HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 287/2/H741    most recent 01023.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Xue, B. Articles by Hay, M. Search for Related Content PubMed PubMed Citation Articles by Xue, B. Articles by Hay, M.

Diminished baroreflex control of heart rate responses in otoconia-deficient C57BL/6JEi head tilt mice

¹Dalton Cardiovascular Research Center and Biomedical Sciences, National Center for Gender Physiology, ²Division of Otolaryngology, Department of Surgery, and ³Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri 65211

Submitted 3 November 2003 ; accepted in final form 24 March 2004

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
The maintenance of stable blood pressure during postural changes is known to involve integration of vestibular and cardiovascular central regulatory mechanisms. Sensory activity in the vestibular system plays an important role in cardiovascular regulation. The purpose of this study was to determine the role of vestibular gravity receptors in normal baroreflex function. Baroreflex heart rate (HR) responses to changes in blood pressure (BP) in otoconia-deficient head tilt (het) mice (n = 8) were compared with their wild-type littermates (n = 12). The study was carried out in conscious male mice chronically implanted with arterial and venous catheters for recording BP and HR and for the infusion of vasoactive drugs. Resting HR was higher in the het mice (661 ± 13 beats/min) than in the wild-type mice (579 ± 20 beats/min). BP was comparable in the het (113 ± 4 mmHg) and wild-type mice (104 ± 4 mmHg). The slopes of reflex decreases in HR in response to phenylephrine (PE) were blunted in the het mice (–5.5 ± 1.5 beats·min^–1·mmHg^–1) compared with the wild-type mice (–8.5 ± 0.9 beats·min^–1·mmHg^–1). Likewise, reflex tachycardic responses to decreases in BP with sodium nitroprusside (SNP) were significantly blunted in the het mice (–0.8 ± 0.3 beats·min^–1·mmHg^–1) versus the wild-type mice (–2.2 ± 0.6 beats·min^–1·mmHg^–1). Frequency-domain analysis of the HR variability suggests that under resting conditions, parasympathetic contribution was lower in the het versus wild-type mice. Mapping of the expression of immediate-early gene product, c-Fos, in forebrain and brain stem nuclei in response to a BP challenge showed no differences between the wild-type and het mice. These results suggest that tonic activity of gravity receptors modulates and is required for normal function of the cardiac baroreflexes.

otoconia receptors; baroreflex; c-Fos expression

Previous neuroanatomical and electrophysiological studies have shown direct projections from vestibular nuclei to brain stem nuclei regulating cardiovascular functions including nucleus tractus solitarius (NTS), dorsal motor vagal nucleus, nucleus ambiguous, caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM) (2, 45, 51–53, 55). Direct stimulation of the vestibular nerves in animals results in increased sympathetic activity to a number of vascular beds (5, 23, 32, 54). However, the importance and role of vestibular inputs in baroreflex regulation of heart rate (HR) have been largely unrecognized, despite the abundant anatomic evidence for synaptic connections from the vestibular nuclear complex to numerous brain stem autonomic nuclei.

