Department of Physiology & Perinatal Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada.
Respir Physiol Neurobiol. 2010 Jul 31;172(3):94-105. doi: 10.1016/j.resp.2010.04.025. Epub 2010 May 2.
Hypothetic mechanisms for respirogenic methylxanthine actions include blockade of adenosine receptors or phosphodiesterase-4 (PDE4) in inspiratory pre-Bötzinger complex (preBötC) networks. Here, we studied this by analyzing stimulating caffeine and theophylline actions on mu-opioid-depressed inspiratory-related rhythm in the ventrolateral aspect of rat brainstem slices. The methylxanthines restored DAMGO (0.5-1 microM) depressed rhythm only at >1mM, which is approximately 10-fold higher than selective for adenosine receptors. Adenosine receptor blockers did neither counter DAMGO inhibition nor change control rhythm, similar to adenosine (0.1-2.5 mM). The specific PDE4 blocker rolipram (5 microM) restored DAMGO-depressed rhythm incompletely, but effectively reversed similar inhibition by clinical mu-agonist (fentanyl, 0.1 microM). At 0.25 microM, rolipram boosted incomplete recovery by 1 mM theophylline of DAMGO-depressed rhythm. Findings indicate that methylxanthines excite rhythmogenic preBötC networks via blockade of cAMP dependent PDE4 and suggest that specific PDE4 inhibitors (plus low methylxanthine doses) stimulate breathing effectively. We discuss why methylxanthine doses for preBötC stimulation need to be higher than those for respirogenic effects in vivo.
推测呼吸性甲基黄嘌呤作用的机制包括在吸气性前包钦格复合体（preBötC）网络中阻断腺苷受体或磷酸二酯酶-4（PDE4）。在这里，我们通过分析咖啡因和茶碱对大鼠延髓脑片腹外侧部中受μ-阿片受体抑制的吸气相关节律的刺激作用来研究这一点。只有在 >1mM 时，甲基黄嘌呤才会恢复 DAMGO（0.5-1 μM）抑制的节律，这大约是对腺苷受体选择性的 10 倍。腺苷受体阻滞剂既不能对抗 DAMGO 抑制，也不能改变对照节律，类似于腺苷（0.1-2.5mM）。特异性 PDE4 阻滞剂罗利普兰（5 μM）不完全恢复 DAMGO 抑制的节律，但有效地逆转了类似的临床μ-激动剂（芬太尼，0.1 μM）的抑制作用。在 0.25 μM 时，罗利普兰将 1 mM 茶碱不完全恢复 DAMGO 抑制的节律提高了 1 倍。研究结果表明，甲基黄嘌呤通过阻断 cAMP 依赖性 PDE4 来兴奋节律生成性 preBötC 网络，并表明特异性 PDE4 抑制剂（加低剂量甲基黄嘌呤）可有效刺激呼吸。我们讨论了为什么用于 preBötC 刺激的甲基黄嘌呤剂量需要高于体内呼吸作用的剂量。
