Role of Endogenous Adenosine in Hypoxic Ventilatory Depression

研究(1)我们研究了腺苷受体拮抗剂茶碱对健康志愿者脑组织氧合和酸碱状态的影响（n=6）。同时测定各组小鼠在正常缺氧和等氧缺氧条件下（PaO2=60、45 mmHg）输注茶碱前后动脉和颈内静脉的分气压和氧饱和度（SO2）。茶碱输注后PjO2和SjO2明显下降。另一方面，在两项研究中，PjCO2和pHj没有发生变化，尽管PaCO2略有但显著降低，pHa随茶碱升高。基于颈静脉血液参数反映脑组织参数的假设，这些数据为茶碱刺激通气作用的机制提供了新的思路，并提示茶碱可能对大脑有不良影响。研究（II）为了检验内源性腺苷在低氧通气反应中的作用，我们在9名正常成人中测量了有或没有使用双吡啶达摩（一种腺苷摄取阻滞剂，可增加血浆腺苷水平）预处理和随后持续缺氧对异氧性进行性和持续性缺氧的更多反应。双嘧达莫预处理显著增加了异氧进行性缺氧时通气反应的斜率，提示内源性腺苷可能对外周化学感受器的活性起作用。在20分钟的持续缺氧中，两项研究的通气逐渐下降到中等水平。然而，通气量下降开始得更早，用双嘧达莫更明显。当9名受试者中有4名单独注射茶碱（腺苷受体拮抗剂）时，持续缺氧期间的通气下降有所减轻。此外，与单独使用茶碱相比，双嘧达莫在茶碱输注后对持续缺氧的通气反应不再产生任何显著变化。因此，我们得出结论，内源性腺苷可能在人类缺氧通气反应中发挥外周和中枢调节作用。少

Study (I)We studied the effect of theophylline, an adenosine receptor antagonist, on the tissue oxygenation and acid-base status in the brain in healthy volunteers (n=6). Partial gas pressures and oxygen saturation (SO2) in an artery and the internal jugular vein were simultaneously measured during normoxia and isocapnic hypoxia (PaO2=60, 45 mmHg) before and after infusion of theophylline. PjO2 as well as SjO2 markedly dropped after theophylline infusion. On the other hand, PjCO2 and pHj did not change in the two studies despite slightly but significantly low PaCO2 and high pHa with theophylline. Based on the assumption that parameters of jugular venous blood reflect those of the brain tissue, these data provide insight into the mechanism of ventilation-stimulating effect of theophylline and suggest a possible adverse effect of theophylline on the brain.Study (II)To examine a role of endogenous adenosine in hypoxic ventilatory response, we measured, in nine normal adults, ventilatory r … More esponses to isocapnic progressive and subsequent sustained hypoxia with and without pretreatment with dipyridamole, an adenosine uptake blocker, which increases plasma levels of adenosine. Pretreatment with dipyridamole significantly augmented the slope of the ventilatory response to isocapnic progressive hypoxia, suggesting a possible role of endogenous adenosine for the activity of peripheral chemoreceptors. During 20 min of sustained hypoxia, ventilation gradually declined to intermediate levels in both studies. However, the decline in ventilation began earlier and was more marked with dipyridamole. When theophylline alone, adenosine receptor antagonist, was injected in 4 out of 9 subjects, the ventilatory decline seen during sustained hypoxia was attenuated. In addition, dipyridamole following theophylline infusion no longer produced any significant change on ventilatory response to sustained hypoxia compared to theophylline alone. We therefore conclude that endogenous adenosine may play a modulatory role both peripherally and centrally in hypoxic ventilatory response in humans. Less