第三型酸敏性離子通道調控由乙型交感神經作用劑所引發之心肌缺血

Abstract

心臟局部血液供應不足而造成的心肌缺血與局部酸化，臨床上常會導致胸 痛甚至是死亡。然而感受疼痛抑或是動物體對此現象的反應機制尚待探索。第 三型酸敏性離子通道分布在傳遞心臟感覺的神經束上，且能接受氫離子的刺激 活化而傳遞神經衝動，因此有極大可能參與心肌缺血後的調控。本研究使用心 電圖無線遙測系統，觀察由Isoproterenol 所引發ASIC3 剔除小鼠心肌缺血的 表現。 Isoproterenol 能夠有效的造成小鼠心跳加速，並且產生ST 波不正常的降 低。除了在組織缺氧的實驗中，證明此藥確實能造成局部缺氧，更進一步由心 肌纖維化的病理染色中，得到Isoproterenol 造成心肌損害的證據。在ASIC3 剔除小鼠的實驗裡，我們觀察到心跳加速以及ST 波不正常降低的表現時間都較 野生型小鼠延長，且有較嚴重的心肌纖維化現象。在ST 波恢復正常之前，我們 發現野生型小鼠表現了較高的副交感神經活性。 為了進一步研究調控原理，我們在Isoproterenol 所引發的心肌缺血模型 中，利用阿托品抑制副交感神經的活性，發現阿托品僅會影響野生型小鼠在心 跳加速與ST 波不正常降低等症狀的恢復情形，而ASIC3 剔除小鼠則不受其影 響。相反的，阿托品並不會影響野生型小鼠在心肌纖維化上的表現，卻能降低 心肌纖維化在ASIC3 剔除小鼠中的表現。此外，我們使用resiniferatoxin (RTX) 除去另一種酸敏性通道TRPV1 的影響，並且發現TRPV1 並未參與調控此較輕微 的心肌缺血現象。然而RTX 會造成神經受損，因此引發許多不預期的反應。 此報告中，我們建立了一個由Isoproterenol 所誘發的小鼠心肌缺血模 型，更進一步用來解釋，ASIC3 極有可能扮演察覺此現象的角色，並引發自律 神經的調節。而TRPV1 並未參與在此調控中

Cardiac ischemia (angina pectoris), the situation when heart receives insufficient blood supply, always causes clinical problems such as chest pain or even death. However, how cardiac sensory neurons respond to ischemia and cause pain sensation is still unknown. Acid-sensing ion channel 3 (ASIC3) is the possible candidate expressed on cardiac sensory afferents to sense protons and solicit some regulations. Here, we used radio-telemetry electrocardiography to examine Isoproterenol (Iso)-induced cardiac ischemia in mice lacking ASIC3. Iso-treated mice increased heart rate (tachycardia) and showed ST-depression in electrocardiogram indicating an episode of cardiac ischemia. These results were further proofed by positive labeling of Hypoxyprobe, which reacts with proteins in hypoxic tissues, and pathological consequences of cardiac fibrosis. ASIC3-/- mice performed longer duration of Iso-induced tachycardia and ST-depression as well as more severe cardiac fibrosis than ASIC3+/+ mice. Furthermore, ASIC3+/+ mice showed higher parasympathetic tones than ASIC3-/- mice just before ST-depression vanished based on heart rate variability analyses. To further resolve the underlying mechanism, we used atropine to block parasympathetic neuron activity in Iso-induced cardiac ischemia and found atropine altered the recovery phases of ST-depression and tachycardia only in ASIC3+/+ but not ASIC3-/- mice. In contrast, atropine didn’t affect Iso-induced cardiac fibrosis in ASIC3+/+ mice, whereas atropine reduced Iso-induced cardiac fibrosis in ASIC3-/- mice. Besides, we used resiniferatoxin (RTX) to rule out contribution of TRPV1 (another acid sensor) and found TRPV1 is not involved in this milder cardiac ischemia. However, unexpected neuropathic effects were generated. In conclusion, we developed an animal model for cardiac ischemia induced by Isoproterenol and demonstrated that ASIC3 is involved in detection and triggering ischemia-induced autonomic regulation. TRPV1 is not involved in this condition.