J Appl Physiol 104: 34-40, 2008.
First published October 4, 2007; doi:10.1152/japplphysiol.00454.2007
8750-7587/08 $8.00
Strong galvanic vestibular stimulation obscures arterial pressure response to gravitational change in conscious rats
Chikara Abe,
Kunihiko Tanaka,
Chihiro Awazu, and
Hironobu Morita
Department of Physiology, Gifu University Graduate School of Medicine, Gifu, Japan
Submitted 27 April 2007
; accepted in final form 27 September 2007
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ABSTRACT
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Galvanic vestibular stimulation (GVS) is known to create an imbalance in the vestibular inputs; thus it is possible that the simultaneously applied GVS obscures adequate gravity-based inputs to the vestibular organs or modifies an input-output relationship of the vestibular system and then impairs the vestibular-mediated response. To examine this, arterial pressure (AP) response to gravitational change was examined in conscious rats with and without GVS. Free drop-induced microgravity and centrifugation-induced hypergravity were employed to elicit vestibular-mediated AP response. GVS itself induced pressor response in an intensity-dependent manner. This pressor response was completely abolished by vestibular lesion, suggesting that the GVS-induced response was mediated by the vestibular system. The pressor response to microgravity (35 ± 3 mmHg) was significantly reduced by simultaneously applied GVS (19 ± 1 mmHg), and pressor response to 3-G load was also significantly reduced by GVS. However, GVS had no effect on air jet-induced pressor response. The effects of GVS on pressor response to gravitational change were qualitatively and quantitatively similar to that caused by the vestibular lesion, effects of which were demonstrated in our previous studies (Gotoh TM, Fujiki N, Matsuda T, Gao S, Morita H. Am J Physiol Regul Integr Comp Physiol 286: R25–R30, 2004; Matsuda T, Gotoh TM, Tanaka K, Gao S, Morita H. Brain Res 1028: 140–147, 2004; Tanaka K, Gotoh TM, Awazu C, Morita H. Neurosci Lett 397: 40–43, 2006). These results indicate that GVS reduced the vestibular-mediated pressor response to gravitational change but has no effect on the non-vestibular-mediated pressor response. Thus GVS might be employed for the acute interruption of the AP response to gravitational change.
microgravity; hypergravity; free drop; vestibular lesion
THE ROLE of the vestibular system in controlling arterial pressure (AP) has been the focus of many studies on both humans and animals (11, 14, 15, 18, 21, 23, 25, 30), and in these studies on animals, the AP and/or autonomic responses to adequate vestibular stimuli, i.e., gravitational or postural change, were compared between intact animals and animals with vestibular lesion (VL) (11, 15, 18, 25). In human studies, however, such invasive and irreversible methods like VL could not be employed. Hence, patients with vestibular dysfunction were recruited, but the number of the patients was limited (13, 30). More importantly, since the vestibular system is known to integrate both vestibular and nonvestibular inputs, including visual, visceral, muscle, and cutaneous signals, chronic dysfunction of the vestibular system may be compensated by the nonvestibular system (16, 31). Thus, in human studies, an alternative method for acutely interrupting the vestibular-mediated AP response to gravitational change is required in order to examine the role of the vestibular system in controlling AP during postural or gravitational change.
Since galvanic vestibular stimulation (GVS) creates an imbalance in the vestibular inputs as well as direction-specific deviation, it has been used for functional exploration of the vestibular system in animals and humans (2–4, 7, 10, 17, 19, 20, 26, 28, 32). Wardman et al. (27) reported that GVS is an application of the precisely controlled change in the activity of vestibular afferents from all vestibular organs without any of the potentially confounding changes in nonvestibular inputs. Thus, it is hypothesized that a continuous application of GVS might obscure the gravity-based input to the vestibular organs and/or might reset the vestibulocardiovascular system and then reduce the vestibular-mediated AP response to gravitational change. Accordingly, the aim of the present study was to examine whether a continuous application of GVS reduces the vestibular-mediated AP response to gravitational change. If this is the case, then there is a possibility that GVS can be used for the acute interruption of the vestibulocardiovascular system. To examine this aim, free drop-induced microgravity and centrifugation-induced hypergravity were used to elicit AP responses in conscious rats, since the pressor responses induced by these maneuvers are mainly mediated by the vestibular system (11, 18, 25).
