下丘脑室旁核CRH神经元激活在慢性充血性心力衰竭中的交感兴奋作用

目的:观察慢性心衰时下丘脑室旁核(PVN)内促肾上腺皮质激素释放激素(CRH)表达变化及其与交感神经活动之间的关系。方法:健康雄性SD大鼠,冠脉结扎制备心衰模型,侧脑室插管渗透压泵持续给药。假手术组和心衰组给予人工脑脊液0.25μL/h,心衰给药组给予CRH抑制剂αh-CRH 15 mg/h。同时,选取健康雄性体内CRH合成不足的Lewis大鼠与同源纯种Fischer 344大鼠分别制备心衰模型和假手术对照进行对比研究。4周后,测定左室舒张末压(LVEDP)、左室内压最大上升和下降速率(±dp/dtmax)、右心室/体重比(RV/BW)、肺/体重比(lung/BW)、肾交感神经放电活动(RSNA)、血浆去甲肾上腺素(NE)浓度和PVN内CRH阳性神经元数目。血浆促肾上腺皮质激素(ACTH)含量。结果:与假手术组相比,SD心衰大鼠PVN内CRH阳性神经元数目明显增加,血浆ACTH浓度升高,RSNA增强,血浆NE浓度增加,LVEDP、lung/BW和RV/BW增加,±dp/dtmax降低;心衰模型后给予αh-CRH可明显逆转上述各种变化(P0.05)。Fisher 344大鼠心衰组和假手术对照相比,PVN内CRH阳性神经元数目明显增加,血浆ACTH浓度升高,RSNA增强,外周血NE浓度升高,LVEDP、RV/BW和lung/BW增加,±dp/dtmax下降(P0.05)。但Lewis大鼠心衰组和假手术对照相比,以上各指标改变均不明显。结论:慢性心衰时,下丘脑室旁核CRH神经元被激活,激活的CRH神经元可增强外周交感神经活动,加重心功能恶化。

Activation of corticotrophin releasing hormone-containing neurons in hypothalamic paraventricular nucleus contributes to sympathoexcitation in rats with congestive heart failure

AIM:To observe the expression of corticotropin releasing hormone (CRH) within the paraventricular nucleus of hypothalamus (PVN) and to explore the relationship between the activated CRH-containing neurons and sympathetic activity in rats with heart failure (HF).METHODS:Healthy male Sprague-Dawley (SD) rats were subjected to coronary artery ligation to induce HF,and chronic intracerebroventricular (ICV) infusion was performed by osmotic pump for 4 weeks.The rats in sham group and HF group were given vehicle (VEH;artificial cerebrospinal fluid 0.25 μL/h).The rats in HF plus treatment group were treated with CRH competitive inhibitor αh-CRH (15 mg/h).Meanwhile,the Lewis rats and Fischer 344 rats for control study also underwent coronary ligation to induce HF or sham surgery.After 4 weeks,left ventricular end-diastolic pressure (LVEDP) and maximum positive/negative change in pressure over time (±dp/dt_max) were determined.The right ventricular-to-body weight (RV/BW) and lung-to-body weight (lung/BW) ratios were calculated.The renal sympathetic nerve activity (RSNA) was recorded and the plasma norepinephrine (NE) level was measured.The expression of CRH in the PVN combined with the plasma adrenocorticotrophic hormone (ACTH) levels were measured.RESULTS:Compared with the sham-SD rats,the HF-SD rats had a greater number of CRH positive neurons in the PVN (accordingly the plasma ACTH levels were increased),accompanied by decreased±dp/dt_max and increased RSNA,plasma NE,LVEDP,lung/BW and RV/BW.However,ICV treatment with αh-CRH attenuated these changes in the HF-SD rats (P<0.05).Compared with the sham-Fisher 344 rats,the HF-Fisher 344 rats also had a greater number of CRH positive neurons in the PVN (accordingly the plasma ACTH levels were increased).In addition,they had significantly increased RSNA and plasma NE level,higher LVEDP,RV/BW and lung/BW,and lower±dp/dt_max(P<0.05).Compared with the SHAM-Lewis rats,the HF-Lewis rats had not significantly changed in the above parameters.CONCLUSION:In CHF,the CRH-containing neurons in PVN are activated,thus aggravating cardiac function by increasing sympathoexcitation.