Maczewski M, Beresewicz A
Department of Clinical Physiology, Medical Centre of Postgraduate Education, Warsaw, Poland.
J Mol Cell Cardiol. 1998 Sep;30(9):1735-47. doi: 10.1006/jmcc.1998.0736.
The role of adenosine and ATP-sensitive potassium channels (KATP) in the mechanism of ischemic preconditioning (IPC)-induced protection against the post-ischemic endothelial dysfunction was studied. Langendorff-perfused guinea-pig hearts were subjected either to 40 min of global ischemia and 40 min reperfusion or were preconditioned prior to the ischemia/reperfusion with three cycles of either 5 min ischemia/5 min reperfusion (IPC) or 5 min infusion/5 min wash-out of adenosine, adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA) or KATP opener, pinacidil. The magnitude of coronary flow reduction caused by NO-synthase inhibitor, Nomega-nitro-l-arginine methyl ester (l-NAME), served as an index of a basal endothelium-dependent vasodilator tone. Coronary overflows produced by a bolus of acetylcholine (ACh) and sodium nitroprusside (SNP) were used as measures of agonist-induced endothelium-dependent and endothelium-independent vascular function, respectively. The coronary flow, LVDP, ACh response and l-NAME response were reduced by 8, 32, 41 and 54%, respectively, while SNP response was not changed in the hearts subjected to ischemia/reperfusion. ACh response was fully restored, l-NAME response was partially restored, and SNP response was not affected in the hearts subjected to IPC. The post-ischemic recoveries of coronary flow and LVDP were not improved by IPC. The protective effect of IPC on the ACh response was mimicked by adenosine, CHA, and pinacidil. The protective effect of IPC, CHA and pinacidil was abolished by KATP antagonist, glibenclamide. The IPC protection was affected neither by a non-specific adenosine antagonist, 8-p-sulfophenyltheophylline, nor by a specific adenosine A1 receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX). Our data indicate that: (1) IPC affords endothelial protection in the mechanism that involves activation of KATP, but not adenosine A1 receptors; (2) exogenous adenosine and A1 receptor agonist afford the protection, which might be of a potential clinical significance; (3) the endothelial dysfunction is not involved in the mechanism of myocardial stunning in guinea-pig hearts.
研究了腺苷和三磷酸腺苷敏感钾通道（KATP）在缺血预处理（IPC）诱导的对缺血后内皮功能障碍的保护机制中的作用。采用Langendorff灌注的豚鼠心脏，使其经历40分钟全心缺血和40分钟再灌注，或者在缺血/再灌注前用三个周期的5分钟缺血/5分钟再灌注（IPC）、5分钟腺苷输注/5分钟腺苷洗脱、腺苷A1受体激动剂N6-环己基腺苷（CHA）或KATP开放剂吡那地尔进行预处理。由一氧化氮合酶抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME）引起的冠状动脉血流减少幅度用作基础内皮依赖性血管舒张张力的指标。分别用乙酰胆碱（ACh）和硝普钠（SNP）推注产生的冠状动脉溢出量作为激动剂诱导的内皮依赖性和内皮非依赖性血管功能的测量指标。在经历缺血/再灌注的心脏中，冠状动脉血流、左心室舒张末期压力（LVDP）、ACh反应和L-NAME反应分别降低了8%、32%、41%和54%，而SNP反应未改变。在经历IPC的心脏中，ACh反应完全恢复，L-NAME反应部分恢复，SNP反应未受影响。IPC未改善缺血后冠状动脉血流和LVDP的恢复。腺苷、CHA和吡那地尔模拟了IPC对ACh反应的保护作用。KATP拮抗剂格列本脲消除了IPC、CHA和吡那地尔的保护作用。IPC保护作用既不受非特异性腺苷拮抗剂8-对磺基苯甲酰基茶碱的影响，也不受特异性腺苷A1受体拮抗剂8-环戊基-1,3-二丙基黄嘌呤（DPCPX）的影响。我们的数据表明：（1）IPC在涉及KATP激活而非腺苷A1受体的机制中提供内皮保护；（2）外源性腺苷和A1受体激动剂提供保护，这可能具有潜在的临床意义；（3）内皮功能障碍不参与豚鼠心脏心肌顿抑的机制。
