Korean J Physiol Pharmacol.  2015 Sep;19(5):427-434. 10.4196/kjpp.2015.19.5.427.

Functional Connections of the Vestibulo-spino-adrenal Axis in the Control of Blood Pressure Via the Vestibulosympathetic Reflex in Conscious Rats

• Lu HJ
• Li MH
• Li MZ
• Park SE
• Kim MS
• Jin YZ
• Park BR

• KMID: 2285587
• DOI: http://doi.org/10.4196/kjpp.2015.19.5.427

Abstract

Significant evidence supports the role of the vestibular system in the regulation of blood pressure during postural movements. In the present study, the role of the vestibulo-spino-adrenal (VSA) axis in the modulation of blood pressure via the vestibulosympathetic reflex was clarified by immunohistochemical and enzyme immunoassay methods in conscious rats with sinoaortic denervation. Expression of c-Fos protein in the intermediolateral cell column of the middle thoracic spinal regions and blood epinephrine levels were investigated, following microinjection of glutamate receptor agonists or antagonists into the medial vestibular nucleus (MVN) and/or sodium nitroprusside (SNP)-induced hypotension. Both microinjection of glutamate receptor agonists (NMDA and AMPA) into the MVN or rostral ventrolateral medullary nucleus (RVLM) and SNP-induced hypotension led to increased number of c-Fos positive neurons in the intermediolateral cell column of the middle thoracic spinal regions and increased blood epinephrine levels. Pretreatment with microinjection of glutamate receptor antagonists (MK-801 and CNQX) into the MVN or RVLM prevented the increased number of c-Fos positive neurons resulting from SNP-induced hypotension, and reversed the increased blood epinephrine levels. These results indicate that the VSA axis may be a key component of the pathway used by the vestibulosympathetic reflex to maintain blood pressure during postural movements.

Keyword

c-Fos protein; Epinephrine; Glutamate; Intermediolateral cell column; Vestibulo-spino-adrenal axis; Vestibulosympathetic reflex

MeSH Terms

Animals
Axis, Cervical Vertebra*
Blood Pressure*
Denervation
Epinephrine
Excitatory Amino Acid Antagonists
Glutamic Acid
Hypotension
Immunoenzyme Techniques
Microinjections
Neurons
Nitroprusside
Rats*
Receptors, Glutamate
Reflex*
Vestibular Nuclei
Natural Resources
Epinephrine
Excitatory Amino Acid Antagonists
Glutamic Acid
Nitroprusside
Receptors, Glutamate

Figure

• 

  Fig. 1 Photomicrographs showing the effect of medial vestibular nucleus (MVN) glutamate on c-Fos protein expression in the spinal cord. (A) Effect of microinjection of glutamate receptor agonists into the left MVN on c-Fos protein expression in the intermediolateral cell column (IMC) of the T7 spinal cord. (B) Effect of pretreatment with microinjection of glutamate receptor antagonists into the left MVN on c-Fos protein expression in the IMC of the T7 spinal cord. Right lower quadrant in A and B represents higher magnification. Rectangles in right lower corner of each diagram represent higher magnification. ACSF, microinjection of artificial cerebrospinal fluid into the MVN; NMDA, microinjection of NMDA into the MVN; AMPA, microinjection of AMPA into the MVN; ACSF+SNP, SNP infusion after pretreatment with ACSF in the MVN; MK801+SNP, SNP infusion after pretreatment with MK801 in the MVN; CNQX+SNP, SNP infusion after pretreatment with CNQX in the MVN. ACSF, artificial cerebrospinal fluid; AMPA, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; IMC, intermediolateral cell column; MK801, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate; NMDA, N-methyl-D-aspartic acid; SNP, sodium nitroprusside.

• 

  Fig. 2 Bar histogram showing the effect of medial vestibular nucleus (MVN) glutamate on c-Fos protein expression in the spinal cord. ACSF, microinjection of artificial cerebrospinal fluid into the MVN; NMDA, microinjection of NMDA into the MVN; AMPA, microinjection of AMPA into the MVN; ACSF+SNP, SNP infusion after pretreatment with ACSF in the MVN; MK801+SNP, SNP infusion after pretreatment with MK801 in the MVN; CNQX+SNP, SNP infusion after pretreatment with CNQX in the MVN. The number of animals in each group was 7. Values are mean±SE. *Significant difference from ACSF group (**p<0.01). †Significant difference from ACSF + SNP group (‡p<0.01). Other notations are as in Fig. 1.