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METHODS
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Animals used in the present study were maintained in accordance with the "Guiding Principles for Care and Use of Animals in the Field of Physiological Science" set by the Physiological Society of Japan. The experiments were approved by the Animal Research Committee of Gifu University. Male Sprague-Dawley rats weighing 230–250 g (8 wk old, n = 30) were used for the experiment.
To examine whether the GVS-induced response is mediated through the vestibular system, the AP response was compared between VL rats and sham-operated rats. VL was chemically induced in six rats (1). Under light enflurane (Ethrane, Abbott Laboratories) inhalation anesthesia applied using face mask, sodium arsanilate solution (100 mg/ml) was injected into the bilateral middle-ear cavity (50 µl/ear). Sham-operated rats were injected with saline solution into the middle-ear cavity instead of sodium arsanilate solution (n = 7). Two days after the sham or VL operation, the stimulating electrodes were bilaterally implanted into the tympanic bulla. Rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and the external acoustic meatus was opened through ventrolateral approach. The stimulating electrodes were bilaterally implanted into the tympanic bulla through the tympanic membrane, and they were fixed using glue. Wires from the electrodes were exteriorized from the back of the neck and fixed by a suture. Penicillin G potassium (6,000 U/day) was injected intramuscularly for 3 days. One week after the implantation of electrodes, a polyethylene catheter (PE-50; Becton Dickinson, Sparks, MD) was inserted into the abdominal aorta via the left femoral artery to measure the AP.
On the next day, the catheter was extended and connected to a pressure transducer (MP5200; Baxter, Deerfield, IL), which was placed at the cardiac level. The signal from the transducer was transmitted to an amplifier (MEG-6108; Nihon-Kohden, Tokyo). With measuring the AP under conscious condition, GVS (0.1-, 0.2-, and 0.5-mA amplitude; 0.5-s plus and 0.5-s minus) was applied for 2 min using an electrical stimulator (NS-101; Unique Medical, Tokyo). The AP and waveform of the GVS were recorded with an analog-to-digital converter (PowerLab; AD Instruments, New South Wales, Australia) at a rate of 100 Hz.
The other 17 rats were used for microgravity, hypergravity, and air jet experiments. One week before the microgravity experiment, rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and the stimulating electrodes were bilaterally implanted into the tympanic bulla as described above.
One to two days before the microgravity experiment, the rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and a polyethylene catheter (PE-50; Becton Dickinson) was inserted into the abdominal aorta via the left femoral artery to measure the AP. The catheter was exteriorized from the back of the neck, and it was protected by a spring and connected to a swivel. The wires of the stimulating electrodes were extended and were also protected by the spring.
Each rat was used twice in the microgravity experiment. The rats were randomly sorted into the following four groups: free movement without GVS group [GVS(off)FM, n = 8], stabilized without GVS group [GVS(off)STAB, n = 8], free movement with GVS group [GVS(on)FM, n = 9], and stabilized with GVS group [GVS(on)STAB, n = 9]. Rats in the FM group were placed in individual cages (30 cm x 18 cm x 20 cm, width x length x height) and free movement was allowed; thus they floated when subjected to microgravity. On the other hand, the movement of the rats in the STAB group was restricted using a horizontal septum (6-cm height); thus they did not float when subjected to microgravity. However, their horizontal movement was not restricted. The catheter from the swivel was connected to a pressure transducer and the signal from the transducer was transmitted to an amplifier as described above. In the GVS(on) group, continuous biphasic and bipolar stimulation (0.5-mA amplitude, 0.5-s plus and 0.5 s minus) was applied using an electrical stimulator (NS-101; Unique Medical, Tokyo). The AP, G level, and waveform of the GVS were recorded with an analog-to-digital converter (PowerLab; AD instruments) at a rate of 100 Hz.