Clarifying the potential roles of the respective vestibular sensors in baroreflex function is difficult in part due to the complexity of the labyrinthine organs themselves. Isolating the influence of gravity receptor input from the input of ampular organs, for example, is not easily accomplished experimentally. However, a new approach to this problem has been described recently, which capitalizes on the complete absence of otoconia in the C57BL/6JEi head tilt (het) mouse (17, 26). These mice, originally described by Sweet (46), carry a spontaneous mutation that has been linked to chromosome 17 and results in complete otoconial agensis (3). This mutation produces a selective loss of gravity receptor function, as shown by the absence of responses to linear acceleration stimuli (26). The specificity of the functional loss in these animals provides an opportunity to better assess the influence of the vestibular otoconial organs on baroreflex function. We hypothesize that the activity of gravity receptors enhances the sensitivity of the cardiac baroreflex, thus facilitating homeostasis during changes in posture. To critically test this, we characterized cardiac baroreflex in normal and het mice. The immediate-early genes are considered useful neurobiological tools for mapping brain functional activity (43). Thus the expression and regional distribution of c-Fos protein in brain stem and forebrain nuclei including the vestibular nuclear complex were also compared between normal and het mice to assess the functional activity of brain structures during BP challenges.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
All experiments were carried out in sibling normal C57BL/6J wild-type (het/+) and C57BL/6JEi-het (het/het) otoconia-deficient head tilt male mice. The source stock for these animals was obtained from the Jackson Laboratory. Het animals are homozygous for a spontaneous mutation located on chromosome 17 (3). The labyrinth and both auditory and vestibular sensory organs are normal in these animals except that the macular gravity receptors are devoid of otoconia (3). Gravity receptors are dysfunctional, but ampullar receptors in the semicircular canals that respond normally to rotational head motion are functional. Vestibular gravity receptor responses to linear acceleration are absent in het mice, whereas responses to cranial rotation are present (21, 25). Het animals exhibit relatively normal postures and locomotion except that they may display a subtle head tilt (hence their name). Systematic study of the activity patterns of freely behaving het mice have shown that there is no difference in mean activity levels compared with normal litter mates (het/+) and that the ratio of activity levels during active and resting periods is the same for het and normal animals under various lighting conditions (17). Het mice cannot swim, and when placed in a tank of water briefly they cannot properly orient to the gravitational force vector and must be rescued. This is in striking contrast to normal mice, which are strong swimmers and orient well under the same circumstances. This fact provides the basis for a definitive behavioral test for het mice under controlled breeding conditions. Swimming behavior has been used to identify otoconial deficiencies in the past (14). A breeding cross of het/het by het/+ animals produces offspring of either het/+ or het/het genotypes only. Under these circumstances, swimming tests provide a definitive identification of the het/het genotype, and this strategy was employed in the present study. All animals were taken from the F₁ generation of a het/het x het/+ cross, and swimming tests were performed to provide behavioral confirmation of otoconia deficiencies. All wild-type animals were good swimmers and orientated normally in water, whereas all het animals could not swim normally nor maintain orientation in the water. The experiments were composed of two parts: 1) evaluation of cardiac baroreflexes, and 2) immunohistochemistry of c-Fos expression in forebrain and brain stem nuclei after an increase or a decrease in BP. The experimental protocols in this study were reviewed and approved by the Animal Care and Use Committee of the University of Missouri.

Evaluation of cardiac baroreflexes. Mice (25–30 g, 6–7 mo old) were anesthetized with a mixture of ketamine and xylazine (100 mg/kg, 10 mg/kg) and supplemented with isofluorane when necessary. Arterial and venous catheters made of Micro-Renathane tubing [MRE-025, 0.64 mm outer diameter (OD), 0.30 mm inner diameter (ID), Braintree Scientific] were chronically implanted into the femoral artery and vein for the measurement of arterial pressure and administration of drugs, respectively. The free ends of these catheters were tunneled subcutaneously and exteriorized at the back of the neck. Catheters were then threaded through a polyethylene tubing (2.80 mm OD, 1.77 mm ID, Becton Dickinson). The tubing was secured with sutures. Experiments were carried out in conscious, unrestrained mice in their own cages 4–5 days after surgery. On the day of the experiment, after the arterial and venous catheters were connected to the pressure transducer and drug infusion lines, the mice were allowed to rest for 45–60 min. Experiments were begun only after stable resting BPs and HRs were obtained. Arterial BP was measured with a MLT0698 Disposable BP transducer and continuously recorded using the Powerlab data-acquisition system (Chart version 4.0 for MacOSX) at 1,000 Hz. HR and mean arterial pressure were computed from the arterial pressure pulse. Cardiac baroreflexes were evoked by increasing arterial pressures with ramp infusions of phenylephrine (PE; 1.0 mg/ml) and by lowering BP with sodium nitroprusside (SNP; 1.0 mg/ml). Infusion rates (0.003 ml/min) were monitored such that BP was increased or decreased 30–40 mmHg over a 30- to 45-s period. The drug order was randomized, and, after the catheter was flushed and reloaded, the mice were allowed to recover for 45–60 min before the infusion of the next drug was started. While baroreflexes were tested, we took precautions to ensure the mice were resting quietly in their cages and the resting BPs and HRs were stable for 45–60 min before beginning the experiment. If at any point during the infusion the mice moved, the data set was discarded and the baroreflex test repeated after an appropriate amount of time (45–60 min).

We also measured BP in wild-type and het mice in the presence of the ganglionic blocker hexamethonium (10 mg/kg iv). The mice were allowed to stabilize for at least 60 min, after which arterial pressure was recorded 20 min before hexamethonium infusion and for 20 min after the treatment.