• 

  Fig. 3 Photomicrographs showing the effect of rostral ventrolateral medullary nucleus (RVLM) glutamate on c-Fos protein expression in the spinal cord. (A) Effect of microinjection of glutamate receptor agonists into the right RVLM on c-Fos protein expression in the IMC of the T7 spinal cord. (B) Effect of pretreatment with microinjection of glutamate receptor antagonists into the right RVLM on c-Fos protein expression in the IMC of the T7 spinal cord. Right lower quadrant in A and B represents higher magnification. Rectangles in right lower corner of each diagram represent higher magnification. ACSF, microinjection of artificial cerebrospinal fluid into the RVLM; NMDA, microinjection of NMDA into the RVLM; AMPA, microinjection of AMPA into the RVLM; ACSF+SNP, SNP infusion after pretreatment with ACSF in the RVLM; MK801+SNP, SNP infusion after pretreatment with MK801 in the RVLM; CNQX+SNP, SNP infusion after pretreatment with CNQX in the RVLM. Other notations are as in Fig. 1.

• 

  Fig. 4 Bar histogram showing the effect of rostral ventrolateral medullary nucleus (RVLM) glutamate on c-Fos protein expression in the spinal cord. ACSF, microinjection of artificial cerebrospinal fluid into the RVLM; NMDA, microinjection of NMDA into the RVLM; AMPA, microinjection of AMPA into the RVLM; ACSF+SNP, SNP infusion after pretreatment with ACSF in the RVLM; MK801+SNP, SNP infusion after pretreatment with MK801 in the RVLM; CNQX+SNP, SNP infusion after pretreatment with CNQX in the RVLM. The number of animals in each group was 7. Values are mean±SE. *Significant difference from ACSF group (**p<0.01). †Significant difference from ACSF+SNP group (‡p<0.01). Other notations are as in Fig. 1.

• 

  Fig. 5 The effect of glutamate on levels of blood epinephrine. (A) Effect of microinjection of glutamate receptor agonists or antagonists into the right medial vestibular nucleus (MVN) on levels of blood epinephrine. (B) Effect of microinjection of glutamate receptor agonists or antagonists into the right rostral ventrolateral medullary nucleus (RVLM) on levels of blood epinephrine. The number of animals in each group was 7. Values are mean±SE. *Significant difference from ACSF group (**p<0.01). †Significant difference from ACSF+SNP group (‡p<0.01). Other notations are as in previous figures.

• 

  Fig. 6 The effect of microinjection of glutamate receptor agonists into the MVN on blood pressure. Microinjection of AMPA or NMDA into the MVN increased blood pressure, but blood pressure was not changed following ACSF microinjection. AMPA or NMDA was injected into the right MVN at a concentration of 1.5 mmol/L and a volume of 10 µL. Arrows indicate microinjection of ACSF and glutamate agonists.

• 

  Fig. 7 Schematic diagram of the vestibulo-spino-adrenal (VSA) axis in the vestibulosympathetic reflex. Dotted lines represent pathway of the VSA axis. VNC, vestibular nuclear complex; NTS, nucleus tractus solitarius; CVLM, caudal ventrolateral medulla; RVLM, rostral ventrolateral medulla; IML, intermediolateral cell column of the spinal cord; AM, adrenal medulla.

Reference

1. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006; 7:335–346. PMID: 16760914.

2. Pilowsky PM, Goodchild AK. Baroreceptor reflex pathways and neurotransmitters: 10 years on. J Hypertens. 2002; 20:1675–1688. PMID: 12195099.

3. Schreihofer AM, Ito S, Sved AF. Brain stem control of arterial pressure in chronic arterial baroreceptor-denervated rats. Am J Physiol Regul Integr Comp Physiol. 2005; 289:R1746–R1755. PMID: 16123230.

4. Holstein GR, Friedrich VL Jr, Kang T, Kukielka E, Martinelli GP. Direct projections from the caudal vestibular nuclei to the ventrolateral medulla in the rat. Neuroscience. 2011; 175:104–117. PMID: 21163335.

