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J Appl Physiol 98: 526-533, 2005. First published October 8, 2004; doi:10.1152/japplphysiol.00970.2004
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Effects of bilateral vestibular nucleus lesions on cardiovascular regulation in conscious cats

R. L. Mori, L. A. Cotter, H. E. Arendt, C. J. Olsheski, and B. J. Yates

Departments of Otolaryngology and Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 3 September 2004 ; accepted in final form 6 October 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The vestibular system participates in cardiovascular regulation during postural changes. In prior studies (Holmes MJ, Cotter LA, Arendt HE, Cas SP, and Yates BJ. Brain Res 938: 62–72, 2002, and Jian BJ, Cotter LA, Emanuel BA, Cass SP, and Yates BJ. J Appl Physiol 86: 1552–1560, 1999), transection of the vestibular nerves resulted in instability in blood pressure during nose-up body tilts, particularly when no visual information reflecting body position in space was available. However, recovery of orthostatic tolerance occurred within 1 wk, presumably because the vestibular nuclei integrate a variety of sensory inputs reflecting body location. The present study tested the hypothesis that lesions of the vestibular nuclei result in persistent cardiovascular deficits during orthostatic challenges. Blood pressure and heart rate were monitored in five conscious cats during nose-up tilts of varying amplitude, both before and after chemical lesions of the vestibular nuclei. Before lesions, blood pressure remained relatively stable during tilts. In all animals, the blood pressure responses to nose-up tilts were altered by damage to the medial and inferior vestibular nuclei; these effects were noted both when animals were tested in the presence and absence of visual feedback. In four of the five animals, the lesions also resulted in augmented heart rate increases from baseline values during 60° nose-up tilts. These effects persisted for longer than 1 wk, but they gradually resolved over time, except in the animal with the worst deficits. These observations suggest that recovery of compensatory cardiovascular responses after loss of vestibular inputs is accomplished at least in part through plastic changes in the vestibular nuclei and the enhancement of the ability of vestibular nucleus neurons to discriminate body position in space by employing nonlabyrinthine signals.

vestibular system; excitotoxicity; compensation; multisensory integration

A SUBSTANTIAL BODY OF EVIDENCE from experiments on both animal and human subjects has demonstrated that the vestibular system contributes to adjusting vascular resistance and blood pressure during movement and changes in posture. Electrical or selective natural stimulation of vestibular receptors in cats elicits alterations in activity of sympathetic efferents innervating vascular smooth muscle (for review, see Refs. 21, 37, 40, 41, 44). In baroreceptor-denervated animals, vestibular-elicited alterations in sympathetic nerve activity can produce changes in blood pressure (35) and blood flow to specific vascular beds (20). Similarly, in humans, modulation of vestibular nerve activity through head-down neck flexion (11, 16, 26, 27, 29), linear acceleration of the body (38), caloric stimulation of the ear (8, 9), or off-vertical-axis rotation (19) elicits alterations in sympathetic nerve firing. Prior studies have also considered whether loss of vestibular inputs may result in susceptibility for blood pressure instability during postural changes. Elderly human subjects, who experience a loss of both orthostatic tolerance and vestibular system function, have been shown to display deficient vestibulosympathetic responses (24, 28). Conscious rats lacking both vestibular and baroreceptor inputs were more deficient in adjusting blood pressure during gravitational stress produced by centrifugation than vestibular-intact animals with denervated baroreceptors (12). In anesthetized cats, bilateral transection of the eighth cranial nerves resulted in orthostatic intolerance during nose-up tilts of the animal's body (10). However, long-term studies of conscious cats with surgical removal of vestibular inputs revealed more complex effects of these lesions. Acutely after the surgery, all animals showed blood pressure instability during 60° nose-up tilts but only when tested under conditions where they were also deprived of visual cues that might indicate body position in space (17). However, after 1 wk, the animals regained the ability to accurately adjust blood pressure during postural alterations.