Immunohistochemistry. All of the animals were killed 2 h after acute hypertension or hypotension was induced by PE or SNP infusion. Immunohistochemistry was performed as described previously (1). Briefly, dissected brains were postfixed overnight in 2% paraformaldehyde in isotonic sodium phosphate-buffered saline (PBS) and cryoprotected with 30% sucrose in PBS for 2 days at 4°C. Frozen coronal sections (40 µm) were cut on a microtome and collected in PBS. Endogenous peroxidase activity was inhibited by pretreatment with 0.3% hydrogen peroxide. Blocking was performed with 5% goat serum. Antibody recognizing c-Fos was used in a dilution of 1:1,000 (Santa Cruz Biotechnology, Santa Cruz, CA). The immunoreaction was detected with a Vectastain ABC kit (Vector Laboratory; Burlingame, CA). Enzymatic development was done with the Metal enhanced 3,3'-diaminobenzidine kit (Pierce; Rickford, IL). After the 3,3'-diaminobenzidine reaction was completed, the tissue was rinsed with PBS, mounted on gel-coated slides, air dried, dehydrated, xylene cleared, and coverslipped with Permount (Fisher Chemicals; Fairlawn, NJ). The mounted tissue sections were then examined under a light microscope for c-Fos expression in various forebrain and brain stem nuclei identified according to the brain atlas of Franklin and Paxinos (16). The total number of labeled cells in a given area was counted in each brain nuclei of every animal.

Data analysis. Baroreflex sensitivity was estimated by calculating the slope of regression lines relating 1) absolute BPs to absolute HRs during PE and SNP infusions, and 2) changes in BP and changes in HR during administration of the vasoactive agents. The resting BP trace was also subjected to a frequency spectral density analysis with the help of a MLS310 HR variability module provided with the Powerlab data-acquisition system (Chart version 4.0 for Mac OSX). The software uses a threshold detector to detect all R waves in the raw tracing and generates R-R intervals that are classified as normal, ectopic, or artifacts. The classified R-R intervals are then subjected to power spectral analysis at given frequency ranges. The frequency ranges chosen with respect to the results in the present study were very low frequency, <0.1 Hz; low frequency (LF), 0.1–1.75 Hz; and high frequency (HF), 1.75–5.0 Hz. The HF range chosen here has been previously reported to reflect only parasympathetic control of HR without sympathetic contribution (27). To assess the parasympathetic and sympathetic contribution to HR modulation in the wild-type and het mice, 120 s of resting BP trace from each animal were subjected to the spectral analysis.

Statistical analysis. All the data are presented as means ± SE. Statistically significant differences between groups were determined using an unpaired t-test and factorial ANOVA where applicable. Statistical significance was accepted when P < 0.05.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Resting BP and HR in conscious mice. Resting values for BP were not significantly different (P = 0.126, unpaired t-test, power value = 0.6) between the wild-type (n = 12, 104 ± 4 mmHg) and het mice (n = 8, 113 ± 4 mmHg). In contrast, resting HRs were significantly higher in het mice (661 ± 13 beats/min, P < 0.05) than in wild-type mice (579 ± 20 beats/min) (Fig. 1). Although we did not measure activity levels, there is no compelling reason to suspect that differences in resting HRs were due to differences in activity levels. Previous studies have shown that mean activity level of het and normal animals did not differ significantly (17), and the experimental design in the present study strictly controlled for movement artifacts.

View larger version (8K): [in this window] [in a new window]   Fig. 1. Resting mean arterial blood pressure (MAP; in mmHg) and heart rate (HR; in beats/min) in wild-type (WT; n = 12) or het (n = 8) mice. Resting values for HR were significantly higher in het than WT mice. *Significant difference compared with WT mice (P < 0.05).

View larger version (20K): [in this window] [in a new window]   Fig. 2. A and B: frequency spectra for one WT (A) and one het mouse (B) are compared. The frequency bands that were analyzed are 0.1–1.75 Hz [low frequency (LF)] and 1.75–5.0 Hz [high frequency (HF)]. C and D: frequency analysis of HR on LF (C) and HF (D) components compared between WT and het mice. n.u., Normalized units. *Significant difference compared with WT mice (P < 0.05).

View larger version (16K): [in this window] [in a new window]   Fig. 3. Comparison of HR responses (in beats/min; A) or change in HR (HR; in beats/min; B) to increases in MAP evoked by phenylephrine (PE) in WT (n = 12) and het mice (n = 7). The straight lines are an average representation of the regression lines fit through the data point. *P < 0.05 by ANOVA; significant differences in slope values between the two groups (P < 0.05 by unpaired t-test).

