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Central GABAA receptors are involved in inflammatory and cardiovascular consequences of endotoxemia in conscious rats

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Abstract

γ-Aminobutyric acid (GABA), the principal brain inhibitory neurotransmitter, modulates inflammatory and neurodegenerative disease. Here, we tested the hypothesis that central GABAergic neurotransmission mediates the detrimental inflammatory, hemodynamic, and cardiac autonomic actions of endotoxemia. The effects of drugs that block GABA receptors or interfere with GABA uptake or degradation on blood pressure (BP), heart rate (HR), and HR variability (HRV) responses elicited by i.v. lipopolysaccharide (LPS) were assessed in conscious rats. The hypotensive effect of LPS (10 mg/kg) was blunted after intracisternal (i.c.) administration of bicuculline (GABAA receptor antagonist) or saclofen (GABAB receptor antagonist). By contrast, the concomitant LPS-evoked tachycardia and decreases in time domain and frequency domain indices of HRV (measures of cardiac autonomic control) were abolished upon treatment with bicuculline but not saclofen. Increases in serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) caused by LPS disappeared in the presence of bicuculline or saclofen, whereas LPS-evoked increases in serum nitric oxide metabolites (NOx) were counteracted by bicuculline only. None of the endotoxemia effects was altered in rats treated with i.c. tiagabine (GABA reuptake inhibitor) or vigabatrin (GABA transaminase inhibitor). These data suggest a major role for central GABAA receptors in the inflammatory and cardiovascular effects of endotoxemia.

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Abbreviations

BP:

Blood pressure

DMV:

Dorsal motor nucleus of the vagus

FFT:

Fast Fourier transform

GABA:

γ-Aminobutyric acid

HF:

High frequency

HR:

Heart rate

HRV:

Heart rate variability

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

LF:

Low frequency

LPS:

Lipopolysaccharide

MAP:

Mean arterial pressure

MAPKERK :

Extracellular signal-regulated mitogen-activated protein kinases

NOx:

Nitric oxide metabolites

rMSSD:

Root mean square of successive beat-to-beat differences in RR interval durations

SDNN:

Standard deviation of beat-to-beat intervals

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

This project was supported by the Science and Technology Development Fund, Egypt (STDF grant no. 14895).

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  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

    Marwa Y. Sallam, Sahar M. El-Gowilly, Abdel-Galil A. Abdel-Galil & Mahmoud M. El-Mas

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  1. Marwa Y. Sallam
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  2. Sahar M. El-Gowilly
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  3. Abdel-Galil A. Abdel-Galil
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  4. Mahmoud M. El-Mas
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Correspondence to Mahmoud M. El-Mas.

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Sallam, M.Y., El-Gowilly, S.M., Abdel-Galil, AG.A. et al. Central GABAA receptors are involved in inflammatory and cardiovascular consequences of endotoxemia in conscious rats. Naunyn-Schmiedeberg's Arch Pharmacol 389, 279–288 (2016). https://doi.org/10.1007/s00210-015-1201-7

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