AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure
AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure
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DOI：
10.1152/ajpheart.01245.2003
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发表时间：
2004-10-01
影响因子：
4.8
通讯作者：
Wang, W
中科院分区：
文献类型：
--
作者：
Zhu, GQ;Gao, L;Wang, W
以往的研究表明，慢性心力衰竭(CHF)犬和大鼠的心脏交感传入反射(CSAR)增强，中枢血管紧张素Ⅱ1型受体(AT(1)R)参与了这种增强反射。本研究旨在探讨侧脑室注射和微量注射AT(1)R反义寡核苷酸是否能减轻冠脉结扎所致心力衰竭大鼠肾交感神经活动(RSNA)的增强和肾交感神经活动(RSNA)的降低。在左心室心外膜表面应用缓激肽诱发CSAR。心外膜注射缓激肽后，CHF大鼠的反射反应增强。侧脑室注射(侧脑室)或室旁核(室旁核)微量注射AT(1)R反义寡核苷酸或杂合寡核苷酸后，每隔50min测定一次缓激肽的反应。在(1)给予反义核酸后5h，室旁核Rm RNA和蛋白水平显著降低。反义寡核苷酸显著降低慢性心力衰竭大鼠的静息RSNA，并使其对缓激肽增强的CSAR反应正常化。杂乱的寡核苷酸不会改变CHF大鼠的静息RSNA或对缓激肽的增强反应。在假手术大鼠中，无论是给予反义寡核苷酸还是杂乱寡核苷酸，都没有发现明显的影响。这些结果有力地表明，中枢性AT(1)R基因反义表达减少了AT(1)R蛋白的表达，并使这一兴奋性交感反射的增强正常化，基因调控蛋白的表达可用于正常化CHF的交感增强。
Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT(1)R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT(1)R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT(1)R mRNA. AT(1)R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT(1)R mRNA antisense reduces expression of AT(1)R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.