View larger version (18K): [in this window] [in a new window]   Fig. 4. Comparison of HR responses (in beats/min; A) or HR (in beats/min; B) to decreases in MAP (in mmHg) evoked by sodium nitroprusside (SNP) in WT (n = 12) and het mice (n = 6). The straight lines are an average representation of the regression lines fit through the data point. *P < 0.05 by ANOVA; significant differences in slope values between the two groups (P < 0.05 by unpaired t-test).

c-Fos expression in forebrain and brain stem nuclei involved in cardiovascular regulation. Intravenous administration of saline at the same volume and rate as the infused PE or SNP did not induce significant c-Fos expression in forebrain and brain stem nuclei in wild-type (n = 2) and het mice (n = 2). Acute hypertension induced a significant increase in c-Fos expression in the area postrema (AP), NTS, and CVLM. Acute hypotension also produced a significant increase in c-Fos expression in the above regions as well as in the RVLM, paraventricular nucleus (PVN), and supraoptic nucleus (SON). However, there were no differences in c-Fos expression in these forebrain and brain stem nuclei between the wild-type (n = 6) and het mice (n = 6) (Fig. 5). Moreover, c-Fos-like immunoreactive neurons were not found in the vestibular nuclei after the BP changes in both mice (Table 1).

View larger version (124K): [in this window] [in a new window]   Fig. 5. Photomicrographs showing Fos-like immunreactive (FLI) neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) of WT and het mice 2 h after intravenous infusion with saline (Sal) or PE (1.0 mg/ml). A: WT + Sal; B: WT + PE; C: het + PE. CC, central canal. Horizontal solid bar = 200 µm.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

There is considerable experimental evidence in animals and humans to suggest an interaction between the VSR and the baroreceptor reflex in maintaining stable BPs during postural changes (20, 36–40). Although the level at which this interaction occurs is unclear, it is generally accepted that the VSR and baroreflexes share common neural pathways (2, 45, 51–53, 55). An orthostatic challenge or stimulation of vestibular nuclei is known to cause increases in muscle or renal sympathetic nerve activity (10, 36, 38, 54), and in the presence of intact baroreflexes these responses are augmented (37, 38, 40). However, very little is known about the influence of vestibular inputs or more specifically the lack of these inputs on cardiac baroreflexes.

In the present study, this issue was addressed by using the het mouse model with selective gravity receptor dysfunction. In the absence of any gravity receptor vestibular inputs, baroreflex HR responses to changes in BP were significantly blunted in het mice compared with wild-type mice. The blunted responses in het animals occurred despite the fact that in both groups, BP challenges clearly were effective in eliciting similar c-Fos expression in brain regions normally mediating baroreflex function. The latter finding is important because it shows that normal afferent activation of baroreceptors occurred in both groups and the blunted baroreflex HR responses observed in the het mice were not due to an impairment of baroreceptor inputs. The baroreflex test in the present study involved no movement of the animals during the test; thus the reflex was exclusively baroreceptive in nature and could not invoke a vestibular reflex in either the normal or het mice. The data suggest that the absence of otoconia in itself leads to disfacilitation of the baroreflexes in het mice. It is reasonable to conclude that there is a general tonic facilitation of cardiac baroreflexes by gravity receptors even in the absence of tilt-evoked orthostatic challenge.

An absence of tonic gravity receptor inputs may also have contributed to the higher resting HRs in the het mice. In a recent study, rats with lesions of the vestibular nuclei were reported to have high basal HRs but similar BPs compared with intact rats (20). It is well accepted that labryrinthectomy induces compensatory changes in the neuronal architecture and function of the vestibular nuclei (7, 9, 49). In view of the evidence showing neural projections from the vestibular nuclei to major brain stem nuclei involved in autonomic control of HR (34, 42), it is conceivable that altered neuronal function or activity in the vestibular nuclear complex of the het mice has downstream effects on the autonomic regulation of HR.

An elevated sympathetic outflow or low parasympathetic outflow to the heart or both could contribute to a higher HR in the het mice. In the present study, frequency-domain analysis of the HR variability under resting conditions suggests that the parasympathetic contribution (HF) to the HR was lower in the het mice compared with the wild-type mice. It is also possible that the sympathetic contribution to HR is elevated in the het mice; however, a definitive conclusion is difficult because the LF peak is not representative of purely sympathetic activity (27). High sympathetic tone under resting conditions may limit the extent to which the het mice can increase the sympathetic outflow to the heart in response to lowering of BP. Consequently, the blunted reflex tachycardic responses to SNP in the het mice could be due to their inability to increase sympathetic outflow any further. However, ganglionic blockade with hexamethonium produced similar decreases in BP in both groups, suggesting that overall sympathetic outflow in wild-type and het mice are not different.