A number of experiments have explored the adaptive plasticity in cardiovascular responses that occurs after peripheral vestibular lesions. Animals in which the cerebellar uvula was ablated before a bilateral labyrinthectomy permanently lost precise compensatory adjustments in blood pressure during nose-up rotations (15). Removal of the adjacent cerebellar nodulus did not affect orthostatic tolerance, suggesting that the effects of the uvula lesions were due to the disruption of specific cerebellar signals to the brain stem (15). Recovery of vestibuloocular responses after damage to the inner ear also requires integrity of the uvula and particularly that projections from the uvula to the vestibular nuclei remain intact (33, 34). Presumably, signals from the uvula facilitate adaptive plasticity in the vestibular nuclei that underlies the recovery of function. Accordingly, it has been hypothesized that return of orthostatic tolerance after removal of labyrinthine inputs may also be due to plasticity in the vestibular nuclei that is dependent on cerebellar signals (15). This notion is supported by the observation that over time some vestibular nucleus neurons regain the ability to respond to whole body rotations in animals lacking labyrinthine inputs (43), presumably due to the fact that these cells also receive somatosensory, visceral, and other sensory signals that reflect body position in space (18). If this premise is correct, then lesions placed in the vestibular nuclei should result in deficits in posturally related cardiovascular adjustments that never resolve.

The present study determined the effects of bilateral chemical lesions of the vestibular nuclei on blood pressure and heart rate responses of conscious cats to nose-up tilts of their body. Lesions were produced by injecting an excitotoxin, ibotenic acid, which destroys cell bodies but spares fibers of passage (7). The lesions were placed in portions of the inferior and medial vestibular nuclei just caudal to the lateral vestibular nucleus, because previous experiments showed that this region mediates vestibular influences on sympathetic nervous system activity (31, 42, 45). Our goal was to test the hypothesis that damage to the medial and inferior vestibular nuclei could permanently compromise orthostatic tolerance in the animals.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
All experimental procedures conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the University of Pittsburgh's Institutional Animal Care and Use Committee. Data were collected from five purpose-bred adult female cats obtained from Liberty Research (North Rose, NY). Animals were spayed before being included in this study to eliminate cyclic changes in hormonal levels.

Overview of experimental procedures.   Changes in blood pressure and heart rate were determined during nose-up static tilts of the whole body at 20, 40, and 60° amplitude. The tilt table was rotated manually and secured in the tilted position using a spring device that permitted rotation to one of the three predetermined amplitudes. Rotations from the Earth-horizontal to the nose-up or ear-down position were performed rapidly, at a velocity of ~60°/s. After initial data collection in vestibular system-intact animals, chemical lesions were placed bilaterally in the medial and inferior vestibular nuclei, and the effects of these lesions on blood pressure and heart rate responses during postural changes were determined. The design of these experiments was similar to that of our previous studies in which the effects of removal of vestibular inputs on autonomic responses to whole body tilts were ascertained (5, 6, 15, 17). For the ~2-mo period preceding data collection, animals were acclimated to being restrained in the prone position on the tilt table. For this purpose, a vinyl bag with attached straps was placed around the animal's body; the straps were secured to the tilt table to prevent the animal's position from shifting during testing. Furthermore, the animal's head was immobilized by inserting a screw into a bolt mounted on the skull. Food was provided at the end of the testing period as a reward, and the experimental session was terminated promptly if the animal attempted to remove itself from restraint or showed any signs of distress (e.g., vocalization that persisted for longer than a few seconds).

Blood pressure was recorded using a telemetry system, including a transducer and attached transmitter (Data Sciences International, Arden Hills, MN) implanted in the animal. The transducer tip was inserted through the wall of the femoral artery and passed into the abdominal aorta, and the transmitter unit was secured in the abdomen. The radio signal generated by this transmitter was detected by using a receiver mounted on the tilt table. Heart rate was determined from blood pressure recordings or by monitoring the electrocardiogram (ECG) with the use of leads implanted subcutaneously in the chest. The insulated wires of the ECG electrodes were led subcutaneously and soldered to a connector mounted on the animal's head behind the fixation bolt.

