Drummond Heather A, Xiang Lusha, Chade Alejandro R, Hester Robert
Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi
Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi.
Physiol Rep. 2017 Aug;5(15). doi: 10.14814/phy2.13368.
Acid-sensing ion channel (ASIC) proteins form extracellular proton-gated, cation-selective channels in neurons and vascular smooth muscle cells and are proposed to act as extracellular proton sensors. However, their importance to vascular responses under conditions associated with extracellular acidosis, such as strenuous exercise, is unclear. Therefore, the purpose of this study was to determine if one ASIC protein, ASIC1a, contributes to extracellular proton-gated vascular responses and exercise tolerance. To determine if ASIC1a contributes to exercise tolerance, we determined peak oxygen (O) uptake in conscious ASIC1a mice during exhaustive treadmill running. Loss of ASIC1a was associated with a greater peak running speed (60 ± 2 vs. 53 ± 3 m·min, = 0.049) and peak oxygen (O) uptake during exhaustive treadmill running (9563 ± 120 vs. 8836 ± 276 mL·kg·h, = 6-7, = 0.0082). There were no differences in absolute or relative lean body mass, as determined by EchoMRI. To determine if ASIC1a contributes to vascular responses during muscle contraction, we measured femoral vascular conductance (FVC) during a stepwise electrical stimulation (0.5-5.0 Hz at 3 V for 60 sec) of the left major hind limb muscles. FVC increased to a greater extent in ASIC1a versus ASIC1a mice (0.44 ± 0.03 vs. 0.30 ± 0.04 mL·min·100 g hind limb mass · mmHg, = 5 each, = 0.0009). Vasodilation following local application of external protons in the spinotrapezius muscle increased the duration, but not the magnitude, of the vasodilatory response in ASIC1a mice. Finally, we examined hind limb vascular density using micro-CT and found increased density of 0-80 m vessels (<0.05). Our findings suggest an increased vascular density and an enhanced vasodilatory response to local protons, to a lesser degree, may contribute to the enhanced vascular conductance and increased peak exercise capacity in ASIC1a mice.
酸敏感离子通道（ASIC）蛋白在神经元和血管平滑肌细胞中形成细胞外质子门控的阳离子选择性通道，并被认为可作为细胞外质子传感器。然而，它们在与细胞外酸中毒相关的条件下（如剧烈运动）对血管反应的重要性尚不清楚。因此，本研究的目的是确定一种ASIC蛋白ASIC1a是否有助于细胞外质子门控的血管反应和运动耐力。为了确定ASIC1a是否有助于运动耐力，我们在有意识的ASIC1a基因敲除小鼠进行力竭性跑步机跑步期间测定了峰值摄氧量。ASIC1a基因敲除与更高的峰值跑步速度（60±2对53±3米·分钟，P=0.049）以及力竭性跑步机跑步期间的峰值摄氧量（9563±120对8836±276毫升·千克·小时，n=6-7，P=0.0082）相关。通过EchoMRI测定，绝对或相对瘦体重没有差异。为了确定ASIC1a是否在肌肉收缩期间对血管反应有贡献，我们在对左后肢主要肌肉进行逐步电刺激（3伏，0.5-5.0赫兹，持续60秒）期间测量了股血管传导性（FVC）。与野生型小鼠相比，ASIC1a基因敲除小鼠的FVC增加幅度更大（0.44±0.03对0.30±0.04毫升·分钟·100克后肢质量·毫米汞柱，每组n=5，P=0.0009）。在斜方肌局部应用外部质子后，血管舒张增加了ASIC1a基因敲除小鼠血管舒张反应的持续时间，但未增加其幅度。最后，我们使用微型CT检查了后肢血管密度，发现0-80微米血管的密度增加（P<0.05）。我们的研究结果表明，血管密度增加以及对局部质子的血管舒张反应增强（程度较小）可能有助于ASIC1a基因敲除小鼠血管传导性增强和峰值运动能力增加。