In humans, activation of the vestibular reflexes after unloading of the baroreceptors with application of lower body negative pressure (LBNP) had an additive effect with regard to increases in sympathetic nerve activity but had no effect on increases in HR (37, 39, 40). This is in contrast to the observations in the present study, where unloading of baroreceptors in the het mice with SNP led to blunted reflex tachycardic responses. One possibility is species differences in autonomic regulation of HR between humans and rodents. In most mammals, resting HRs are predominantly under parasympathetic control and reflex increases in HR in response to unloading of baroreceptors is due to withdrawal of vagal tone and sympathetic activation (4, 18, 33). Compared with humans, mice have a lower parasympathetic drive under resting conditions (8), and it may be the case that the high resting HRs in mice are the result of greater sympathetic drive (22). However, there are also several studies in the literature that suggest that in mice vagal innervation accounts for more of the total range of HR changes than sympathetic innervation (19, 48). This is not unlike the autonomic regulation of HR in humans except in mice the baroreflexes operate around an even higher set point. In response to unloading of baroreceptors, the mice may be unable to withdraw vagal tone or increase sympathetic tone to the heart as much as humans. Although this accounts for the smaller reflex tachycardic responses in mice in general, it does not completely account for the discrepancy between the observation in the study by Ray (37) and the present study. A more likely explanation for these differences is the experimental conditions under which the interaction was studied. In the study by Ray (37), vestibular reflexes are being activated on top of the baroreflex responses evoked by LBNP. Any facilitatory effects of vestibular inputs on HR are probably being masked by significant vagal withdrawal, which has already occurred in response to LBNP. It is possible that the absence of any inputs from the gravity receptors is far more effective in unmasking the influence of vestibular inputs on baroreflex control of HR. Our conclusions are supported by a recent study in rats by Gotoh et al. (20). In this study, activation of vestibular reflexes in response to an increase in gravity resulted in significant bradycardia, which was completely abolished in rats with vestibular lesions. Bradycardia was also attenuated in sinoaortic denervated rats with vestibular lesions despite augmented increases in BP and sympathetic activity. The authors conclude that vestibular inputs can cause bradycardia independent of changes in arterial BP. In light of these observations, the significantly attenuated baroreflex HR responses in the het mice suggest not only that gravity receptor inputs play a significant role in the modulation of cardiac baroreflexes but also that this influence may be, in part, tonic in nature.

The immediate-early genes are considered useful neurobiological tools for mapping brain functional activity (43). Several experimental studies have demonstrated that hypertension and hypotension elicits the expression of c-Fos protein in several forebrain and brain stem nuclei affecting cardiovascular function (29, 31, 35). In the present study, the significant increases in c-Fos expression occur in the area postrema, NTS, VLM, supraoptic nucleus, and paraventricular nucleus after acute BP changes (increase or decrease) in wild-type and het mice, which are consistent with those of previous observations (29, 31). However, the immunohistochemical results also indicate that BP manipulations alone do not produce differences in c-Fos expression in the vestibular nuclei of either group. Recently, Kim et al. (29) reported that c-Fos-like immunoreactive neurons were expressed bilaterally in vestibular nuclei after acute hypotension in normal but not bilaterally labyrinthectomized, anesthetized rats. On the basis of these findings, the authors suggested that peripheral vestibular receptors are essential for neuronal activation in vestibular nuclei after acute changes in BP. Het mice lack otoconia in the two gravity-sensing organs of their inner ear, the utricle and saccule, preventing them from experiencing gravity or linear acceleration (3, 26). Therefore, in the present study, based on the findings of Kim et al. (29), one would expect c-Fos labeling in the vestibular nuclei of wild-type mice but not in het mice after BP manipulations. However, our results do not confirm this expectation. The reason for the discrepancy between the two studies is unknown, but it may reflect differences in experimental conditions, in particular, the use of anesthetized animals by Kim and co-workers. Erickson and Millhorn (13) reported that hypoxic stimulation of the carotid sinus induced c-Fos expression in the bilateral medial vestibular nuclei of urethane-chloralose-anesthetized rats but not in conscious rats. It is known that anesthetic agents such as urethane tend to increase c-Fos expression in brain nuclei regulating cardiovascular function (41, 47). Thus the contrasting c-Fos results of the two studies may be due to differences associated with the use of unanesthetized versus anesthetized animals.

In summary, cardiac baroreflex responses to systemic increases (PE infusion) and decreases (SNP infusion) in BP were significantly blunted in otoconia-deficient (het) mice. These results suggest that tonic activity of gravity receptors modulates and is required for normal function of the cardiac baroreflexes.

	GRANTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This study was supported by National Aeronautics and Space Administration RPG: Human Health From Earth To Space: MO Partnership for Understanding Sex Differences in Physiology (to M. Hay and T. A. Jones) and National Institutes of Health (NIH) Grants HL-62261 (to M. Hay) and R01 DC8–4477 (to S. M. Jones).

