Korean J Physiol Pharmacol.  2017 Nov;21(6):675-686. 10.4196/kjpp.2017.21.6.675.

Dual control of the vestibulosympathetic reflex following hypotension in rats

• Park SE
• Jin YZ
• Park BR

• KMID: 2395263
• DOI: http://doi.org/10.4196/kjpp.2017.21.6.675

Abstract

Orthostatic hypotension (OH) is associated with symptoms including headache, dizziness, and syncope. The incidence of OH increases with age. Attenuation of the vestibulosympathetic reflex (VSR) is also associated with an increased incidence of OH. In order to understand the pathophysiology of OH, we investigated the physiological characteristics of the VSR in the disorder. We applied sodium nitroprusside (SNP) to conscious rats with sinoaortic denervation in order to induce hypotension. Expression of pERK in the intermediolateral cell column (IMC) of the T4~7 thoracic spinal regions, blood epinephrine levels, and blood pressure were evaluated following the administration of glutamate and/or SNP. SNP-induced hypotension led to increased pERK expression in the medial vestibular nucleus (MVN), rostral ventrolateral medullary nucleus (RVLM) and the IMC, as well as increased blood epinephrine levels. We co-administered either a glutamate receptor agonist or a glutamate receptor antagonist to the MVN or the RVLM. The administration of the glutamate receptor agonists, AMPA or NMDA, to the MVN or RVLM led to elevated blood pressure, increased pERK expression in the IMC, and increased blood epinephrine levels. Administration of the glutamate receptor antagonists, CNQX or MK801, to the MVN or RVLM attenuated the increased pERK expression and blood epinephrine levels caused by SNP-induced hypotension. These results suggest that two components of the pathway which maintains blood pressure are involved in the VSR induced by SNP. These are the neurogenic control of blood pressure via the RVLM and the humoral control of blood pressure via epinephrine release from the adrenal medulla.

Keyword

Epinephrine; Glutamate; Intermediolateral cell column; Orthostatic hypotension; pERK; Vestibulosympathetic reflex

MeSH Terms

6-Cyano-7-nitroquinoxaline-2,3-dione
Adrenal Medulla
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Animals
Blood Pressure
Denervation
Dizocilpine Maleate
Dizziness
Epinephrine
Excitatory Amino Acid Antagonists
Glutamic Acid
Headache
Hypotension*
Hypotension, Orthostatic
Incidence
N-Methylaspartate
Nitroprusside
Rats*
Receptors, Glutamate
Reflex*
Spinal Cord Lateral Horn
Syncope
Vestibular Nuclei
6-Cyano-7-nitroquinoxaline-2,3-dione
Dizocilpine Maleate
Epinephrine
Excitatory Amino Acid Antagonists
Glutamic Acid
N-Methylaspartate
Nitroprusside
Receptors, Glutamate
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

Figure

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  Fig. 1 The effect of intravenous injection of sodium nitroprusside (SNP) and glutamate receptor agonists on blood pressure. ACSF, AMPA, and NMDA, microinjection of artificial cerebrospinal fluid, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid, and N-methyl-D-aspartic acid, respectively, into the MVN. Intravenous injection of SNP at a dose of 15 µg/kg led to a decrease in blood pressure. Microinjection of AMPA or NMDA into the left MVN at a concentration of 1.5 mM and a volume of 10 µl led to increased blood pressure. Blood pressure did not change following the application of ACSF. Arrows indicate the microinjection of ACSF and glutamate receptor agonists. In scale bar, vertical line represents the level of blood pressure (40 mmHg) and horizontal line represents time (1 min).

• 

  Fig. 2 Photomicrographs showing the expression of pERK in the medial vestibular nucleus (MVN), rostral ventrolateral medullary nucleus (RVLM) and intermediolateral cell column (IMC) of the T6 spinal cord, following intravenous injection of SNP. CONT, control with intravenous saline injection; SNP, intravenous SNP injection. Dotted circles represent the location of each nucleus. Scale bar=1 mm in MVN, 400 µm in RVLM and in IMC.

• 

  Fig. 3 Photomicrographs showing the effect of the application of glutamate to the medial vestibular nucleus (MVN) on pERK expression in the spinal cord. (A) The effect of microinjection of glutamate receptor agonists into the left MVN on pERK expression in the intermediolateral cell column of the T6 spinal cord. (B) The effect of a microinjection of glutamate receptor antagonists into the left MVN on pERK expression in the intermediolateral cell column of the T6 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 right lower quadrants A and B represent a higher magnification. 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. (C) Bar histogram showing the effect of the application of glutamate to the medial vestibular nucleus (MVN) on pERK 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. Six animals were included in each group. Values are represented as the mean±SE. *Significant difference from ACSF group (**p<0.01). †Significant difference from ACSF+SNP group (‡p<0.01).

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  Fig. 4 Photomicrographs showing the effect of glutamate application to the rostral ventrolateral medullary nucleus (RVLM) on pERK expression in the spinal cord. (A) The effect of a microinjection of a glutamate receptor agonist into the right RVLM on pERK expression in the intermedio-lateral cell column of the T6 spinal cord. (B) The effect of a pretreatment of a glutamate receptor antagonist into the right RVLM on pERK expression in the intermediolateral cell column of the T6 spinal cord. The right lower quadrants in A and B represent a higher magnification. Notations are as in the previous figures. (C) A bar histogram showing the effect of glutamate application to the rostral ventrolateral medullary nucleus (RVLM) on pERK expression in the spinal cord. Six animals were included in each group. Values are represented as the mean±SE. *Significant difference from ACSF group (**p<0.01). †Significant difference from ACSF+SNP group (‡p<0.01). Notations are as in the previous figures.

• 

  Fig. 5 Expression of pERK in the intermediolateral cell column of T6 spinal cord following microinjection of a glutamate receptor agonist or antagonist into the medial vestibular nucleus. (A) A photograph showing a Western blot for the expression of pERK from a cell membrane fraction of the intermediolateral cell column. (B) The relative density of expression was represented as the ratio between the levels of expression of pERK1/2 protein and β–actin. Six animals were included in each group. Values are represented as the mean SD. *Significant difference from ACSF group (*p<0.05). †Significant difference from ACSF+SNP group (†p<0.05).

• 

  Fig. 6 The effect of glutamate on the blood levels of epinephrine. (A) The effect of microinjection of a glutamate receptor agonist or antagonist into the left medial vestibular nucleus (MVN) on levels of blood epinephrine. (B) The effect of microinjection of a glutamate receptor agonist or antagonist into the left rostral ventrolateral medullary nucleus (RVLM) on the levels of blood epinephrine. Six animals were included in each group. Values are represented as the mean±SE. *Significant difference from ACSF group (**p<0.01). †Significant difference from ACSF+SNP group (‡p<0.01). Notations are as in the previous figures.

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  Fig. 7 A schematic diagram of the neurogenic and humoral control of the vestibulosympathetic reflex. VNC, vestibular nuclear complex; RVLM, rostral ventrolateral medullary nuclei; IMC, intermediolateral cell column of the spinal cord; AM, adrenal medulla; NTS, nucleus tractus solitarius; CVLM, caudal ventrolateral medullary nucleus.

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