Guggilam Anuradha, Patel Kaushik P, Haque Masudul, Ebenezer Philip J, Kapusta Daniel R, Francis Joseph
Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA-70803, United States.
Eur J Heart Fail. 2008 Jul;10(7):625-34. doi: 10.1016/j.ejheart.2008.05.004. Epub 2008 Jun 11.
To investigate evidence for the interplay between cytokines, angiotensin II and nNOS in the paraventricular nucleus (PVN), for regulating sympathetic outflow in a rat model of CHF.
Heart failure was induced in Sprague-Dawley rats by coronary artery ligation. One group of rats was treated with pentoxifylline (PTX, 30 mg/kg IP), a cytokine blocker, or vehicle, for 5 weeks. Another group of rats was pre-treated with PTX before coronary ligation to study prior cytokine blocking effect on survival. Both groups were combined in the analysis. Echocardiography demonstrated an increase in LV end-diastolic pressure and Tei index after 5 weeks in CHF rats. ELISA revealed a significant increase in plasma TNF-alpha and IL-1beta in CHF rats. Inducible NOS (iNOS) and angiotensin receptor-type 1 (AT-1R) mRNA expressions were increased, while neuronal NOS (nNOS) was decreased in the PVN of CHF rats; these changes were reversed by PTX. PTX treatment also decreased plasma norepinephrine and epinephrine levels and improved baroreflex control of renal sympathoexcitation in CHF rats. Immunohistochemistry revealed elevated 3-nitrotyrosine formation in the heart and the PVN of CHF rats, but not in PTX treated rats.
PTX decreased both peripheral and central cytokine expression, alleviated nitric oxide dysregulation, and inhibited the formation of peroxynitrite in the PVN resulting in decreased sympathoexcitation in CHF rats.
研究在慢性心力衰竭大鼠模型中，细胞因子、血管紧张素II和神经元型一氧化氮合酶（nNOS）在室旁核（PVN）之间相互作用以调节交感神经输出的证据。
通过冠状动脉结扎在Sprague-Dawley大鼠中诱导心力衰竭。一组大鼠用己酮可可碱（PTX，30mg/kg腹腔注射），一种细胞因子阻滞剂，或溶剂处理5周。另一组大鼠在冠状动脉结扎前用PTX预处理以研究预先进行细胞因子阻断对生存的影响。两组合并进行分析。超声心动图显示，心力衰竭大鼠在5周后左心室舒张末期压力和Tei指数增加。酶联免疫吸附测定（ELISA）显示，心力衰竭大鼠血浆肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）显著增加。诱导型一氧化氮合酶（iNOS）和1型血管紧张素受体（AT-1R）mRNA表达增加，而心力衰竭大鼠PVN中的神经元型一氧化氮合酶（nNOS）减少；这些变化被PTX逆转。PTX治疗还降低了心力衰竭大鼠血浆去甲肾上腺素和肾上腺素水平，并改善了压力反射对肾交感神经兴奋的控制。免疫组织化学显示，心力衰竭大鼠心脏和PVN中3-硝基酪氨酸形成增加，但在PTX治疗的大鼠中未增加。
PTX降低外周和中枢细胞因子表达，减轻一氧化氮调节异常，并抑制PVN中过氧亚硝酸盐的形成，从而导致心力衰竭大鼠交感神经兴奋降低。
