Repeated short episodes of hypoxia produces a sustained increase in phrenic nerve output lasting well beyond 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, intravenous) caused an acute increase in phrenic nerve inspiratory burst amplitude reaching 70±48% baseline (BL) after 2 min (P=0.01. This increased bursting was not sustained (2±32%BL at 60 min, P=0.9). When CX717 was delivered 2 min prior to a single episode of isocapnic hypoxia (5-min, PaO₂ = 44±9 mmHg) facilitation of phrenic nerve burst amplitude occurred (96±62%BL at 60 min, P<0.001). However, when CX717 was given 2 min prior to three, 5-min hypoxic episodes (PaO₂ = 45±6 mmHg) pLTF was attenuated and did not reach statistical significance (24±29%BL, P=0.08). In the absence of CX717 pretreatment, pLTF was observed after three (74±33%BL at 60 min, P<0.001) but not one episode of hypoxia (1±8%BL at 60 min, P=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.

中文翻译：

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安帕金预处理可以使单次缺氧发作产生膈肌运动促进，而不会增加额外发作的益处

反复短时间的缺氧会导致膈神经输出持续增加，持续时间远远超过 AIH 暴露（即膈长期促进，pLTF）。用安帕金斯（一种变构调节 AMPA 受体的药物）进行预处理，可使一次短暂的缺氧发作产生 pLTF，在缺氧后持续长达 90 分钟。在这里，我们检验了安帕金预处理会增强反复缺氧引起的 pLTF 幅度的假设。在尿烷麻醉、机械通气和迷走神经切断术的成年雄性 Sprague-Dawley 大鼠中记录膈神经输出。初步实验表明，安帕金 CX717（15 mg/kg，静脉注射）导致 2 分钟后膈神经吸气爆发幅度急剧增加，达到基线（BL）的 70±48%（P=0.01。这种增加的爆发没有持续（60 分钟时为 2±32%BL，P=0.9）。当 CX717 在单次等碳酸性缺氧发作前 2 分钟（5 分钟，PaO₂ = 44±9 mmHg) 促进了膈神经爆发幅度（60 分钟时为 96±62%BL，P<0.001）。然而，当 CX717 在 3 次、5 分钟缺氧发作（PaO ₂ = 45±6 mmHg）前 2 分钟给予时，pLTF 减弱并且没有达到统计学意义（24±29%BL，P=0.08）。在没有 CX717 预处理的情况下，在 3 次（60 分钟时为 74±33%BL，P<0.001）但没有一次缺氧（60 分钟时为 1±8%BL，P=0.9）后观察到 pLTF。我们得出结论，当安帕金预处理后重复缺氧时，pLTF 不会增强。相反，安帕金和单次缺氧发作的组合似乎是产生持续增加膈运动输出的理想选择。