Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, China.
PLoS One. 2011;6(11):e25618. doi: 10.1371/journal.pone.0025618. Epub 2011 Nov 4.
Adenosine, a catabolite of ATP, displays a wide variety of effects in the heart including regulation of cardiac response to myocardial ischemia and reperfusion injury. Nonetheless, the precise mechanism of adenosine-induced cardioprotection is still elusive. Isolated Sprague-Dawley rat hearts underwent 30 min global ischemia and 120 min reperfusion using a Langendorff apparatus. Both adenosine and acetylcholine treatment recovered the post-reperfusion cardiac function associated with adenosine and muscarinic receptors activation. Simultaneous administration of adenosine and acetylcholine failed to exert any additive protective effect, suggesting a shared mechanism between the two. Our data further revealed a cross-talk between the adenosine and acetylcholine receptor signaling in reperfused rat hearts. Interestingly, the selective M(2) muscarinic acetylcholine receptor antagonist methoctramine significantly attenuated the cardioprotective effect of adenosine. In addition, treatment with adenosine upregulated the expression and the maximal binding capacity of muscarinic acetylcholine receptor, which were inhibited by the selective A(1) adenosine receptor antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) and the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME). These data suggested a possible functional coupling between the adenosine and muscarinic receptors behind the observed cardioprotection. Furthermore, nitric oxide was found involved in triggering the response to each of the two receptor agonist. In summary, there may be a cross-talk between the adenosine and muscarinic receptors in ischemic/reperfused myocardium with nitric oxide synthase might serve as the distal converging point. In addition, adenosine contributes to the invigorating effect of adenosine on muscarinic receptor thereby prompting to regulation of cardiac function. These findings argue for a potentially novel mechanism behind the adenosine-mediated cardioprotection.
腺嘌呤核苷，三磷酸腺苷的代谢产物，在心内显示出广泛的效应，包括调节心肌对缺血和再灌注损伤的反应。尽管如此，腺苷诱导的心脏保护的确切机制仍不清楚。使用 Langendorff 仪器，分离的 Sprague-Dawley 大鼠心脏经历 30 分钟的整体缺血和 120 分钟的再灌注。腺苷和乙酰胆碱治疗均恢复了与腺苷和毒蕈碱受体激活相关的再灌注后心脏功能。同时给予腺苷和乙酰胆碱未能发挥任何附加的保护作用，表明这两种药物具有共同的机制。我们的数据进一步揭示了再灌注大鼠心脏中腺苷和乙酰胆碱受体信号之间的串扰。有趣的是，选择性 M2 毒蕈碱乙酰胆碱受体拮抗剂甲硫氯胺显著减弱了腺苷的心脏保护作用。此外，腺苷处理上调了毒蕈碱乙酰胆碱受体的表达和最大结合能力，这被选择性 A1 腺苷受体拮抗剂 8-环戊基-1,3-二丙基黄嘌呤（DPCPX）和一氧化氮合酶抑制剂 N（ω）-硝基-L-精氨酸甲酯（L-NAME）抑制。这些数据表明，在观察到的心脏保护背后，可能存在腺苷和毒蕈碱受体之间的功能偶联。此外，发现一氧化氮参与触发两种受体激动剂的反应。总之，在缺血/再灌注心肌中，可能存在腺苷和毒蕈碱受体之间的串扰，一氧化氮合酶可能作为远端汇聚点。此外，腺苷有助于腺苷对毒蕈碱受体的刺激作用，从而促进心脏功能的调节。这些发现为腺苷介导的心脏保护背后的潜在新机制提供了依据。