A free drop was performed to induce microgravity; this experiment was performed at the Microgravity Laboratory of Japan (Toki, Gifu, Japan). All equipments used in the experiment were fixed in the payload space in an airtight capsule (outer diameter, 900 mm; height, 2,280 mm). The free drop was performed in a tube having a diameter of 1,500 mm and a length of 100 m in a free drop zone. After the capsule was placed in the tube, the tube was sealed and evacuated to eliminate aerodynamic resistance. The capsule dropped until it reached the breaking zone, thus inducing microgravity for 4.5 s. The average AP for 2 s before the induction of microgravity was obtained to provide a value that corresponded to 1 G. The average AP for 4 s during microgravity was also obtained.
One day after the microgravity experiment, hypergravity (3 G) and air jet stress were applied to nine rats, which were used in the microgravity experiment. For this experiment, the AP responses were measured with or without GVS when the rats were subjected to a 3-G load or air jet stress. Each rat was placed in the individual cage (30 cm x 18 cm x 20 cm, width x length x height), which was placed inside the rotating box of the centrifuge. The 3-G load in the dorsoventral direction was applied to the unrestrained conscious rats by centrifugation using a custom-made gondola-type rotating box (Shimadzu Kyoto, Japan) (11, 18). Air jet stress consisted of a pulse (1-s duration) of compressed air (23 g/mm2) aimed at the forehead from a 1-mm opening at the front of tube. The 3-G load (1-min duration) and air jet stress were repeatedly applied three times, and averaged data of AP response was evaluated in each rat.
All data are presented as means ± SE. For data analysis in Table 1 and Fig. 3, bottom, one-way ANOVA was applied. Repeated-measures two-way ANOVA was used in Fig. 1, bottom; Fig. 3, top; Fig. 5, top; and Fig. 4, right. If the F-ratio indicated statistical significance, the Student-Newman-Keuls post hoc test was used for among-groups comparison. Data in Fig. 5, bottom, were analyzed using paired t-test. The significance level was set at P < 0.05 for the post hoc test and paired t-test.
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Fig. 2. Typical responses illustrating the AP of a free-moving rat without galvanic vestibular stimulation [GVS(off)FM], a free-moving rat with galvanic vestibular stimulation [GVS(on)FM], a stabilized rat without galvanic vestibular stimulation [GVS(off)STAB], and a stabilized rat with galvanic vestibular stimulation [GVS(on)STAB]. A sudden change in gravity from 1 G to 0 G was produced by a free drop.
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Fig. 4. Left: typical responses illustrating the AP of a GVS(off) rat and a GVS(on) rat. A sudden change in gravity from 1 G to 3 G was produced by a centrifuge device. Right: change ( ) in the AP (top) and heart rate (bottom) of GVS(off) rats (n = 9) and GVS(on) rats (n = 9). The horizontal bar indicates period of 3-G load. *P < 0.05 vs. GVS(off) group.
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RESULTS
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Figure 1, top, shows typical responses of the AP to 0.1-, 0.2-, and 0.5-mA GVS in a sham-operated rat and a VL rat. At the onset of GVS, the AP rapidly and transiently increased and then recovered toward the pre-GVS control level; however it remained elevated in the sham-operated rat. In contrast, no AP response was observed in the VL rat. Summarized data are presented in Fig. 1, bottom, where the 4 s-average of AP was compared between just before the GVS induction and 30 s after the GVS induction. In sham-operated rats, the AP was significantly increased during GVS of all current sizes. However, this pressor response was completely abolished in VL rats. During 0.1- and 0.2-mA stimulation, no behavioral alteration was observed; however, a slight head sway was observed during 0.5-mA stimulation.
Table 1 shows the baseline data of AP and heart rate measured just before the application of microgravity, hypergravity, or air jet. The baseline AP in GVS(on) was significantly higher than that in corresponding GVS(off) rats in all the experiments.
