Department of Physical Therapy, University of Florida, Gainesville, Florida.
Breathing Research and Therapeutics Center, University of Florida, Gainesville, Florida.
J Neurophysiol. 2021 Oct 1;126(4):1420-1429. doi: 10.1152/jn.00307.2021. Epub 2021 Sep 8.
Repeated short episodes of hypoxia produce a sustained increase in phrenic nerve output lasting well beyond acute intermittent hypoxia (AIH) exposure (i.e., phrenic long-term facilitation; pLTF). Pretreatment with ampakines, drugs which allosterically modulate AMPA receptors, enables a single brief episode of hypoxia to produce pLTF, lasting up to 90 min after hypoxia. Here, we tested the hypothesis that ampakine pretreatment would enhance the magnitude of pLTF evoked by repeated bouts of hypoxia. Phrenic nerve output was recorded in urethane-anesthetized, mechanically ventilated, and vagotomized adult male Sprague-Dawley rats. Initial experiments demonstrated that ampakine CX717 (15 mg/kg iv) caused an acute increase in phrenic nerve inspiratory burst amplitude reaching 70 ± 48% baseline (BL) after 2 min ( = 0.01). This increased bursting was not sustained (2 ± 32% BL at 60 min, = 0.9). When CX717 was delivered 2 min before a single episode of isocapnic hypoxia (5 min, [Formula: see text] = 44 ± 9 mmHg), facilitation of phrenic nerve burst amplitude occurred (96 ± 62% BL at 60 min, < 0.001). However, when CX717 was given 2 min before three, 5-min hypoxic episodes ([Formula: see text] = 45 ± 6 mmHg) pLTF was attenuated and did not reach statistical significance (24 ± 29% BL, = 0.08). In the absence of CX717 pretreatment, pLTF was observed after three (74 ± 33% BL at 60 min, < 0.001) but not one episode of hypoxia (1 ± 8% BL at 60 min, = 0.9). We conclude that pLTF is not enhanced when ampakine pretreatment is followed by repeated bouts of hypoxia. Rather, the combination of ampakine and a single hypoxic episode appears to be ideal for producing sustained increase in phrenic motor output. Pretreatment with ampakine CX717 created conditions that enabled an acute bout of moderate hypoxia to evoke phrenic motor facilitation, but this response was not observed when ampakine pretreatment was followed by intermittent hypoxia. Thus, in anesthetized and spinal intact rats, the combination of ampakine and one bout of hypoxia appears ideal for triggering respiratory neuroplasticity.
反复的短暂缺氧会导致膈神经输出持续增加，这种增加持续时间远远超过急性间歇性缺氧（AIH）暴露的时间（即膈神经长期易化；pLTF）。用ampakines 预处理，这种药物可以变构调节 AMPA 受体，可使单次短暂缺氧产生 pLTF，在缺氧后长达 90 分钟持续存在。在这里，我们测试了这样一个假设，即ampakine 预处理会增强反复缺氧发作引起的 pLTF 的幅度。膈神经输出在麻醉、机械通气和迷走神经切断的成年雄性 Sprague-Dawley 大鼠中进行记录。初步实验表明，ampakine CX717（静脉注射 15 mg/kg）在 2 分钟后引起膈神经吸气爆发幅度的急性增加，达到基线（BL）的 70±48%（ = 0.01）。这种爆发增加没有持续（60 分钟时 2±32%BL， = 0.9）。当 CX717 在单次等碳酸缺氧（5 分钟，[公式：见正文] = 44±9mmHg）发作前 2 分钟给予时，膈神经爆发幅度的易化发生（60 分钟时 96±62%BL， < 0.001）。然而，当 CX717 在三次、5 分钟缺氧发作前 2 分钟给予时（[公式：见正文] = 45±6mmHg），pLTF 减弱且无统计学意义（24±29%BL， = 0.08）。在没有 CX717 预处理的情况下，三次（60 分钟时 74±33%BL， < 0.001）但不是一次缺氧（60 分钟时 1±8%BL， = 0.9）后观察到 pLTF。我们得出结论，当 ampakine 预处理后紧接着是反复的缺氧发作时，pLTF 不会增强。相反，ampakine 和单次缺氧发作的组合似乎是产生膈神经运动输出持续增加的理想选择。ampakine CX717 的预处理创造了条件，使急性中度缺氧发作能够引起膈神经运动易化，但当 ampakine 预处理后紧接着是间歇性缺氧时，这种反应就不会出现。因此，在麻醉和脊髓完整的大鼠中，ampakine 和一次缺氧发作的组合似乎是触发呼吸神经可塑性的理想选择。
