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

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.

Activation of central GABAB receptors offsets the cyclosporine counteraction of endotoxic cardiovascular outcomes in conscious rats

“…In the current study, we reasoned that central GABAergic neuronal circuits might play a role in the CSA counteraction of the cardiovascular actions of endotoxemia. The likelihood of this assumption is supported by the information that links GABAergic neurotransmission to cardiovascular control on the one hand and to inflammatory reactions including those induced by endotoxemia on the other . Additionally, evidence suggests that GABAergic transmission mediates some of the adverse effects of CSA especially neurotoxicity.…”

“…Six groups of male rats ( n = 6–8 each) were used that received one of the following regimens: (i) LPS (10 mg/kg i.v.) + cremophor, (ii) LPS + CSA (10 mg/kg i.v.) (iii) LPS + muscimol (GABA A receptor agonist, 1 μg/10 μL/rat i.c.)…”

“…Endotoxic shock is accompanied by increased mortality despite the use of appropriate antibiotics, adequate resuscitation, and modern intensive care . Several theories implicate bacterial products such as endotoxin as a major initiator of the endotoxic shock cascade that leads to hypotension, cardiac autonomic dysfunction, multiple organ failure, and death . During severe infection, endotoxins initiate an intense primary immune response characterized by the release of potent proinflammatory cytokines such as the tumor necrosis factor‐alpha (TNF‐α) and interleukins (ILs).…”

“…In two recent studies , we reported on the interaction between cardiovascular manifestations of endotoxemia and central GABAergic transmission on the one hand and the immunosuppressant drug cyclosporine (CSA) on the other. In the first study, we found that selective blockade of central GABA A (bicuculline), but not GABA B (saclofen), receptors blunts endotoxemia‐evoked inflammatory, hypotensive, and cardiac autonomic imbalances in rats . In the other study, the same cardiovascular and inflammatory responses elicited by endotoxemia were largely eliminated after consequent administration of CSA .…”

“…With the idea in mind that the cardiovascular and autonomic effects of endotoxemia are blunted after CSA treatment or GABA receptor blockade , the current study investigated whether the counteracting effects of CSA on endotoxemia in rats would be ameliorated in situations of upregulated central GABA activity. This was achieved by studying the effect of central administration of pharmacologic maneuvers that selectively activate GABA A or GABA B receptors or elevate synaptic GABA levels on the LPS‐CSA hemodynamic interaction.…”