Fong Robert, Khokhar Suhail, Chowdhury Atif N, Xie Kelvin G, Wong Josiah Hiu-Yuen, Fox Aaron P, Xie Zheng
Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois.
College of Medicine, University of Illinois, School of Life Sciences, Chicago, Illinois.
J Neurophysiol. 2017 Sep 1;118(3):1591-1597. doi: 10.1152/jn.00393.2017. Epub 2017 Jun 28.
Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP])-elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A receptor blockade and [cAMP] elevation play a role in caffeine's ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP] and adenosine receptor blockade play a role in this response. Currently, there is no method to accelerate emergence from anesthesia. Patients "wake" when they clear the anesthetic from their systems. Previously, we have shown that caffeine can accelerate emergence from anesthesia. In this study, we show that caffeine is effective even at high levels of anesthetic. We also show that caffeine operates by both elevating intracellular cAMP levels and by blocking adenosine receptors. This complicated pharmacology makes caffeine especially effective in accelerating emergence from anesthesia.
多项研究探索了加速麻醉苏醒的不同方法。此前，我们已经表明，三种能提高细胞内cAMP的药物（福斯高林、茶碱和咖啡因）可加速大鼠的麻醉苏醒。然而，我们早期的研究留下了两个主要问题未得到解答。第一，提高cAMP的药物在所有麻醉浓度下都有效吗？第二，鉴于咖啡因是所测试药物中最有效的，既然两种药物都能提高cAMP，为什么咖啡因比福斯高林更有效？在我们当前的研究中，测量了成年大鼠暴露于3%异氟醚60分钟后的麻醉苏醒时间。即使在使用的高麻醉水平下，咖啡因也能显著加速麻醉苏醒。咖啡因有多种作用，包括阻断腺苷受体。我们表明，选择性A腺苷受体拮抗剂普雷拉登特或提高细胞内cAMP（[cAMP]）的药物福斯高林可加速麻醉恢复。当同时测试普雷拉登特和福斯高林时，对麻醉恢复时间的影响是相加的，这表明这些药物通过不同途径起作用。此外，普雷拉登特和福斯高林的组合与咖啡因的效果相当，这表明A受体阻断和[cAMP]升高在咖啡因加速麻醉苏醒的能力中都起作用。由于啮齿动物的麻醉被认为与人类相似,这些结果表明，咖啡因可能使人类在所有麻醉浓度下都能快速且均匀地从全身麻醉中苏醒，并且[cAMP]升高和腺苷受体阻断在这一反应中都起作用。目前，没有加速麻醉苏醒的方法。患者在体内清除麻醉剂后“醒来”。此前，我们已经表明咖啡因可以加速麻醉苏醒。在这项研究中，我们表明即使在高麻醉水平下咖啡因也是有效的。我们还表明，咖啡因通过提高细胞内cAMP水平和阻断腺苷受体来发挥作用。这种复杂的药理学特性使咖啡因在加速麻醉苏醒方面特别有效。
