心力衰竭时中枢盐皮质激素受体通过促炎因子发挥交感兴奋作用  

Brain mineralocorticoid receptor induces sympathetic drive by increasing circulating proinflammatory cytokines in neart failure

作　　者：闫宁[1] 藏好晶[1] 雷敬辉[2] 康玉明[1] 

机构地区：[1]山西医科大学基础医学院生理学系,太原市030012 [2]中国科学院动物研究所

出　　处：《中国心血管病研究》2013年第8期620-626,I0001,共8页Chinese Journal of Cardiovascular Research

基　　金：高等学校博士学科点专项科研基金博导类资助课题（20101417110002）;山西省自然科学基金（2010011052-1）

摘　　要：目的探讨RU28318阻断中枢盐皮质激素受体（MR）的作用，验证慢性充血性心力衰竭时，中枢内MR的交感兴奋作用是通过提高外周血促炎因子（PIC）实现的。方法采用结扎冠状动脉左前降支致心肌梗死的方法制备心衰大鼠模型，假手术对照只穿线不结扎。大鼠分两部分处理：一部分给药组大鼠6周内每天口服MR阻滞剂奥孕酸钾（RU28318），每天30mg／kg，溶于饮用水中，对照组给普通饮用水；另一部分使用抗PIG药物己酮可可碱（pentoxifylline，fyIx），每天30mg／kg，溶人饮用水中，以确定单纯促炎因子减少能否足以引起RU28318所致的结果。6周后，保证各组至少有12只动物存活。测定各组大鼠血流动力学指标，评价左心功能；电生理记录肾交感神经放电（RSNA）；ELISA技术测定血浆去甲肾上腺素（NE），PIC包括肿瘤坏死因子-α（TNF-α）、白介素-α（IL-1α）含量，以及脑组织TNF—d和脑脊液中前列腺素E2（PGE2）水平。通过免疫组织化学染色和Westernblot评价环氧酶-2（cox-2）的表达。结果对心衰大鼠外周使用抑制PIC合成的药物PTX产生的各项结果和用RU28318处理的心衰大鼠很相似：治疗后的心衰大鼠右室体重比（RV／BW）降低，左室舒张末压（LVEDP）、肺体重比（1ung／BW）下降，说明右室重构和肺淤血都有所减轻；但心功能没有明显改善（左室最大上升／下降速率LV＋dp／dtmax变化没有统计学意义）；血浆PIC中TNF—d、IL-1和IL-6水平均降低；肾交感神经放电减弱，同时血中NE减少；下丘脑室旁核（PVN）COX-2染色减弱，蛋白含量降低；同时脑脊液中PGE2减少。结论慢性心衰时，利用RU28318阻断MR产生的交感活动抑制是通过降低血中促弗I天l千耗椎阳的．Objective To examined the impact of oral administration of a selective mineralocorticoid re- ceptor （MR） antagonist, RU28318, on blood-borne cytokines that may contribute to the sympathetic drive in heart failure （HF）. Methods Sprague-Dawly （SD） rats were underwent coronary ligation to induce HF, or sham surgery. Followed by 6 weeks treatment with RU28318, 30 mg/kg per day, orally or vehicle （drinking water）. An- other set of rats were treated with anticytokine agents pentoxifylline （PTX, 30 mg/kg daily, in drinking water） to determine whether the PIC lowering effect of PIC antagonism is sufficient to account for the observed responses to RU28318. After 6 weeks, at the end of the experiment, ensure that in each group there are at least 12 animals survived. Left ventricular function parameters were determined by hemodynamic measurements. RV/BW and lung/ BW ratios were calculated, the RSNA was recorded. The plasma NE, P1C level was measured using ELISA tech-niques. Immunohistochemical studies and Western blot were performed to assess the expression of COX-2 in PVN. Results Treatment of HF rats with PTX and RU28318 produced very similar results： RU28318 or PTX -treated HF rats had lower left ventricular end-diastolic pressure （LVEDP）, lower right ventricle/body weight（RV/BW） and lung/body weight ratios （lung/BW）, but no improvement in left ventricular function. Treated rats had lower RSNA and plasma norepinephrine levels, lower plasma TNF-ct,IL-I~ and IL-6, less COX-2 staining in PVN and less prostaglandin E2 （PGE2） in cerebrospinal fluid. COX-2 protein expression in hypothalamus was higher, in HF ＋ VEH versus SHAM ＋ VEH rats, this increases was attenuated in HF＋RU28318/PTX. Conclusion This study re- veals an effect of MR antagonism RU28318 to minimize cytokine-induced sympathetic drive in rats with HF.

关 键 词：充血性心力衰竭 下丘脑室旁核 交感神经系统 盐皮质激素受体 促炎因子 

分 类 号：R589[医药卫生—内分泌]