Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y
Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y
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DOI：
10.1172/jci.insight.135519
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发表时间：
2020-06-04
期刊：
影响因子：
8
通讯作者：
Vaseghi, Marmar
中科院分区：
文献类型：
--
作者：
Hoang, Jonathan D.;Salavatian, Siamak;Vaseghi, Marmar
交感神经系统在室性心动过速（VT）的发生中起重要作用。然而，尽管使用了最大剂量的β受体阻滞剂治疗，许多患者仍会发生VT，这可能是由于交感神经共递质（如神经肽Y（NPY））的作用。本研究的目的是在猪模型中确定普萘洛尔在高于临床推荐剂量时是否可以通过星状神经节刺激阻断交感神经兴奋的心室电生理效应，以及是否有任何残留效应由NPY介导。在较高的交感神经刺激频率（10和20与4 Hz）下观察到心脏NPY的释放更大。尽管使用更高剂量的普萘洛尔（1.0 mg/kg）治疗，交感神经刺激的电生理学效应仍然存在，激活恢复间期（ARI）（动作电位时程（APD）的替代物）剩余缩短。然而，用NPY Y-1受体拮抗剂BIBO 3304辅助治疗，在增强肌力的同时减少了这些电生理效应。这些数据表明，高剂量β受体阻滞剂治疗不足以阻断交感神经兴奋的电生理效应，并且体内这些电效应的一部分由NPY介导。Y-1受体阻滞剂可能是β-肾上腺素能受体阻滞剂的一种有前途的辅助治疗。
The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y-1 receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y-1 receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.