Blood pressure and heart rate were monitored during nose-up body tilts under two conditions, which have been described previously (17). In some trials, the animal could visualize the laboratory and thus could potentially determine body orientation by using visual information; this testing situation will subsequently be referred to as the "visual cues present" (VCP) condition. During other tilts, the animal's visual field rotated with its body so that no visual cues regarding body position in space were available; this testing situation will henceforth be called the "visual cues absent" (VCA) condition. Table rotations of 20, 40, and 60° amplitudes were randomly dispersed throughout the recording session so that the animals could not predict the amplitude of tilt at the onset of each rotation. Tilts persisted for 40–60 s and were separated by at least 1 min. Data were analyzed only for trials in which the animals remained sedentary, with limbs fully extended, and did not vocalize. Our experience is that conscious cats typically cannot be tilted for longer than 1 min without movement or vocalizations occurring. Each animal was routinely tested twice per day, once in the morning and again in the early afternoon. Only a small amount of food was provided as a reward between the testing sessions such that having material in the gastrointestinal tract did not impact on cardiovascular regulation.

Blood pressure and heart rate responses to tilts were recorded in animals with an intact labyrinth over a period of 30–83 days (median of 68 days). Subsequently, lesions were placed bilaterally in the caudal vestibular nuclei as described below, and data collection continued in the same manner as before the lesions. The postlesion recordings began the day after the surgery and were performed for 4 wk.

Surgical procedures.   Two recovery surgeries were required to instrument animals for recording of blood pressure and heart rate during nose-up tilts. An initial recovery surgery was performed to secure a bolt to the skull to permit head fixation and to implant ECG recording electrodes. After animals were trained to remain sedentary in the tilt apparatus during testing, a second surgical procedure was performed to implant the telemetric blood pressure recording system; because this battery-powered unit has a functional life span of only a few months, it was necessary to place the device after the ~2-mo training period was complete. Both surgeries were performed using sterile procedures in a dedicated operating suite. Animals were initially anesthetized by using an intramuscular injection of ketamine (15 mg/kg) and acepromazine (0.2 mg/kg). Subsequently, an endotracheal tube and intravenous catheter were inserted. Anesthesia was then maintained using 1–2% isoflurane vaporized in O2 such that areflexia was present and heart rate was stable. Ringer lactate solution was infused intravenous to replace fluid loss during surgery, and a heating pad was used to maintain rectal temperature near 38°C. A Duragesic patch (fentanyl transdermal system, 25 µg/h delivery; Janssen Pharmaceutica Products, Titusville, NJ) was applied to the animal's skin before surgeries and left in place for 3 days to provide analgesia.

After initial data collection, a third surgery was performed to produce vestibular nucleus lesions bilaterally. Anesthesia was provided during this surgery as in the first two surgeries. A midline incision was made from the rostral ridge of the supraoccipital bone to C1, and a small craniotomy was performed by removing the caudal portions of the extraoccipital and supraoccipital bone. A restricted portion of the cerebellar nodulus was then aspirated to allow visualization of landmarks on the surface of the fourth ventricle; a previous study demonstrated that nodulus lesions did not affect cardiovascular responses during postural alterations and did worsen or prolong the deficits in correcting blood pressure after the subsequent removal of vestibular inputs (15). The remaining portion of the nodulus was gently retracted to provide access to the caudal vestibular nuclei on one side. Using surface landmarks as a guide, the 25-gauge pipette tip of a 1-µl Hamilton syringe (7000 Series, Hamilton, Reno, NV) was then inserted into the caudal and medial portion of the vestibular nucleus complex. The syringe was positioned by using a micromanipulator such that the tip entered the brain stem at an angle of ~45°, and it was inserted for ~0.5 mm. Subsequently, 0.1 µl of saline containing 1 µg of the excitotoxin ibotenic acid (Sigma-Aldrich, St. Louis MO) was injected over a period of 5 min; after waiting another 5 min, the pipette tip was withdrawn. A second ibotenic acid injection was made ~0.5 mm lateral to the first; a third was made ~0.5 rostral to the previous two, and between them in the medial-lateral plane. A similar set of injections was made on the contralateral side, and the muscle and skin overlying the craniotomy were closed by using sutures. A dose of 3 mg/kg of the nonsteroidal anti-inflammatory drug ketoprofen was injected every 12 h for 3 days to provide analgesia. To ensure that animals received proper hydration and nutrition, an intravenous injection port remained in place for 2 days after surgery, and 50 ml of 5% dextrose solution were administered intravenously each day. In addition, feeding was done by hand until the animal's spontaneous consumption of food and water returned to prelesion levels.

