Abstract 5833: Bilateral Paraventricular Nucleus Tumor Necrosis Factor-alpha Blockade Modulates Neurotransmitters in Heart Failure
Objective: Increased proinflammatory cytokines (PICs) after myocardial infarction augment the progression of heart failure (HF) and are independent predictors of mortality in patients with HF. Recently, we demonstrated that increased brain PICs in HF rats increased paraventricular nucleus (PVN) superoxide and down-regulated neuronal nitric oxide synthase (nNOS), thereby contributing to sympathoexcitation. In this study, we explored the possible roles of brain PICs and their effects on modulating PVN neurotransmitters in the exaggerated sympathetic activity in HF.
Methods and results: Sprague-Dawley rats with HF or SHAM rats were treated for 4-weeks with a continuous bilateral PVN infusion of the cytokine blockers, pentoxifylline (PTX, 10 μg/h and 30 μg/h) or etanercept (ETN, 2.5 μg/h and 7.5 μg/h), or vehicle. HF rats had increased neuronal excitation accompanied by higher levels of glutamate and norepinephrine (NE), and lower levels of gamma-aminobutyric acid (GABA) and nNOS, when compared to SHAM rats. Plasma levels of cytokines, NE, epinephrine and angiotensin II, were increased in HF rats; renal sympathetic nerve activity (RSNA) was also increased in these animals. Low doses of PTX or ETN attenuated, and high doses prevented, the decreases in PVN GABA and nNOS, the increases in PVN glutamate and NE, and the increases in RSNA seen in HF rats.
Conclusion: This study, for the first time, demonstrates that PVN PICs modulate neurotrans-mitters in the PVN and contribute to sympathoexcitation in HF.