Brain tumor necrosis factor-{alpha} modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure.

Cardiovasc Res. 2009 May 20; Kang YM, He RL, Yang LM, Qin DN, Guggilam A, Elks C, Yan N, Guo Z, Francis JAIMS: Increased proinflammatory cytokines after myocardial infarction augment the progression of heart failure (HF) and are of prognostic significance. Recently, we demonstrated that increased proinflammatory cytokines in the brains of HF rats increased paraventricular nucleus superoxide and down-regulated neuronal nitric oxide synthase (nNOS), contributing to sympathoexcitation. In this study, we explored the possible roles of brain proinflammatory cytokines and their effects on modulating paraventricular nucleus neurotransmitters in the exaggerated sympathetic activity in HF. METHODS: Sprague-Dawley rats with HF or sham-operated control (SHAM) rats were treated for 4 weeks with a continuous intracerebroventricular (ICV) infusion of the cytokine blockers, pentoxifylline (PTX, 10 microg/h and 40 microg/h) or etanercept (ETN, 5microg/h and 10 microg/h), or vehicle. Another set of HF and SHAM rats were treated with intraperitoneal (IP) infusion of a similar dose of PTX or ETN. RESULTS: HF rats had increased neuronal excitation accompanied by higher levels of glutamate, norepinephrine (NE) and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), nNOS and 67-kDa isoform of glutamate decarboxylase (GAD67) compared to SHAM rats. Plasma cytokines, NE, epinephrine, angiotensin II, and renal sympathetic nerve activity were also increased in HF rats. ICV treatment with low doses of PTX or ETN attenuated, and high doses prevented, the increased glutamate, NE and TH and decreased GABA, nNOS and GAD67 in the PVN and renal sympathetic nerve activity of HF rats. IP treatment with similar doses of PTX or ETN did not affect glutamate, NE, TH, GABA, nNOS and GAD67 in the paraventricular nucleus and had no effect on renal sympathetic nerve activity of HF rats. CONCLUSION: This study, for the first time, demonstrates that proinflammatory cytokines modulate neurotransmitters in the paraventricular nucleus and contribute to sympathoexcitation in HF.