	ACKNOWLEDGMENTS

 
We gratefully acknowledge Dr. Jaya Pamidimukkala for critical review of the manuscript.

	FOOTNOTES

 

Address for reprint requests and other correspondence: M. Hay, Dalton Cardiovascular Research Center, Research Park, Univ. of Missouri, Columbia, MO 65211 (E-mail: haym{at}missouri.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 REFERENCES

 

1. Bachtell RK, Wang YM, Freeman P, Risinger FO, and Ryabinim AE. Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors. Brain Res 847: 157–165, 1999.[CrossRef][ISI][Medline]
2. Balaban CD. Vestibular nucleus projections to the parabrachial nucleus in rabbits: implications for vestibular influences on the autonomic nervous system. Exp Brain Res 108: 367–381, 1996.[ISI][Medline]
3. Bergstrom B, You Y, Erway LC, Lyon MF, and Schimenti JC. Deletion mapping of the head tilt (het) gene in mice: a vestibular mutation causing specific absence of otoliths. Genetics 150: 815–822, 1998.[Abstract/Free Full Text]
4. Chen RYZ, Fan FC, Schuessler GB, and Chien S. Baroreflex control of heart rate in humans during nitroprusside-induced hypotension. Am J Physiol Regul Integr Comp Physiol 243: R18–R24, 1982.[Abstract/Free Full Text]
5. Cobbold AF, Megirian D, and Sherrey JH. Vestibular evoked activity in autonomic motor outflows. Arch Ital Biol 106: 113–123, 1968.[ISI][Medline]
6. Cowley AW. Long-term control of arterial blood pressure. Physiol Rev 72: 231–300, 1992.[Abstract/Free Full Text]
7. Curthoys IS and Halmagyi GM. Vestibular compensation: a review of the oculomotor, neural, and clinical consequences of unilateral vestibular loss. J Vestib Res 5: 67–107, 1995.[CrossRef][Medline]
8. Desai KH, Sato R, Schauble E, Barsh GS, Kobilka BK, and Bernstein D. Cardiovascular indexes in the mouse at rest and with exercise: new tools to study models of cardiac disease. Am J Physiol Heart Circ Physiol 272: H1053–H1061, 1997.[Abstract/Free Full Text]
9. Dieringer N. Vestibular compensation: neural plasticity and its relations to functional recovery after labyrinthine lesions in frogs and other vertebrates. Prog Neurobiol 46: 97–129, 1995.[CrossRef][ISI][Medline]
10. Doba N and Reis DJ. Role of the cerebellum and the vestibular apparatus in regulation of orthostatic reflexes in the cat. Circ Res 40: 9–18, 1974.[Medline]
11. Eckberg DL, Abboud FM, and Mark AL. Modulation of carotid baroreflex responsiveness in man: effects of posture and propranolol. J Appl Physiol 41: 383–387, 1976.[Abstract/Free Full Text]
12. Eckberg DL and Sleight P. Human Baroreflexes in Health and Disease. New York: Oxford University Press, 1992, p. 3–299.
13. Erickson JT and Millhorn DE. Fos-like protein is induced in neurons of the medulla oblongata after stimulation of the carotid sinus nerve in awake and anesthetized rats. Brain Res 567: 11–24, 1991.[CrossRef][ISI][Medline]
14. Erway L, Hurley LS, and Fraser AS. Congenital ataxia and otolith defects due to manganese deficiency in mice. J Nutr 100: 643–654, 1970.[Abstract/Free Full Text]
15. Farquhar WB, Taylor A, Darling SE, Chase KP, and Freeman R. Abnormal baroreflex responses in patients with idiopathic orthostatic intolerance. Circulation 12: 3086–3091, 2000.
16. Franklin KBJ and Paxinos G. The Mouse Brain in Stereotaxic Coordinates. San Diego, CA: Academic, 1996.
17. Fuller PM, Jones TA, Jones SM, Fuller CA. Neurovestibular modulation of circadian and homeostatic regulation: a vestibulo-hypothalamic connection? Proc Natl Acad Sci USA 99: 15723–15728, 2002.[Abstract/Free Full Text]
18. Furlan R, Jacob G, and Snell M. Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation 98: 2154–2159, 1998.[Abstract/Free Full Text]
19. Gehrmann J, Hammer PE, Maguire CT, Wakimoto H, Triedman JK, and Berul CI. Phenotypic screening for heart rate variability in the mouse. Am J Physiol Heart Circ Physiol 279: H733–H740, 2000.[Abstract/Free Full Text]
