环氧化酶-2 的抑制可降低阿霉素诱导心力衰竭大鼠下丘脑的兴奋。
Inhibition of cyclooxygenase-2 reduces hypothalamic excitation in rats with adriamycin-induced heart failure.
机构信息
Department of Physiology, Shantou University Medical College, Shantou, PR China.
出版信息
PLoS One. 2012;7(11):e48771. doi: 10.1371/journal.pone.0048771. Epub 2012 Nov 13.
BACKGROUND
The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the progression of heart failure (HF). We investigated whether cyclooxygenase-2 (COX-2) inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in rats with adriamycin-induced heart failure.
METHODOLOGY/PRINCIPAL FINDING: Heart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg). On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB) or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW) and lung to body weight (LW/BW) ratios, heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular peak systolic pressure (LVPSP) and maximum rate of change in left ventricular pressure (LV±dp/dtmax) were improved in HF+CLB rats. Angiotensin II (ANG II), norepinephrine (NE), COX-2 and glutamate (Glu) in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH) positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats.
CONCLUSIONS
These results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure.
背景
下丘脑室旁核（PVN）在心力衰竭（HF）的进展中起重要作用。我们研究了 PVN 中环氧化酶-2（COX-2）的抑制是否会减弱阿霉素诱导的心力衰竭大鼠交感神经系统（SNS）和肾素-血管紧张素系统（RAS）的活性。
方法/主要发现：通过腹腔内注射阿霉素在 2 周内诱导心力衰竭（累积剂量为 15mg/kg）。在第 19 天，大鼠给予 COX-2 抑制剂塞来昔布（CLB）或生理盐水每日胃内给药。CLB 治疗可降低死亡率，并减轻 HF 大鼠的心肌萎缩和肺充血。与 HF 大鼠相比，HF+CLB 大鼠的心室重量与体重（VW/BW）和肺重量与体重（LW/BW）比值、心率（HR）、左心室舒张末期压（LVEDP）、左心室收缩压峰值（LVPSP）和左心室压力最大变化率（LV±dp/dtmax）均有所改善。PVN 中的血管紧张素 II（ANG II）、去甲肾上腺素（NE）、COX-2 和谷氨酸（Glu）在 HF 大鼠中增加。HF 大鼠血浆中 ANG II 和 NE 水平升高，心肌中 ANG II 水平升高，血浆和心肌中 ANP 水平降低。CLB 治疗可减轻这些 HF 诱导的变化。HF 大鼠 PVN 中的 COX-2 阳性神经元和促肾上腺皮质激素释放激素（CRH）阳性神经元多于对照组大鼠。CLB 治疗可减少 HF 大鼠 PVN 中的 COX-2 阳性神经元和 CRH 阳性神经元。
结论
这些结果表明，PVN COX-2 可能是 PVN 神经元激活和兴奋性神经递质释放的中间步骤，进一步导致阿霉素诱导的心力衰竭中的交感神经兴奋和 RAS 激活。COX-2 抑制剂的治疗可减轻阿霉素诱导的心力衰竭中的交感神经兴奋和 RAS 激活。
Zotero 插件