5. Lan Y, Yang YZ, Jiang X, Li LW, Jin GS, Kim MS, Park BR, Jin YZ. Additive role of the vestibular end organ and baroreceptors on the regulation of blood pressure in rats. Korean J Physiol Pharmacol. 2013; 17:367–373. PMID: 23946697.

6. Yates BJ, Yamagata Y, Bolton PS. The ventrolateral medulla of the cat mediates vestibulosympathetic reflexes. Brain Res. 1991; 552:265–272. PMID: 1913189.

7. Yates BJ, Miller AD. Properties of sympathetic reflexes elicited by natural vestibular stimulation: implications for cardiovascular control. J Neurophysiol. 1994; 71:2087–2092. PMID: 7931504.

8. Yates BJ. Vestibular influences on the sympathetic nervous system. Brain Res Brain Res Rev. 1992; 17:51–59. PMID: 1638275.

9. Normand H, Etard O, Denise P. Otolithic and tonic neck receptors control of limb blood flow in humans. J Appl Physiol (1985). 1997; 82:1734–1738. PMID: 9173934.

10. Kerman IA, Yates BJ, McAllen RM. Anatomic patterning in the expression of vestibulosympathetic reflexes. Am J Physiol Regul Integr Comp Physiol. 2000; 279:R109–R117. PMID: 10896871.

11. Cui J, Mukai C, Iwase S, Sawasaki N, Kitazawa H, Mano T, Sugiyama Y, Wada Y. Response to vestibular stimulation of sympathetic outflow to muscle in humans. J Auton Nerv Syst. 1997; 66:154–162. PMID: 9406120.

12. Cui J, Iwase S, Mano T, Kitazawa H. Responses of sympathetic outflow to skin during caloric stimulation in humans. Am J Physiol. 1999; 276:R738–R744. PMID: 10070134.

13. Yates BJ, Aoki M, Burchill P, Bronstein AM, Gresty MA. Cardiovascular responses elicited by linear acceleration in humans. Exp Brain Res. 1999; 125:476–484. PMID: 10323294.

14. Bent LR, Bolton PS, Macefield VG. Modulation of muscle sympathetic bursts by sinusoidal galvanic vestibular stimulation in human subjects. Exp Brain Res. 2006; 174:701–711. PMID: 16721608.

15. Voustianiouk A, Kaufmann H, Diedrich A, Raphan T, Biaggioni I, Macdougall H, Ogorodnikov D, Cohen B. Electrical activation of the human vestibulo-sympathetic reflex. Exp Brain Res. 2006; 171:251–261. PMID: 16308690.

16. Balaban CD, Beryozkin G. Vestibular nucleus projections to nucleus tractus solitarius and the dorsal motor nucleus of the vagus nerve: potential substrates for vestibulo-autonomic interactions. Exp Brain Res. 1994; 98:200–212. PMID: 8050507.

17. Porter JD, Balaban CD. Connections between the vestibular nuclei and brain stem regions that mediate autonomic function in the rat. J Vestib Res. 1997; 7:63–76. PMID: 9057160.

18. Holstein GR, Friedrich VL Jr, Martinelli GP. Projection neurons of the vestibulo-sympathetic reflex pathway. J Comp Neurol. 2014; 522:2053–2074. PMID: 24323841.

19. Barcroft H, Konzett H. On the actions of noradrenaline, adrenaline and isopropyl noradrenaline on the arterial blood pressure, heart rate and muscle blood flow in man. J Physiol. 1949; 110:194–204. PMID: 15406390.

20. Lan Y, Lu HJ, Jiang X, Li LW, Yang YZ, Jin GS, Park JY, Kim MS, Park BR, Jin YZ. Analysis of the baroreceptor and vestibular receptor inputs in the rostral ventrolateral medulla following hypotension in conscious rats. Korean J Physiol Pharmacol. 2015; 19:159–165. PMID: 25729278.

21. Kim MS, Kim JH, Kry D, Choi MA, Choi DO, Cho BG, Jin YZ, Lee SH, Park BR. Effects of acute hypotension on expression of cFos-like protein in the vestibular nuclei of rats. Brain Res. 2003; 962:111–121. PMID: 12543461.

