Chronic Tumor Necrosis Factor‐α infusion induces sympathoexcitation by modulating nitric oxide synthase in rats

Inflammatory molecules specifically tumor necrosis factor‐alpha plays an important role in cardiovascular disorders. Recent findings from our lab suggest that the paraventricular nucleus (PVN) activated TNF‐a induces oxidative and nitrosative stress and contribute to increased sympathetic activity in heart failure rats. In this study, we determined whether chronic TNF‐a infusion induced exaggerated sympathetic activity is modulated by neuronal nitric oxide in the PVN of rats. Methods and results: Sprague‐dawley rats were treated chronically for 5 days with TNF‐a and/or a blocker of cytokine production, pentoxifylline (PTX) or vehicle. Real‐time PCR, immunohistochemistry and Western blotting revealed that mRNA and protein levels for TNF‐a, eNOS and iNOS were increased in the left ventricle and in the PVN, whereas nNOS protein levels were significantly decreased in the PVN of rats treated chronically with TNF‐a. Treatment with PTX restored nNOS level in the PVN and decreased iNOS and eNOS in the LV. Plasma catecholamines measured using HPLC and renal sympathetic nerve activity was increased in TNF‐a treated rats. In contrast, treatment with PTX attenuated catecholamine levels and decreased RSNA. Conclusions: TNF‐a induces exaggerated sympathetic activity by modulating nitric oxide in the PVN and in the left ventricle of rats.