Figure 2 shows the typical responses of the G value and the AP obtained from a rat in the GVS(off) and GVS(on) groups. The G value decreased smoothly at the onset of free drop and reached a value of <0.001 G at 100 ms after the start of the free drop, and this value was maintained throughout the drop. In a GVS(off)FM rat, the AP increased from 105 mmHg and reached a peak value of 164 mmHg at 2.3 s after induction of microgravity; bradyarrhythmia occurred, and subsequently, the AP decreased to 133 mmHg. The pressor response to microgravity was attenuated by GVS, STAB, and combination of GVS and STAB. Bradyarrhythmia was observed in five rats in the GVS(off)FM group, but it was not observed in GVS(on)FM, GVS(off)STAB, and GVS(on)STAB groups.
Figure 3, top, shows individual and averaged data of AP during the 1-G control period and the microgravity period. In a GVS(off)FM group, the AP increased from 101 ± 5 to 136 ± 6 mmHg; this pressor response was significantly attenuated by GVS(on) [F(1, 15) = 21.491, P = 0.0003]. The AP response to microgravity in the STAB group was also attenuated by GVS(on) [F(1,15) = 96.802, P < 0.0001]. The microgravity-induced pressor responses were compared among four groups (Fig. 3, bottom). The pressor response was calculated as the difference between the 2 s-average of AP just before the induction of microgravity and 4-s average of AP under the influence of microgravity. In the GVS(off)FM group, the pressor response to microgravity was 35 ± 3 mmHg, which was significantly attenuated by GVS [19 ± 1 mmHg in the GVS(on)FM group] and stabilization [24 ± 2 mmHg in the GVS(off)STAB group]. The microgravity-induced pressor response was further attenuated by GVS and stabilization [5 ± 1 mmHg in the GVS(on)STAB group].
Figure 4, left, shows the typical responses of the G value and the AP to hypergravity in a GVS(off) rat and a GVS(on) rat. The G value increased smoothly and reached 3 G at 7 s after the start of the rotation, and this value was maintained for 1 min. The averaged data of AP and heart rate are shown in Fig. 4, right. In the GVS(off) rats, the AP gradually increased at the onset of hypergravity and reached a peak value (137 ± 4 mmHg) at 15 s after the onset. This pressor response (19 ± 3 mmHg) was significantly reduced in GVS(on) rats (6 ± 1 mmHg); however, the absolute pressure reached was quite similar (139 ± 4 mmHg), since GVS itself increased baseline AP (Table 1). Heart rate of GVS(off) rats was gradually and significantly decreased and bottomed (–38 ± 9 beats/min) at 15 s after the onset of hypergravity, while in GVS(on) rats, heart rate did not change during 3-G load.
Figure 5, top, shows individual and averaged data of AP during the pre-air jet control period and air jet period. In GVS(off) rats, the AP increased from 115 ± 3 to 141 ± 5 mmHg. This pressor response was not affected by GVS(on) [F(1, 16) = 0.835, P = 0.3744], i.e., the AP increased from 128 ± 3 to 150 ± 4 mmHg in GVS(on) rats. Thus, in contrast to the pressor response to microgravity or hypergravity, GVS did not suppress the pressor response induced by the air jet.
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DISCUSSION
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The major findings of the present study are 1) GVS induced an increase in AP, which was abolished by VL; 2) GVS reduced the pressor response to gravitational change; and 3) the air jet-induced pressor response was not affected by GVS.
Previously, we had demonstrated that the vestibular system plays a significant role in controlling AP under the influence of microgravity (25). In unrestrained conscious rats, the AP increased during the free drop-induced microgravity (38 ± 4 mmHg); this pressor response was attenuated by VL (20 ± 2 mmHg) or STAB (27 ± 2 mmHg) and completely eliminated by the combination of VL and STAB (7 ± 5 mmHg) (25). These results indicate that the pressor response to free drop-induced microgravity was mediated via the vestibular system and nonvestibular system, which could be blocked by body stabilization. For GVS electrode implantation, the tympanic membrane was penetrated, and the electrodes were fixed in the tympanic bulla. This surgical procedure might impair the vestibular function. However, the microgravity-induced pressor response was not affected by this surgical procedure, i.e., the pressor response in the present study [35 ± 3 mmHg in GVS(off)FM and 24 ± 2 mmHg in GVS(off)STAB] was similar to that in the previous study in which implantation of GVS electrodes was not performed (25). These results suggest that the vestibulocardiovascular reflex was well preserved in the present study.