Data recording procedures.   During recording sessions, a cable was attached to the head-mounted connector to allow ECG signals to be fed to an amplifier (model 1700, A-M Systems, Carlsberg, WA); activity was amplified by a factor of 104 and filtered with a band pass of 10–10,000 Hz. Subsequently, these signals were recorded digitally using a 1401-plus data collection system (Cambridge Electronic Design, Cambridge, UK) interfaced with Macintosh (Apple Computer, Cupertino, CA) G4 computer. A voltage proportional to blood pressure produced by the Data Sciences International telemetric blood pressure recording system was digitized and sampled at 200 Hz. A potentiometer mounted on the tilt table provided a recording of table position; the voltage from this potentiometer was digitized and sampled at 100 Hz.

The Spike-2 software package (Cambridge Electronic Design) was used for data analysis. Mean blood pressure was determined for the following times relative to each tilt: 5 s before tilt onset and 0, 2, 4, 6, 8, 10, 20, and 40 s after the tilt amplitude reached its peak. In addition, heart rate was calculated over 3-s bins during the tilt cycle. Statistical analyses of data were performed with the use of the Prism 4 software package (GraphPad Software, San Diego, CA) running on a Macintosh G5 computer. A nonparametric ANOVA procedure (Kruskal-Wallis test) in combination with a post hoc test (Dunn's multiple-comparison test) was used to compare baseline and tilt-elicited changes in blood pressure and heart rate before and at various periods subsequent to removal of vestibular inputs. Statistical significance was set at P < 0.05. Pooled data are presented as means ± SE.

Verification of vestibular lesions.   At the conclusion of data recording, animals were anesthetized with an intraperitoneal injection of pentobarbital sodium (40 mg/kg) and perfused transcardially with phosphate-buffered saline followed by 4% paraformaldehyde fixative. The brain stem was removed and sectioned in the transverse plane at 50-µm thickness. Sections were stained using thionine and inspected for damage produced by ibotenic acid injections (e.g., areas with loss of cell bodies or containing substantial gliosis).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Placement of lesions.   After ibotenic acid injections into the vestibular nuclei, all animals exhibited considerable postural instability as well as nystagmus that remained present until euthanasia occurred. Examination of postmortem histological material confirmed that the injection cannula was positioned in the target region of the caudal medial and inferior vestibular nuclei. In some cases, the area of the lesion was defined by a region of the vestibular nuclei devoid of cell bodies and surrounded by dense gliosis (see Fig. 1 for an example). In other animals, however, the precise portion of the vestibular nuclei affected by the ibotenic acid injections was more difficult to define. It is likely that replacement of neuronal cell bodies by glia in these cats resulted in the lesioned area having a similar appearance as the surrounding structures. Nonetheless, the presence of notable postural instability and nystagmus in the animals confirmed that vestibular nucleus neurons had been destroyed by the ibotenic acid injections.



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  		Fig. 1. Photomicrograph of damage to the vestibular nuclei produced by ibotenic acid injections in animal 4. This histological section is through the rostral portion of the inferior vestibular nucleus (IVN) and also includes the caudal portion of the lateral vestibular nucleus (LVN), ~5 mm rostral to the obex. The area of the lesion is encircled by a dashed line and is defined by a region devoid of cell bodies that is surrounded by dense gliosis. 4V, fourth ventricle; MVN, medial vestibular nucleus; P, cerebellar peduncle; PH, prepositus hypoglossi; RB, restiform body; RF, reticular formation.

