Central GABAA Receptors Provoke Inflammatory and Cardiovascular Consequences of Endotoxemia in Conscious Rats

Abstract

Gamma‐aminobutyric acid (GABA), the principal brain inhibitory neurotransmitter, plays a key role in inflammatory and neurodegenerative disease. In this study, 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 BP lowering effect of LPS (10 mg/kg) was blunted after intracisternal (i.c.) administration of bicuculline (GABAA receptor antagonist, 3 μg/rat) or saclofen (selective GABAB receptor antagonist, 50 μg/rat). By contrast, the concomitant LPS‐evoked tachycardia and decreases in time‐ and frequency domain indices of HRV, measures of cardiac autonomic control, were abolished upon treatment with bicuculline but not saclofen. The increases in serum tumor necrosis factor‐α and interleukin‐6 caused by LPS disappeared in rats treated concurrently with bicuculline or saclofen, whereas the LPS‐evoked increases in serum nitric oxide metabolites was reversed by bicuculline only. We also report that none of the effects of endotoxemia was altered in rats treated with i.c. tiagabine (GABA reuptake inhibitor, 100 μg/rat) or vigabatrin (GABA transaminase inhibitor, 200 μg//rat). These data suggest a major role for central GABAA receptors in the inflammatory and cardiovascular effects of endotoxemia.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895).