Kurz T, Offner B, Schreieck J, Richardt G, Tölg R, Schömig A
Medizinische Klinik der Technischen Universität München, Klinikum rechts der Isar, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Nov;352(5):491-6. doi: 10.1007/BF00169382.
In myocardial ischemia, nonexocytotic noradrenaline release has been identified as underlying mechanism of ischemia-evoked noradrenaline release. Nonexocytotic noradrenaline release can be suppressed by inhibitors of the neuronal noradrenaline carrier (uptake), such as desipramine. Utilizing this pharmacological intervention the role of local noradrenaline release in the genesis of ischemia-induced ventricular arrhythmias was studied. Regional ischemia was induced in rat isolated perfused hearts by ligature of the left anterior descending coronary artery, and the venous effluent obtained during the first 2 min of reperfusion was used to measure the release of endogenous noradrenaline by high-performance liquid chromatography methods. Coronary occlusion caused ventricular fibrillation in a well reproducible manner with an incidence of 70 to 80% during a 30 min observation period. Blockage of uptake1 by desipramine decreased the occurrence of ischemia-induced ventricular fibrillation to 60% (0.01 mumol/l) or 20% (0.1 mumol/l), and ventricular fibrillation was completely suppressed by 1 mumol/l desipramine. Likewise, desipramine (0.01-1 mumol/l) concentration-dependently reduced endogenous noradrenaline release during 30 min of regional myocardial ischemia. Nisoxetine, a structurally unrelated inhibitor of uptake1, also suppressed ischemia-evoked ventricular fibrillation. In contrast to its antifibrillatory effect during regional myocardial ischemia, desipramine precipitated arrhythmias when ventricular fibrillation was induced by perfusing normoxic hearts with exogenous noradrenaline. Combination of desipramine (0.1 mumol/l) with exogenous noradrenaline (0.01 to 1 mumol/l) increased the incidence of ventricular fibrillation compared to noradrenaline perfusion alone. Under these conditions, uptake1-blockade is known to increase the extracellular concentration of the perfused noradrenaline. Finally, in the isolated, spontaneously beating papillary muscle of the left rat heart, desipramine (0.1 and 1.0 mumol/l) had no effect on the upstroke velocity of action potentials, the action potential duration and the effective refractory period. In conclusion, the findings demonstrate that nonexocytotic noradrenaline release is an important mediator of ischemia-induced ventricular fibrillation in isolated hearts of the rat. It is also documented that uptake1 inhibitors such as desipramine reveal their effects on ventricular fibrillation secondary to their action on transmembrane noradrenaline transport.
在心肌缺血中，非胞吐性去甲肾上腺素释放已被确认为缺血诱发的去甲肾上腺素释放的潜在机制。非胞吐性去甲肾上腺素释放可被神经元去甲肾上腺素载体（摄取）抑制剂如地昔帕明抑制。利用这种药理学干预，研究了局部去甲肾上腺素释放在缺血诱导的室性心律失常发生中的作用。通过结扎左冠状动脉前降支在大鼠离体灌注心脏中诱导局部缺血，并使用再灌注最初2分钟内获得的静脉流出物，通过高效液相色谱法测量内源性去甲肾上腺素的释放。冠状动脉闭塞以可良好重复的方式引起心室颤动，在30分钟观察期内发生率为70%至80%。地昔帕明阻断摄取1可将缺血诱导的心室颤动发生率降至60%（0.01μmol/L）或20%（0.1μmol/L），1μmol/L地昔帕明可完全抑制心室颤动。同样，地昔帕明（0.01 - 1μmol/L）在局部心肌缺血30分钟期间浓度依赖性地减少内源性去甲肾上腺素释放。尼索西汀是一种结构上无关的摄取1抑制剂，也可抑制缺血诱发的心室颤动。与局部心肌缺血期间的抗纤颤作用相反，当用外源性去甲肾上腺素灌注正常氧合心脏诱发心室颤动时，地昔帕明会引发心律失常。与单独的去甲肾上腺素灌注相比，地昔帕明（0.1μmol/L）与外源性去甲肾上腺素（0.01至1μmol/L）联合使用会增加心室颤动的发生率。在这些条件下，已知摄取1阻断会增加灌注的去甲肾上腺素的细胞外浓度。最后，在大鼠离体自发跳动的左心室乳头肌中，地昔帕明（0.1和1.0μmol/L）对动作电位的上升速度、动作电位持续时间和有效不应期没有影响。总之，这些发现表明非胞吐性去甲肾上腺素释放是大鼠离体心脏中缺血诱导的心室颤动的重要介质。还证明了摄取1抑制剂如地昔帕明对心室颤动的作用是继发于其对跨膜去甲肾上腺素转运的作用。