 
Prelesion changes in heart rate and blood pressure during postural alterations.   Baseline blood pressure and heart rate values for all animals are shown in Tables 1 and 2, Fig. 2 denotes the changes in blood pressure and heart rate from these baseline values elicited by 60° tilt during the VCA condition, and Fig. 3A illustrates the cardiovascular response to a single 60° tilt in one animal (animal 4). The typical response to 60° tilt delivered in either the VCA or VCP condition (not illustrated) was a modest increase in blood pressure and heart rate, similar to that described in previous studies (15, 17). Tilts of 20 and 40° amplitudes produced similar but smaller cardiovascular responses.


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  		Table 1. Effects of bilateral vestibular nucleus lesions on baseline blood pressure determined before each whole body tilt

 

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  		Table 2. Effects of bilateral vestibular nucleus lesions on baseline heart rate determined before each whole body tilt

 


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  		Fig. 2. Mean changes in blood pressure (A) and heart rate (B) that occurred at different times during 60° nose-up tilt in the visual cues absent condition before vestibular nucleus lesions. Alterations in blood pressure and heart rate are relative to baseline values determined before each tilt. Time is indicated relative to that at which the tilt reached its maximal amplitude (time 0). Error bars indicate 1 SE.

 


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  		Fig. 3. Recordings of blood pressure during 60° nose-up tilt in the visual cues absent condition made before lesions (A) and in the second week after ibotenic acid injections into the vestibular nuclei (B). Both responses were obtained from animal 4. Rotation of the tilt table from the Earth-horizontal to the 60° nose-up position is indicated by a trapezoidal waveform beneath each blood pressure trace.

 
Effects of vestibular nucleus lesions on baseline blood pressure and heart rate.   In all animals, vestibular nucleus lesions resulted in a significant alteration in baseline mean blood pressure (Table 1), and in four of the animals baseline heart rate changed as well (Table 2). Nonetheless, the effects were not the same in all cases. Blood pressure dropped after the lesions in animals 1 and 2, whereas in the other animals it increased. Typically, baseline blood pressure tended to recover toward prelesion values over time, but it remained altered from values recorded before ibotenic acid injections after 1 wk. Among the four animals in which baseline heart rate changed after lesions, an increase was noted in three cases (animals 1, 3, and 4) and a small decrease was observed in the fourth (animal 2); in the latter animal, heart rate was not significantly different from that recorded before lesions after the first week after ibotenic acid injections. In the three animals for which damage to the vestibular nuclei produced an increase in heart rate, the alteration persisted for longer than 1 wk after the lesions, although recovery was observed over time. For example, in animal 3, the following baseline heart rates were determined for each week following the lesions: 186 ± 1 beats/min in the first week, 216 ± 2 beats/min in the second wk, 201 ± 1 beats/min in the third week, and 173 ± 1 beats/min in the fourth week. The values for the first 3 wk after ibotenic acid injections were significantly higher than the baseline heart rate (173 ± 0.3 beats/min) ascertained before the lesions, but those for the fourth week were statistically indistinguishable.

