Heart and Vascular Institute and Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania.
Am J Physiol Heart Circ Physiol. 2020 May 1;318(5):H1316-H1324. doi: 10.1152/ajpheart.00137.2020. Epub 2020 Apr 17.
The exercise pressor reflex arises from contracting muscle and is manifested by increases in arterial pressure, heart rate, and cardiac contractility. In patients with peripheral artery disease, the exercise pressor reflex is exaggerated. This effect is believed to be caused by a metabolite whose concentration is increased when the working muscles are inadequately perfused. Previous work in rats with simulated peripheral artery disease has shown that pharmacological blockade of acid-sensing ion channel 3 (ASIC3), which is found on group III and IV afferents, prevented the exaggeration of the exercise pressor reflex. Blockade of ASIC3, however, may have off-target effects that preclude a conclusion that ASIC3 plays a role in evoking the reflex in rats with simulated peripheral artery disease. In the present experiments performed in decerebrated rats with simulated peripheral artery disease, we compared the exercise pressor reflex in rats with a functional knockout of the ASIC3 (KO) with the reflex in their wild-type counterparts (WT). We found that the exercise pressor reflex in ASIC3 KO rats was significantly lower than the exercise pressor reflex in their WT counterparts ( < 0.05). ASIC 3 KO rats demonstrated lower pressor responses to intra-arterial injection of diprotonated phosphate (86 mM; pH 6.0), lactic acid (12 mM; pH 2.85), and capsaicin (0.2 μg; pH 7.2) ( < 0.05). In contrast, both ligated WT and ASIC3 KO rats displayed similar pressor responses to tendon stretch ( > 0.05). We conclude that ASIC3 play an important role in evoking the exaggerated exercise pressor reflex in rats with peripheral artery disease. We used a genetic approach to test the hypothesis that the magnitude of the exercise pressor reflex evoked in ligated ASIC3 KO rats was significantly lower than the magnitude of the exercise pressor reflex evoked in their ligated wild-type (WT) counterparts. The pressor response to contraction in ligated ASIC3 KO rats was significantly smaller than was the pressor response to contraction in ligated WT rats.
运动加压反射源于肌肉收缩，表现为动脉血压、心率和心肌收缩力增加。在患有外周动脉疾病的患者中，运动加压反射会被夸大。这种效应被认为是由一种代谢物引起的，当工作肌肉灌注不足时，其浓度会增加。先前在模拟外周动脉疾病的大鼠中的研究表明，阻断位于 III 型和 IV 型传入神经上的酸感应离子通道 3（ASIC3）的药理学阻断作用可防止运动加压反射的夸大。然而，ASIC3 的阻断可能具有脱靶效应，从而不能得出 ASIC3 在模拟外周动脉疾病的大鼠中引起反射的结论。在本实验中，我们在模拟外周动脉疾病的去大脑大鼠中进行了实验，比较了 ASIC3 功能敲除（KO）大鼠与野生型（WT）大鼠的运动加压反射。我们发现，ASIC3 KO 大鼠的运动加压反射明显低于 WT 大鼠（<0.05）。ASIC3 KO 大鼠对二质子化磷酸盐（86mM；pH6.0）、乳酸（12mM；pH2.85）和辣椒素（0.2μg；pH7.2）的动脉内注射的加压反应较低（<0.05）。相比之下，结扎 WT 和 ASIC3 KO 大鼠对肌腱拉伸的加压反应相似（>0.05）。我们得出结论，ASIC3 在诱发外周动脉疾病大鼠运动加压反射过度方面发挥重要作用。我们使用基因方法来测试以下假设：在结扎的 ASIC3 KO 大鼠中诱发的运动加压反射的幅度明显低于在结扎的 WT 大鼠中诱发的运动加压反射的幅度。结扎的 ASIC3 KO 大鼠的收缩加压反应明显小于结扎的 WT 大鼠的收缩加压反应。