20. Gotoh TM, Fujiki N, Mattsuda T, Gao S, and Morita H. Roles of baroreflex and vestibulosympathetic reflex in controlling arterial blood pressure during gravitational stress in conscious rats. Am J Physiol Regul Integr Comp Physiol 286: R25–R30, 2004.[Abstract/Free Full Text]
21. Harrod CG and Baker JF. The vestibulo-ocular reflex (VOR) in otoconia deficient head tilt mutant mice versus wild type C57BL/6 mice. Brain Res 972: 75–83, 2003.[CrossRef][ISI][Medline]
22. Ishii K, Kuwahara M, Tsubone H, and Sugano S. Autonomic nervous function in mice and voles (Microtus arvalis): investigation by power spectral analysis of heart rate variability. Lab Anim 30: 359–364, 1996.[Abstract/Free Full Text]
23. Ishikawa T and Mikazawa T. Sympathetic responses evoked by vestibular stimulation and their interactions with somatosympathetic reflexes. J Auton Nerv Syst 1: 243–254, 1980.[CrossRef][ISI][Medline]
24. Jacobsen TN, Morgan BJ, and Scherrer U. Relative contribution of cardiopulmonary and sinoaortic baroreflexes in causing sympathetic activation in the human skeletal muscle circulation during orthostatic stress. Circ Res 73: 367–378.
25. James MA and Potter JF. Orthostatic blood pressure changes and arterial baroreflex sensitivity in elderly subjects. Age Ageing 28: 522–530, 1999.[Abstract/Free Full Text]
26. Jones SM, Erway LC, Bergstrom RA, Schimenti JC, and Jones TA. Vestibular responses to linear acceleration are absent in otoconia-deficient C57BL/6JEi-het mice. Hear Res 135: 56–60, 1999.[CrossRef][ISI][Medline]
27. Just A, Faulhaber J, and Ehmke H. Autonomic cardiovascular control in conscious mice. Am J Physiol Regul Integr Comp Physiol 279: R2214–R2221, 2000.[Abstract/Free Full Text]
28. Kamiya A, Iwase S, Kitazawa H, Mano T, Vinogradova OL, and Kharchenko IB. Baroreflex control of muscle sympathetic nerve activity after 120 days of 6° head-down bed rest. Am J Physiol Regul Integr Comp Physiol 278: R445–R452, 2000.[Abstract/Free Full Text]
29. Kim MS, Kim JH, Kry D, Choi MA, Choi DO, Cho BG, Jin YZ, Lee SH, and Park BR. Effects of acute hypotension on expression of cFos-like protein in the vestibular nuclei of rats. Brain Res 962: 111–121, 2003.[CrossRef][ISI][Medline]
30. Kuipers NT, Sauder CL, and Ray CA. Aging attenuates the vestibulosympathetic reflex in humans. J Physiol 548: 955–961, 2003.[Abstract/Free Full Text]
31. Li YW and Dampney RA. Exprssion of Fos-like protein in brain following sustained hypertension and hypotension in conscious rabbits. Neuroscience 61: 613–634, 1994.[CrossRef][ISI][Medline]
32. Megirian D and Manning JW. Input-output relations in the vestibular system. Arch Ital Biol 105: 151–164, 1967.
33. Pagani M, Somers VK, and Furlan R. Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension 12: 600–610, 1988.[Abstract/Free Full Text]
34. Porter JD and Balaban CD. Connections between the vestibular nuclei and brain stem regions that mediate autonomic function in the rat. J Vestib Res 7: 63–76, 1997.[CrossRef][ISI][Medline]
35. Potts PD, Polson JW, Hirooka Y, and Dampney RA. Effects of sinoaortic denervation on Fos expression in the brain evoked by hypertension and hypotension in conscious rabbits. Neuroscience 77: 503–520, 1997.[CrossRef][ISI][Medline]
36. Ray CA. Effect of gender on vestibular sympathoexcitation. Am J Physiol Regul Integr Comp Physiol 279: R1330–R1333, 2000.[Abstract/Free Full Text]
37. Ray CA. Interaction of the vestibular system and baroreflexes on sympathetic nerve activity in humans. Am J Physiol Heart Circ Physiol 279: H2399–H2404, 2000.[Abstract/Free Full Text]
38. Ray CA and Carter JR. Vestibular activation of sympathetic nerve activity. Acta Physiol Scand 177: 313–319, 2003.[CrossRef][ISI][Medline]
39. Ray CA and Monahan KD. Aging attenuates the vestibulosympathetic reflex in humans. Circulation 105: 956–961, 2002.[Abstract/Free Full Text]
40. Ray CA and Monahan KD. The vestibulosympathetic reflex in humans: neural interactions between cardiovascular reflexes. Clin Exp Pharmacol Physiol 29: 98–102, 2002.[CrossRef][ISI][Medline]
