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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.

In addition to insulin sensitization, the thiazolidenedione drug pioglitazone exhibits favorable circulatory effects. Here, we hypothesized that pioglitazone protects against the hypertension and related vascular derangements caused by the immunosuppressant drug cyclosporine (CSA). Compared with vehicle (olive oil)-treated rats, chronic treatment with CSA (20 mg/kg/day s.c., for 14 days) increased blood pressure (BP), reduced the aortic protein expression of phosphorylated eNOS (p-eNOS), and impaired responsiveness of isolated aortas to endothelium-dependent vasorelaxations induced by carbachol. The effects of CSA on BP, aortic p-eNOS, and carbachol relaxations were abolished upon concurrent administration of pioglitazone (2.5 mg/kg/day). Serum levels of adiponectin, an adipose tissue-derived adipokine, were not altered by CSA but showed significant elevations in rats treated with pioglitazone or pioglitazone plus CSA. The possibility that alterations in the antioxidant and/or lipid profile contributed to the CSA-pioglitazone BP interaction was investigated. Pioglitazone abrogated the oxidative (aortic superoxide dismutase), lipid peroxidation (aortic malondialdyde), and dyslipidemic (serum LDL levels and LDL/HDL ratio) effects of CSA. Histologically, CSA caused focal disruption in the endothelial lining of the aorta and this effect disappeared in rats co-treated with pioglitazone. Collectively, pioglitazone abrogates the hypertensive effect of CSA via ameliorating detrimental changes in vascular endothelial NOS/NO pathway and oxidative and lipid profiles caused by CSA.

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