Despite decades of research, the exact pathogenic mechanisms underlying acute mountain sickness (AMS) are still poorly understood. This fact frustrates the search for novel pharmacological prophylaxis for AMS. The prevailing view is that AMS results from an insufficient physiological response to hypoxia and that prophylaxis should aim at stimulating the response. Starting off from the opposite hypothesis that AMS may be caused by an initial excessive response to hypoxia we suggest that directly or indirectly blunting specific parts of the response might provide promising research alternatives. This reasoning is based on the observations that 1) humans, once acclimatized, can climb Mt Everest experiencing arterial partial oxygen pressures (PaO₂) as low as 25 mmHg without AMS symptoms, 2) paradoxically AMS usually develops at much higher PaO₂ levels, and 3) several biomarkers, suggesting initial activation of specific pathways at such PaO₂, are correlated with AMS. Apart from looking for substances that stimulate certain hypoxia triggered effects, such as the ventilatory response to hypoxia, we suggest to also investigate pharmacological means aiming at blunting certain other specific hypoxia activated pathways, or stimulating their agonists, in the quest for better pharmacological prophylaxis for AMS.

中文翻译：

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寻找更好的急性高山病药物预防方法：寻找其他方向


尽管经过数十年的研究，人们对急性高山病（AMS）的确切致病机制仍然知之甚少。这一事实阻碍了 AMS 新型药物预防的探索。普遍的观点是，AMS 是由于对缺氧的生理反应不足造成的，预防措施应旨在刺激反应。从相反的假设出发，即 AMS 可能是由最初对缺氧的过度反应引起的，我们建议直接或间接削弱反应的特定部分可能会提供有希望的研究替代方案。这一推理基于以下观察：1) 人类一旦适应了环境，就可以在动脉氧分压 (PaO ₂ ) 低至 25 mmHg 的情况下攀登珠穆朗玛峰而不会出现 AMS 症状，2) 矛盾的是，AMS 通常在 PaO ₂水平高得多时发生， 3) 一些生物标志物表明在这样的PaO ₂下特定途径的初始激活与AMS相关。除了寻找刺激某些缺氧触发效应（例如对缺氧的通气反应）的物质外，我们建议还研究旨在削弱某些其他特定缺氧激活途径或刺激其激动剂的药理学手段，以寻求更好的药物预防AMS。