Oncotarget

Research Papers: Pathology:

Ketamine-mediated afferent-specific presynaptic transmission blocks in low-threshold and sex-specific subpopulation of myelinated Ah-type baroreceptor neurons of rats

Lu-Qi Wang, Sheng-Zhi Liu, Xin Wen, Di Wu, Lei Yin, Yao Fan, Ye Wang, Wei-Ran Chen, Pei Chen, Yang Liu, Xiao-Long Lu, Hong-Li Sun, Weinian Shou, Guo-Fen Qiao and Bai-Yan Li _

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Oncotarget. 2015; 6:44108-44122. https://doi.org/10.18632/oncotarget.6586

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Abstract

Lu-Qi Wang1,2,*, Sheng-Zhi Liu1,*, Xin Wen1,*, Di Wu2, Lei Yin2, Yao Fan1, Ye Wang3, Wei-Ran Chen1, Pei Chen2, Yang Liu1, Xiao-Long Lu1, Hong-Li Sun3, Weinian Shou4, Guo-Fen Qiao1,2 and Bai-Yan Li1

1 Department of Pharmacology, Harbin Medical University, Harbin, China

2 Key Laboratory of Cardiovascular Medicine Research of Ministry of Education, Harbin Medical University, Harbin, China

3 Department of Pharmacology, Daqing Campus of Harbin Medical University, Daqing, China

4 Riley Heart Research Center, Division of Pediatric Cardiology, Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

* These authors have contributed equally to this work

Correspondence to:

Bai-Yan Li, email:

Guo-Fen Qiao, email:

Keywords: nodose ganglia (NG), nucleus of the solitary tract (NTS), presynaptic neurotransmission, baroreflex afferent pathway, ketamine (Ket), Pathology Section

Received: July 10, 2015 Accepted: November 29, 2015 Published: December 12, 2015

Abstract

Background: Ketamine enhances autonomic activity, and unmyelinated C-type baroreceptor afferents are more susceptible to be blocked by ketamine than myelinated A-types. However, the presynaptic transmission block in low-threshold and sex-specific myelinated Ah-type baroreceptor neurons (BRNs) is not elucidated.

Methods: Action potentials (APs) and excitatory post-synaptic currents (EPSCs) were investigated in BRNs/barosensitive neurons identified by conduction velocity (CV), capsaicin-conjugated with Iberiotoxin-sensitivity and fluorescent dye using intact nodose slice and brainstem slice in adult female rats. The expression of mRNA and targeted protein for NMDAR1 was also evaluated.

Results: Ketamine time-dependently blocked afferent CV in Ah-types in nodose slice with significant changes in AP discharge. The concentration-dependent inhibition of ketamine on AP discharge profiles were also assessed and observed using isolated Ah-type BRNs with dramatic reduction in neuroexcitability. In brainstem slice, the 2nd-order capsaicin-resistant EPSCs were identified and ~50% of them were blocked by ketamine concentration-dependently with IC50 estimated at 84.4 µM compared with the rest (708.2 µM). Interestingly, the peak, decay time constant, and area under curve of EPSCs were significantly enhanced by 100 nM iberiotoxin in ketamine-more sensitive myelinated NTS neurons (most likely Ah-types), rather than ketamine-less sensitive ones (A-types).

Conclusions: These data have demonstrated, for the first time, that low-threshold and sex-specific myelinated Ah-type BRNs in nodose and Ah-type barosensitive neurons in NTS are more susceptible to ketamine and may play crucial roles in not only mean blood pressure regulation but also buffering dynamic changes in pressure, as well as the ketamine-mediated cardiovascular dysfunction through sexual-dimorphic baroreflex afferent pathway.


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