Effects of vestibular nucleus lesions on blood pressure regulation during postural alterations.   Figure 3B illustrates a postlesion recording of blood pressure made during 60° tilt in the VCA condition; this trace was collected from animal 4 during the second week after ibotenic acid injections. Figure 4 shows the effects of vestibular nucleus lesions on the change in blood pressure from baseline levels for all amplitudes of tilts performed in the VCA condition; each animal is represented in a separate panel. To simplify comparisons, the blood pressure changes are plotted relative to those that occurred before lesions. Figure 5 provides similar data for responses recorded during the VCP condition. In all animals, the blood pressure responses to 60 and 40° nose-up tilts performed in both the VCA and VCP conditions were altered by damage to the medial and inferior vestibular nuclei. Little change in blood pressure was noted during 20° tilts either before or after the lesions. The effects on the blood pressure responses to 60° tilt were only a few millimeters of mercury in magnitude in animals 1 and 5, but they were larger in the other three cases. In animal 2, the vestibular nucleus lesions resulted in a significant blood pressure increase during 60° nose-up tilt, whereas in animals 3 and 4 blood pressure dropped significantly more than before lesions. In all three of these animals, similar data were recorded in the VCA and VCP conditions. The effects of the ibotenic acid injections on regulation of blood pressure were particularly prominent in animal 4; in this case, marked orthostatic intolerance occurred after the lesions (see Fig. 3).



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  		Fig. 4. Effects of vestibular nucleus lesions on mean changes in blood pressure from pretilt levels that occurred at different times during nose-up tilts in the visual cues absent condition. To simplify comparisons, the blood pressure changes are plotted relative to those that occurred before lesions. Reponses to 20, 40, and 60° tilt amplitudes are designated by different symbols; solid symbols indicate changes in blood pressure after ibotenic acid injections into the vestibular nuclei that were significantly different from those determined before lesions (P < 0.05). Each animal is depicted in a different panel; the left side represents data recorded during the first week after the lesions, and the right side shows pooled data recorded during the subsequent 3 wk. Error bars indicate 1 SE.

 


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  		Fig. 5. Effects of vestibular nucleus lesions on mean changes in blood pressure from pretilt levels that occurred at different times during nose-up tilts in the visual cues present condition. Data are represented as in Fig. 4.

 
The effects of vestibular nucleus lesions on blood pressure responses to 60° nose-up tilt persisted for longer than 1 wk in all animals, but they diminished over time except in animal 4. In this case, there was no indication of improvement, as exemplified by comparing the responses to 60° nose-up tilt in the first and fourth weeks after the lesions. This comparison considered the changes in blood pressure from baseline values, relative to those noted before lesions, at 6 s after the tilt reached its peak amplitude, and maximal effects on cardiovascular responses were noted. At this time point, during the first week after lesions the blood pressure response was decreased by 17 ± 1 mmHg in the VCA condition and 13 ± 3 mmHg in the VCP condition. In the fourth week after ibotenic acid injections, the blood pressure response was decreased by 19 ± 1 mmHg in both the VCA and VCP conditions.

Effects of vestibular nucleus lesions on heart rate responses during postural alterations.   Figure 6 shows the effects of vestibular nucleus lesions on the change in heart rate from baseline levels for all amplitudes of tilts performed in the VCA condition. Each animal is represented in a separate panel, and heart rate changes are plotted relative to those that occurred before lesions. Figure 7 provides similar data for responses recorded during the VCP condition. In four of the animals (animals 2, 3, 4, and 5), ibotenic acid injections resulted in heart rate increases from baseline values during 60° nose-up tilt that were significantly larger than those before lesions. The augmentation of heart rate responses was noted during both the VCA and VCP testing conditions. Furthermore, the effects persisted for longer than 1 wk after production of the lesions, but they diminished over time.



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  		Fig. 6. Effects of vestibular nucleus lesions on mean changes in heart rate from pretilt levels that occurred at different times during nose-up tilts in the visual cues absent condition. To simplify comparisons, the heart rate changes are plotted relative to those that occurred after lesions. Data are represented as in Fig. 4.

 


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  		Fig. 7. Effects of vestibular nucleus lesions on mean changes in heart rate from pretilt levels that occurred at different times during nose-up tilts in the visual cues present condition. Data are represented as in Fig. 4.

