Carlsson L, Abrahamsson T
Department of Pharmacology, University of Göteborg, Sweden.
J Pharmacol Exp Ther. 1988 Nov;247(2):715-20.
The noradrenergic amine carrier has an important role in mediating the local release of norepinephrine (NE) during myocardial ischemia. The effects of the antidepressant or putative antidepressant drugs desipramine, 2-hydroxy desipramine, nisoxetine, (S)-oxaprotiline and (R)-oxaprotiline with respect to this release mechanism were investigated in the isolated rat heart submitted to total stop-flow ischemia and subsequent reperfusion. During the reperfusion phase a massive efflux of NE was observed, which was reduced in a concentration-dependent manner in the presence of the antidepressant drugs. The potency (pIC50) of the antidepressants in inhibiting the ischemia-induced NE release varied between 9.16 (desipramine) and 6.17 [(R)-oxaprotiline]. On the other hand, lidocaine (10 microM) or clonidine (1 microM) did not reduce the magnitude of the NE efflux. No attenuation in NE efflux could be detected when desipramine (0.1 microM) was present only during the reperfusion period. During repeated periods (3 x 20 min) of ischemia, desipramine (0.1 microM) reduced markedly the loss of NE. In another experiment in the isolated guinea pig heart, desipramine (0.1 microM) was also found to attenuate the ischemia-induced mobilization of NE to the same significant extent as in the isolated perfused rat heart. Chronic treatment (3 weeks) of rats with desipramine as well as acute administration of desipramine to rats (2 hr before the initiation of perfusion) caused a pronounced reduction in the ischemia-induced release of NE in the isolated perfused heart. In conclusion, these experiments strongly suggest that a major part of the ischemia-induced release of NE is mediated by the amine carrier associated with the noradrenergic nerve terminal membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
去甲肾上腺素能胺载体在心肌缺血期间介导去甲肾上腺素（NE）的局部释放中起重要作用。在离体大鼠心脏经历完全停流缺血及随后的再灌注过程中，研究了抗抑郁药或假定的抗抑郁药地昔帕明、2-羟基地昔帕明、尼索西汀、（S）-奥沙普替林和（R）-奥沙普替林对这种释放机制的影响。在再灌注阶段观察到NE大量外流，在抗抑郁药存在的情况下，其以浓度依赖的方式减少。抗抑郁药抑制缺血诱导的NE释放的效力（pIC50）在9.16（地昔帕明）和6.17[（R）-奥沙普替林]之间变化。另一方面，利多卡因（10 microM）或可乐定（1 microM）并未降低NE外流的幅度。当地昔帕明（0.1 microM）仅在再灌注期存在时，未检测到NE外流的减弱。在重复的缺血期（3×20分钟），地昔帕明（0.1 microM）显著减少了NE的损失。在另一个离体豚鼠心脏实验中，还发现地昔帕明（0.1 microM）在与离体灌注大鼠心脏相同的显著程度上减弱了缺血诱导的NE动员。用地昔帕明对大鼠进行慢性治疗（3周）以及在灌注开始前2小时对大鼠急性给予地昔帕明，均导致离体灌注心脏中缺血诱导的NE释放明显减少。总之，这些实验强烈表明，缺血诱导的NE释放的主要部分是由与去甲肾上腺素能神经末梢膜相关的胺载体介导的。（摘要截短至250字）