GVS has been considered as the externally applied vestibular stimulation and been used for exploration of the vestibular function, i.e., GVS was used as a vestibular stimulation and responses of ocular movement, body sway, electromyogram, and sympathetic nerve activity were examined in both human and animal studies (2–4, 10, 17, 19, 20, 26, 28, 32). In human studies, surface electrodes were bilaterally placed over the mastoid process, while in animal studies, the electrodes were implanted in the tympanic cavity as we used in the present study. The current size of the GVS may depend on the species, position, and impedance of electrodes, and stimulation pattern (frequency and duration). The current size of the surface GVS was 2 mA in the human study (3, 4) and 0.62 mA in the guinea pig (17). On the other hand, 0.05–1 mA was employed in chronically implanted electrodes to the tympanic cavity in cats (2), 0.45 mA in frogs (19), and 0.052–5 mA in rats (20, 24).
In the present study, duration and frequency of the GVS were fixed, and the amplitude was altered (0.1, 0.2, and 0.5 mA) while measuring AP. A significant and intensity-dependent pressor response was observed, and the pressor response was completely abolished by VL. These results suggest that the GVS-induced pressor response was mediated by the vestibular system. In other words, up to 0.5-mA GVS, the pressor response was not caused by nonspecific stimulation. No behavioral alteration was observed at 0.1- and 0.2-mA stimulation, while a slight body sway was observed at 0.5-mA stimulation. Thus we employed 0.5 mA as amplitude of GVS in the present study, since this stimulation elicited vestibular-mediated AP response and body sway. In this regard, 0.5-mA GVS was relatively strong. Using this intensity, the baseline AP of the GVS(on) rats was significantly higher than that of the GVS(off) rats by 13–23 mmHg in the microgravity, hypergravity, and air jet experiments.
GVS itself elicited a vestibular-mediated AP increase, and this makes it difficult to interpret results. Although the pressor response to gravitational change was significantly reduced by simultaneously applied GVS, and two-way ANOVA revealed the significant interaction between GVS and gravitational change (Figs. 3 and 4), the absolute pressure reached were quite similar. These results suggest that the increased baseline level of the AP might limit further increase in AP in GVS(on) rats. However, this might not be true, since in the air jet experiment, there was no difference in the pressor response between GVS(on) and GVS(off) rats irrespective of the significant increase in the baseline AP in the GVS(on) rats. Air jet is one of the pure psychoemotional stresses, and evokes pressor response mainly due to a sympathetic-mediated vasoconstriction (9, 29). The vestibular system might not be involved in the air jet-induced pressor response, since this response was not affected by VL (24 ± 3 mmHg in VL rats and 21 ± 1 mmHg in intact rats, unpublished observation from our laboratory). These observations indicate that GVS reduced the vestibular-mediated pressor response but did not affect the non-vestibular-mediated pressor response. Thus it is possible that the reduced pressor response to gravitational change in GVS(on) rats was not due to indirect factors such as elevation of the baseline AP but rather due to a more specific effect on the vestibular system.
Although the mechanism of GVS-induced reduction of the vestibular-mediated AP response is not clear from the present study, three possibilities can be considered. First, GVS might counteract and mask the gravitational change-related vestibular input at the vestibular afferents. It is generally accepted that GVS stimulates both the semicircular canals and the otolith organs (5, 8). Thus it is possible that repeatedly applied GVS elicits continuous activation of the vestibular system, and this might counteract and mask the gravitational change-induced signals.