 
Effects of vestibular nucleus lesions on integrated cardiovascular responses during postural alterations.   In animals 4 and 5, and to a lesser extent in animal 3, the tilt-related drops in blood pressure from baseline values relative to those observed before lesions were accompanied by augmented increases in heart rate. Presumably, blood pressure may have dropped even more during the tilts if the increases in heart rate had not occurred. It is not clear whether the changes in both the heart rate and blood pressure responses were directly related to the lesions or whether the increase in heart rate was triggered secondarily through the baroreceptor reflex or other mechanisms when blood pressure began to change. Similarly, in animal 2 damage to the vestibular nuclei resulted in a significantly larger rise in both heart rate and blood pressure during tilts than occurred before lesions; it is possible that the heart rate increases resulted directly from the lesions, thereby producing a secondary change in blood pressure. These observations show that the interactions of multiple systems that participate in cardiovascular control during postural alterations can complicate the interpretation of the effects of vestibular nucleus lesions on tilt-related blood pressure and heart rate responses.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This study showed that damage to the vestibular nuclei alters resting blood pressure and heart rate and that it also results in changes in the cardiovascular responses that normally occur during postural alterations. Our findings are similar to those reported in a preliminary study conducted on rodents (14). The effects of vestibular nucleus lesions on cardiovascular regulation persisted for over 1 wk, and in some cases (e.g., animal 4) were still present 1 mo after the lesions. In contrast, removal of labyrinthine inputs through peripheral lesions produced deficits in adjusting blood pressure during postural alterations that dissipate within 1 wk (17). These observations support the hypothesis that recovery of compensatory cardiovascular responses after loss of vestibular inputs is accomplished at least in part through plastic changes in the vestibular nuclei and the enhancement of the ability of vestibular nucleus neurons to discriminate body position in space by employing nonlabyrinthine signals (18, 43). Nonetheless, baseline blood pressure and heart rate as well as alterations in these parameters during tilts returned to values similar to those observed before lesions in most animals. One possible explanation for these findings is that vestibular nucleus neurons that were not killed after the ibotenic acid injections acquired a larger role in cardiovascular regulation over time as a result of adaptive plasticity. Another possibility is that some vestibular nucleus neurons were initially damaged by the ibotenic acid injections but ultimately recovered such that the size of the effective lesion diminished (7). A third feasibility is that, subsequent to the lesions, brain regions other than the vestibular nuclei attained a larger role in adjusting blood pressure. Further experiments will be required to determine the mechanisms through which normalization of compensatory cardiovascular responses occurs after damage to the vestibular nuclei.

It is also noteworthy that vestibular nucleus lesions resulted in deficits in regulating blood pressure during whole body tilts performed both when visual information regarding body position in space was available (VCP condition) and when these sensory cues were absent (VCA condition). In contrast, bilateral vestibular neurectomy only resulted in cardiovascular disturbances when no visual signals reflecting body position in space were present (17). These observations suggest that the influences of visual information on autonomic control are mediated at least partly by the vestibular nuclei. Accordingly, previous experiments have revealed that vestibular nucleus neurons in cats, including those with inputs from the labyrinth, receive visual inputs (1–3, 23, 32, 36). Thus lesions within the central vestibular system could have more serious consequences than those occurring peripherally, because they may diminish the capacity for both labyrinthine and nonlabyrinthine signals to contribute to autonomic regulation.

After vestibular nucleus lesions, there was variability between animals with regard to the magnitude of the deficits in adjusting blood pressure during postural alterations. In some cases, the effects on blood pressure regulation were only a few millimeters of mercury in magnitude, whereas in animal 4 the changes in blood pressure from baseline values during tilts, relative to those noted before lesions, were >15 mmHg. This variation in efficacy of the lesions was presumably partly correlated to the fraction of vestibular nucleus neurons participating in autonomic control that was destroyed. Another contributing factor was the relative ability of other mechanisms, such as the baroreceptor reflex, to compensate for the diminished vestibulocardiovascular responses. In animals 3, 4, and 5, the significant decreases in blood pressure responses during 60° tilts were accompanied by an augmentation in heart rate, which should serve to increase blood pressure (14). Although it is not known whether these increases in heart rate were a direct result of the lesions, or were a secondary response elicited by baroreceptors in response to decreases in blood pressure, it seems ensured that blood pressure would have dropped even more if heart rate had remained stable. Animal 2 differed from the others, in that the increases in heart rate during postural alterations after ibotenic acid injections were accompanied by a rise in blood pressure. One possible explanation for these findings is related to the fact that multiple sensory inputs are integrated to produce changes in blood pressure. For example, neurons in the cat rostral ventrolateral medulla that are components of the baroreceptor reflex circuitry also mediate vestibulosympathetic responses (39, 46, 47); the processing of both baroreceptor and vestibular signals by these cells likely explains why the two reflex mechanisms have additive effects on cardiovascular control (22, 25). After damage to the vestibular nuclei, neurons that regulate blood pressure will have fewer sensory inputs available, and the likelihood is higher that an error will be made in determining the correct compensatory response during postural changes, such that blood pressure may either drop below or rise above the target level.