41. Rocha MJ and Herbert H. Effects of anesthetics on Fos protein expression in autonomic brain nuclei related to cardiovascular regulation. Neuropharmacology 36: 1779–1781, 1997.[CrossRef][ISI][Medline]
42. Ruggiero DA, Mtui EP, Otake K, and Anwar M. Vestibular afferents to the dorsal vagal complex: substrate for vestibular-autonomic interactions in the rat. Brain Res 743: 294–302, 1996.[CrossRef][ISI][Medline]
43. Sharp FR, Sagar SM, and Swanson RA. Metabolic mapping with cellular resolution: c-fos vs. 2-deoxyglucose. Crit Rev Neurobiol 7: 205–228, 1993.[ISI][Medline]
44. Shortt TL and Ray CA. Sympathetic and vascular responses to head-down neck flexion in humans. Am J Physiol Heart Circ Physiol 272: H1780–H1784, 1997.[Abstract/Free Full Text]
45. Steinbacher JRBC and Yates BJ. Processing of vestibular and other inputs by the caudal ventrolateral medullary reticular formation. Am J Physiol Regul Integr Comp Physiol 271: R1070–R1077, 1996.[Abstract/Free Full Text]
46. Sweet H. Head tilt (het). Mouse Newslett 63: 19, 1980.
47. Takayama K, Suzuki T, and Miura M. The comparison of effects various anesthetics on expression of Fos protein in the rat brain. Neurosci Lett 176: 59–62, 1994.[CrossRef][ISI][Medline]
48. Uechi M, Asai K, Osaka M, Smith A, Sato N, Wagner TE, Ishikawa Y, Hayakawa H, Vatner DE, Shannon RP, Homcy CJ, and Vatner SF. Depressed heart rate variability and arterial baroreflex in conscious transgenic mice with overexpression of cardiac G_s. Circ Res 82: 416–423, 1998.[Abstract/Free Full Text]
49. Yamanaka T, Him A, Cameron SA, and Dutia MB. Rapid compensatory changes in GABA receptor efficacy in rat vestibular neurones after unilateral labyrinthectomy. J Physiol 523: 413–424, 2000.[Abstract/Free Full Text]
50. Yates BJ. Vestibular influences on the autonomic nervous system. Ann NY Acad Sci 781: 458–473, 1996.[Abstract]
51. Yates BJ, Balaban CD, Miller AD, Endo K, and Yamaguchi Y. Vestibular inputs to the lateral tegmental field of the cat: potential role in autonomic control. Brain Res 689: 197–206, 1995.[CrossRef][ISI][Medline]
52. Yates BJ, Goto T, and Bolton PS. Responses of neurons in the rostral ventrolateral medulla of the cat to natural vestibular stimulation. Brain Res 601: 255–264, 1993.[CrossRef][ISI][Medline]
53. Yates BJ, Grelor L, Kerman IA, Balaban CD, Jakus J, and Miller AD. Organization of vestibular inputs to nucleus tractus solitarius and adjacent structures in cat brain stem. Am J Physiol Regul Integr Comp Physiol 267: R974–R983, 1994.[Abstract/Free Full Text]
54. Yates BJ and Miller AD. Properties of sympathetic reflexes elicited by natural vestibular stimulation: implications for cardiovascular control. J Neurophysiol 71: 2087–2092, 1994.[Abstract/Free Full Text]
55. Yates BJ, Yamagata Y, and Bolton PS. The ventrollateral medulla of the cat mediates vestibulosympathetic reflexes. Brain Res 552: 265–272, 1991.[CrossRef][ISI][Medline]

This article has been cited by other articles:

				J. Thireau, B. L. Zhang, D. Poisson, and D. Babuty Heart rate variability in mice: a theoretical and practical guide Exp Physiol, January 1, 2008; 93(1): 83 - 94. [Abstract] [Full Text] [PDF]

				V. Baudrie, D. Laude, and J.-L. Elghozi Optimal frequency ranges for extracting information on cardiovascular autonomic control from the blood pressure and pulse interval spectrograms in mice Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R904 - R912. [Abstract] [Full Text] [PDF]

				H. M. Stauss Power spectral analysis in mice: what are the appropriate frequency bands? Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R902 - R903. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 287/2/H741    most recent 01023.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Xue, B. Articles by Hay, M. Search for Related Content PubMed PubMed Citation Articles by Xue, B. Articles by Hay, M.