DIFFERENTIAL CONTRIBUTION OF N-METHYL-d-ASPARTATE AND NON-N-METHYL-d-ASPARTATE RECEPTORS IN THE INTERMEDIOLATERAL CELL COLUMN OF THE THORACIC SPINAL CORD TO SYMPATHETIC VASOMOTOR TONE DURING EXPERIMENTAL ENDOTOXEMIA IN THE RAT

Abstract

Although the rostral ventrolateral medulla maintains neurogenic vasomotor tone via glutamatergic excitation to sympathetic preganglionic neurons located at the intermediolateral cell column (IML) of thoracic spinal cord, the relative contribution of N-methyl-d-aspartate (NMDA) and non-NMDA receptors on IML neurons at rest or during endotoxemia remain unknown. The present study addressed this issue using a combination of physiological, pharmacological, and double-immunofluorescence approaches. Adult male Sprague-Dawley rats maintained under propofol anesthesia were used. Intrathecal administration of equimolar concentrations (75, 150, or 300 nmol) of an NMDA antagonist, dizocilpine (MK801), or a non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, into T10 to T12 spinal cord elicited a reduction in resting vasomotor tone that was comparable in time course and in magnitude. Although both glutamate receptor antagonists exacerbated mortality and potentiated the elicited hypotension, bradycardia, or reduction in vasomotor tone during experimental endotoxemia induced by intravenous administration of Escherichia coli lipopolysaccharide (30 mg kg-1; results comparable to 6-cyano-7-nitroquinoxaline-2,3-dione at 150 nmol) were obtained only when MK801 was given at 300 nmol. Confocal microscopy further showed that augmented immunoreactivity of NR1 subunit on IML neurons coincided with the phase of endotoxemia when vasomotor tone was augmented; GluR1 immunoreactivity remained stable throughout experimental endotoxemia. These findings suggest that NMDA and non-NMDA receptors on IML neurons contribute to the generation of resting sympathetic vasomotor tone. However, up-regulation of NMDA receptors on IML neurons plays a crucial role in the maintenance of vasomotor tone during endotoxemia.

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

“…Previous research has revealed that NR1 expression is upregulated during inflammation and plays an important role in maintaining the vasomotor tone in the intermediolateral cell column (IML) during endotoxemia (Poon et al, 2006). However, the mechanism underlying NMDAR expression is unclear.…”

“…Previous studies have indicated that NR1 plays a crucial role in maintaining the vasomotor tone in the IML during endotoxemia (Poon et al, 2006). Furthermore, the upregulation of NR1 expression in the spinal cord plays an important role in the development of hyperalgesia after inflammation (Q.…”

“…The development of neuronal injuries mediated by HIV-1 infection or LPS infusion can be arrested by treatment with the NMDAR antagonist MK801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate] or memantine (Zheng et al, 2001;Glezer et al, 2003;Kowal et al, 2004). Although accumulated evidence indicates that NR1 expression is altered during neuroinflammation (Poon et al, 2006;Q. Zhou et al, 2006), the precise role played by NR1 in neuroinflammation remains unknown.…”

Mouse models of sepsis elicit spontaneous action potential discharge and enhance intracellular Ca2+ signaling in postganglionic sympathetic neurons

“…This is particularly true for postganglionic sympathetic neurons innervating the spleen, which substantially reduce tumor necrosis factor-a production from splenic macrophages during endotoxemia (Huston et al, 2006;Rosas-Ballina et al, 2008;Vida et al, 2011;Martelli et al, 2014). Catecholamines also promote protective cardiovascular effects during sepsis that partially counteract the severe hypotension and global tissue hypoxia that ensue (Jones et al, 1994;Poon et al, 2006). Augmentation of the endogenous sympathetic response may therefore provide an effective therapeutic intervention for patients suffering from this condition.…”

Endotoxemia Enhances Catecholamine Secretion From Male Mouse Adrenal Chromaffin Cells Through an Increase In Ca2+ Release From the Endoplasmic Reticulum

“…Inhibition of preganglionic sympathetic neuron activation produces more severe hypotension and increases the mortality rate of endotoxemia (2,18,80). ACCs make an important contribution to this compensatory response because adrenal demedullation, adrenalectomy, adrenal denervation, and ligation of the adrenal vein are associated with more severe hypotension and higher mortality rates during endotoxemia (1)(2)(3)(4)18).…”