Whenever a chemical lesioning technique is employed, there is concern that toxin could spread to nontarget tissues. In all cases, postmortem analysis of histological sections revealed that the injection cannula was placed in the target region, and there was no evidence of cell loss outside of the vestibular nuclei. Even if damage had occurred in brain stem areas adjacent to the medial and inferior vestibular nuclei, previous studies in acute preparations demonstrated that inactivation of these regions does not diminish the amplitude of vestibulosympathetic responses (30). Thus it seems likely that the effects of the ibotenic acid injections were related to the destruction of vestibular nucleus neurons. Another caveat is that a small portion of the nodulus was removed in the animals so that structures on the surface of the fourth ventricle could be visualized and injection sites could be localized through reference to these landmarks. However, prior experiments in conscious cats demonstrated that nodulus lesions did not affect cardiovascular responses during postural alterations and did worsen or prolong the deficits in correcting blood pressure after the subsequent removal of vestibular inputs (15). Furthermore, studies employing stimulation techniques have demonstrated that, although a restricted portion of the cerebellar uvula participates in cardiovascular control, the nodulus does not appear to play a substantial role in regulating blood pressure (4). It is thus unlikely that damage to the nodulus affected the results of the present experiments.

Conclusions and perspectives.   The present paper demonstrates that lesions of the inferior and adjacent medial vestibular nuclei produce deficits in controlling blood pressure that differ from those subsequent to removal of vestibular inputs through a vestibular neurectomy. In particular, recovery from the effects of vestibular nucleus lesions occurs slower than after elimination of labyrinthine signals. Furthermore, visual inputs do not ameliorate the disturbances in cardiovascular regulation resulting from central vestibular system damage, as they do after transection of the eighth cranial nerves. These findings support the hypothesis that return of orthostatic tolerance after loss of labyrinthine inputs is dependent on plasticity within the vestibular nuclei and enhancement of the ability of vestibular nucleus neurons to detect body position in space through the use of nonlabyrinthine inputs. However, the magnitude of the deficits was small in most animals, presumably because of limited lesion size and the existence of additional mechanisms (e.g., the baroreceptor reflex) capable of adjusting blood pressure during postural alterations. These findings, if translated to human patients, suggest that substantial autonomic disturbances would only likely occur when extensive damage occurs within the vestibular nuclei. These disturbances could be exacerbated in cases where the baroreceptor reflex or other cardiovascular system control mechanisms were dysfunctional.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by National Institutes of Health (NIH) Grant R01 DC-00693 (to B. J. Yates). Core support was provided by NIH Grants EY-08098 and DC-05205. R. L. Mori was supported by training grant NGT5–50292 from the National Aeronautics and Space Administration (Graduate Student Researcher Program).


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Katie Wilkinson, Arju Ali, Sunil Misra, Toshiharu Shintani, and Brian Jian for valuable technical assistance in the completion of these studies.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. J. Yates, Univ. of Pittsburgh, School of Medicine, Dept. of Otolaryngology, Eye and Ear Institute, Rm. 519, Pittsburgh, PA 15213 (E-mail: byates{at}pitt.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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