22. Li XL, An Y, Jin QH, Kim MS, Park BR, Jin YZ. Changes of some amino acid concentrations in the medial vestibular nucleus of conscious rats following acute hypotension. Neurosci Lett. 2010; 477:11–14. PMID: 20399837.

23. Li XL, Nian B, Jin Y, Li LW, Jin GS, Kim MS, Park BR, Jin YZ. Mechanism of glutamate receptor for excitation of medial vestibular nucleus induced by acute hypotension. Brain Res. 2012; 1443:27–33. PMID: 22305141.

24. Park BR, Kim MS, Kim JH, Jin YZ. Effects of acute hypotension on neuronal activity in the medial vestibular nuclei of rats. Neuroreport. 2001; 12:3821–3824. PMID: 11726802.

25. Morgan JI, Curran T. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci. 1991; 14:421–451. PMID: 1903243.

26. Takayama K, Suzuki T, Miura M. The comparison of effects of various anesthetics on expression of Fos protein in the rat brain. Neurosci Lett. 1994; 176:59–62. PMID: 7970238.

27. Wei S, Lei M, Tong M, Ding J, Han Q, Xiao M. Acute baroreceptor unloading evokes Fos expression in anesthetized rat brain. Brain Res Bull. 2008; 76:63–69. PMID: 18395612.

28. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. New York, NY, USA: Academic Press;2007.

29. Kim MS, Jin BK, Chun SW, Lee MY, Lee SH, Kim JH, Park BR. Effect of MK801 on cFos-like protein expression in the medial vestibular nucleus at early stage of vestibular compensation in uvulonodullectomized rats. Neurosci Lett. 1997; 231:147–150. PMID: 9300643.

30. Kim MS, Choi DO, Choi MA, Kim JH, Kim KY, Lee MY, Rhee JK, Chun SW, Park BR. Immunohistochemical detection of phosphorylated form of extracellular signal-regulated kinase 1/2 in rat vestibular nuclei following hemorrhagic hypotension. Neurosci Lett. 2004; 360:49–52. PMID: 15082176.

31. Guyenet PG, Haselton JR, Sun MK. Sympathoexcitatory neurons of the rostroventrolateral medulla and the origin of the sympathetic vasomotor tone. Prog Brain Res. 1989; 81:105–116. PMID: 2616776.

32. Granata AR, Denavit-Saubie M. Bulbospinal sympathoexcitatory pathways in the rat. Brain Res Bull. 1994; 34:601–605. PMID: 7922604.

33. Choi MA, Lee JH, Hwang JH, Choi SJ, Kim MS, Park BR. Signaling pathway of glutamate in the vestibular nuclei following acute hypotension in rats. Brain Res. 2008; 1229:111–117. PMID: 18639534.

34. Yates BJ, Grélot L, Kerman IA, Balaban CD, Jakus J, Miller AD. Organization of vestibular inputs to nucleus tractus solitarius and adjacent structures in cat brain stem. Am J Physiol. 1994; 267:R974–R983. PMID: 7524372.

35. Kesse WK, Parker TL, Coupland RE. The innervation of the adrenal gland. I. The source of pre- and postganglionic nerve fibres to the rat adrenal gland. J Anat. 1988; 157:33–41. PMID: 3198482.

36. Minson J, Arnolda L, Llewellyn-Smith I, Pilowsky P, Chalmers J. Altered c-fos in rostral medulla and spinal cord of spontaneously hypertensive rats. Hypertension. 1996; 27:433–441. PMID: 8698450.

37. Minson J, Kapoor V, Llewellyn-Smith I, Pilowsky P, Chalmers J. Kainic acid injection in NTS evokes hypertension and c-fos expression in spinal cord. Neuroreport. 1992; 3:437–440. PMID: 1633282.

38. Li LW, Jin GS, Yang YZ, Ameer AN, Kim MS, Park BR, Jin YZ. Effect of glutamate on the vestibulo-solitary projection after sodium nitroprusside-induced hypotension in conscious rats. Korean J Physiol Pharmacol. 2015; 19:275–281. PMID: 25954134.

39. Kerman IA, McAllen RM, Yates BJ. Patterning of sympathetic nerve activity in response to vestibular stimulation. Brain Res Bull. 2000; 53:11–16. PMID: 11033203.