From the Florey Institute of Neuroscience and Mental Health (S.L., C.N.M., R.R.), University of Melbourne, Parkville, Australia.
Department of Physiology (S.L., A.M.A.), University of Melbourne, Parkville, Australia.
Hypertension. 2019 Oct;74(4):896-902. doi: 10.1161/HYPERTENSIONAHA.119.12937. Epub 2019 Aug 5.
Early and preferential activation of cardiac sympathetic nerve activity (CSNA) is one of the strongest prognostic markers of heart failure (HF) in patients. Our previous studies have implicated central angiotensin mechanisms as playing a critical role in generating this increase in cardiac sympathetic drive. However, it is unclear if inhibition of ATR (angiotensin type-1 receptors) in different neural groups in the sympathetic pathway to the heart, such as the sympathetic preganglionic neurons in the intermediolateral column of the spinal cord, can reduce cardiac sympathetic drive. We hypothesized that in HF, localized intrathecal administration of the ATR antagonist losartan, specifically into the T1-2 subarachnoid space, would decrease CSNA. In normal conscious sheep, intrathecal infusion of Ang II (angiotensin II; 3.0 nmol/mL per hour), significantly increased mean arterial pressure and CSNA; this effect was abolished by prior administration of losartan (1 mg/h). In an ovine rapid ventricular pacing model of HF, the resting levels of heart rate and CSNA were significantly elevated compared with normals. Intrathecal infusion of losartan (1 mg/h) in HF significantly reduced CSNA and heart rate but did not change arterial pressure. The ATR binding density in the spinal cord was also elevated in the HF group. Our data suggest that ATRs within the spinal cord are responsible, in part, for the increased CSNA in HF and may represent a target for the selective reduction of CSNA in HF.
心脏交感神经活动（CSNA）的早期和优先激活是心力衰竭（HF）患者最强的预后标志物之一。我们之前的研究表明，中枢血管紧张素机制在产生这种心脏交感神经驱动增加方面起着关键作用。然而，尚不清楚是否抑制心脏交感神经通路中不同神经群的 ATR（血管紧张素 1 型受体），如脊髓中间外侧柱中的交感节前神经元，可以降低心脏交感神经驱动。我们假设，在 HF 中，局部鞘内给予 ATR 拮抗剂 losartan，特别是在 T1-2 蛛网膜下腔空间，将降低 CSNA。在正常意识绵羊中，鞘内输注 Ang II（血管紧张素 II；每小时 3.0 nmol/mL）显着增加平均动脉压和 CSNA；这一作用被预先给予 losartan（1 mg/h）所消除。在 HF 的快速心室起搏模型中，与正常相比，静息心率和 CSNA 水平显着升高。HF 中鞘内输注 losartan（1 mg/h）显着降低 CSNA 和心率，但不改变动脉压。脊髓中的 ATR 结合密度在 HF 组中也升高。我们的数据表明，脊髓内的 ATR 部分负责 HF 中 CSNA 的增加，并且可能代表 HF 中 CSNA 选择性降低的靶标。