Second, GVS might reset the operating point of the vestibulocardiovascular system. Since both decrease and increase in gravity elicited an increase in AP, the gravity-AP relationship can be roughly depicted as V shaped (Fig. 6). During GVS, the transfer function of the vestibulocardiovascular system might not be altered and the gravity-AP relationship itself might not be affected, but the operating point might shift to a higher AP range, and then the pressor response to a given gravitational change became small, since the gravity-AP relationship operated at a less-steep portion (Fig. 6, top).
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Fig. 6. Possible mechanisms that reduce pressor response to gravitational change. Since both increase and decrease in gravity elicited an increase in AP, the gravity-AP relationship can be depicted as V shaped. GVS might alter the operating point (top) or slope (bottom) of the gravity-AP relationship.
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Third, GVS might alter the transfer function of the vestibulocardiovascular system and alter the slope of the gravity-AP relationship (Fig. 6, bottom). GVS has been used as a test input for functional exploration of the vestibular system (2–4, 7, 10, 17, 19, 20, 26, 28, 32). Speaking generally, once the test input is applied to the system, the system responds appropriately, and transfer function of the system can be estimated from the input-output relationship. The test input does not alter the transfer function of the system, i.e., test input does not modify the input-output relationship of the system. However, if the intensity of the input is large or input is applied repeatedly, the input acts as a parametric forcing that alters the transfer function of the system, and then the input-output relationship is modified. In the present study it is possible that GVS acted as the parametric forcing of the vestibulocardiovascular system, and the gravity-AP relationship became less steep; the pressor response to a given gravitational change then became small. These possibilities have to be examined in future studies.
The role of the vestibular system in controlling AP in humans has been the focus of many studies. To examine this, the vestibular system has been stimulated by head flexion, GVS, caloric stimulation, linear acceleration, and on- or off-axis rotation, and then the sympathetic and/or cardiovascular responses were measured (4, 6, 12, 13, 22). However, conflicting results were obtained, i.e., the semicircular canal stimulation by rotation did not alter the AP (12), while caloric stimulation resulted in a pressor response (13). Furthermore, the otolith stimulation due to head-down rotation increased muscle sympathetic nerve activity (22), while linear acceleration decreased this activity (6). Hence, the role of the vestibular system on the AP control in humans remains unclear. This is probably due to difference in stimuli, interaction between the vestibular system and other AP control systems, and more importantly because there is no method similar to VL available for interrupting the vestibular system in human studies.
In the present study we demonstrated that GVS reduced the AP response to gravitational change. This is consistent with our previous study, in which microgravity- and hypergravity-induced AP response was reduced by VL (11, 18, 25). These results indicate that GVS has an effect similar to VL and could be employed for an acute interruption of the vestibular-mediated cardiovascular response to gravitational change. Thus we can estimate the role of the vestibular system in controlling AP by comparing the AP response to gravitational change with or without GVS. The feasibility of employing GVS to interrupt the vestibular origin AP response has to be examined in human studies.
In conclusion, GVS counteracts or modifies the vestibulocardiovascular response and locks the vestibular apparatus into a new steady state and then reduces AP response to gravitational change in conscious rats. Thus GVS could be employed as a tool for acute interruption of the vestibulocardiovascular response.
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GRANTS
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This study was supported by the "Ground-Based Research Program for Space Utilization" promoted by the Japan Space Forum.
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ACKNOWLEDGMENTS
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We thank the support staff at the Microgravity Laboratory of Japan for kindly providing technical assistance with the free-drop experiment.
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FOOTNOTES
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Address for reprint requests and other correspondence: H. Morita, Dept. of Physiology, Gifu Univ. Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan (e-mail: zunzunmorita{at}gmail.com)
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.
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Copyright © 2008 by the American Physiological Society.
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ABSTRACT
METHODS
, Sham-operated rats; 
, VL rats. In both sham-operated and VL rats, significant interaction between GVS(off) and GVS(on) was found by 2-way ANOVA. Sham-operated rats, n = 7; VL rats, n = 6. *P < 0.05 vs. GVS(off). 
P < 0.05 vs. VL group.
