves from the kidney provided the triggering
mechanism for the rise in arterial pressure in renal
hypertension. 9 ' M
Activation of mechanoreceptors or stimulation of
chemoreceptors as a result of impaired renal blood
flow or altered chemical composition of the urine has
been shown to increase afferent renal nerve activity. 3031 Electrical stimulation of the afferent renal
nerves has been shown to result in an increase in renal
and mesenteric vascular resistance that is mediated by
an activation of the sympathetic nervous system.14
Thus, it was postulated that renal wrapping or reduced
renal blood flow activated the afferent nerves from the
kidney and caused an elevation in arterial pressure.20
This hypothesis is consistent with observations demonstrating an enhanced functional contribution of the
sympathetic nervous system in one-kidney renal
hypertension.19
Studies using anterograde tracing methods have
shown that the majority of afferent nerves from the left
kidney enter the spinal cord at the level of T9 to LI .23~23
These observations were confirmed physiologically in
this study when removal of these dorsal roots effectively abolished the mesenteric vasoconstriction resulting
from electrical afferent nerve stimulation.
The present experiments directly tested the contribution of afferent nerves from the kidney in one-kidney renal hypertension. Left dorsal roots between T9
and LI were sectioned to selectively remove afferent
input to the central nervous system from the kidney.
This procedure failed to alter the onset of the rise in
arterial pressure or to reverse established hypertension
in the one-kidney Grollman wrapped rats. The changes
in water intake and body weight that normally accom-
727
pany the rise in arterial pressure also were unaffected
by dorsal rhizotomy. The inability of the dorsal rhizotomy to affect the course of hypertension suggests that
the renal afferent nerves have little direct influence on
the hypertensive process.
Other possible pathways through which renal afferent nerves could enter the central nervous system also
were tested by selective denervation. It has been
shown that some afferent fibers may traverse the ventral roots of the spinal cord.26 To determine the possible involvement of these fibers in the hypertensive
process, combined dorsal and ventral rhizotomies
were performed. This procedure also failed to influence the onset of hypertension. As afferent nerves
from the kidney may pass through the vagus,32 the
effect of subdiaphragmatic vagotomy was also tested.
Although differences in water intake and body weight
were observed, denervation of the vagus was ineffective in altering the rise in arterial pressure during the
2-week period.
Some remaining afferent fibers passing through T8
and L2 may be sustaining the hypertension; however,
denervation of the majority of the fibers would be
expected to cause a greater reduction in arterial pressure in animals with established hypertension. An exaggerated hypotensive response was not observed after
dorsal rhizotomy.
Section of the spinal cord at C8 was effective in
preventing the rise in arterial pressure in one-kidney,
one-wrap renal hypertension. This finding is consistent with the increased functional contribution of the
sympathetic nervous system that has been observed in
the early and chronic stages of this model of hypertension.19 In addition, the dorsal rhizotomy procedure did
not affect the sympathetic nervous system contribution
as ganglionic blockade responses were similar in dorsal rhizotomized and sham-operated rats. This observation suggests that the mechanism of renal hypertension is not altered by dorsal rhizotomy.
In summary, the removal of renal afferent nerves did
not prevent, reverse, or affect the mechanism mediating one-kidney, one-wrap renal hypertension. Although nerves from the kidney may be entering the
central nervous system through dorsal roots other than
T9 to LI, the results of this study strongly suggest that
afferent renal nerves alone are not responsible for the
development of this kind of hypertension. It is possible, however, that these nerves interact with other central nervous system influences, either neural or humoral, to modulate the hypertensive process.
Acknowledgments
The authors thank Ms. Janet Wall for her excellent secretarial
assistance.
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728
HYPERTENSION
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J Y Pan, V S Bishop, N A Ball and J R Haywood
Hypertension. 1985;7:722-728
doi: 10.1161/01.HYP.7.5.722
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