Schömig A, Fischer S, Kurz T, Richardt G, Schömig E
Circ Res. 1987 Feb;60(2):194-205. doi: 10.1161/01.res.60.2.194.
The release of endogenous noradrenaline and its deaminated metabolite dihydroxyphenylglycol in the myocardium have been studied in the isolated perfused heart of the rat subjected to three models of energy depletion: ischemia, anoxia, and cyanide intoxication. Anoxia and cyanide intoxication were combined with substrate deficiency at constant perfusion flow. All three energy-depleting procedures caused a similar overflow of noradrenaline which, following a constant delay of 10 minutes without increased release, amounted to more than 25% of total heart content within 40 minutes. This noradrenaline overflow was not diminished in the absence of extracellular calcium and was inhibited by the uptake1 blocker desipramine in all three experimental models, indicating a common and nonexocytotic release mechanism. In the presence of glucose, neither anoxia nor cyanide intoxication resulted in a measurable noradrenaline overflow. Conversely, blockade of glycolysis or glucose depletion prior to ischemia or cyanide poisoning accelerated the noradrenaline overflow, demonstrating a key role of the sympathetic nerve cells' energy status in causing nonexocytotic catecholamine release. Blockade of energy metabolism in the presence of oxygen (cyanide model) resulted in the overflow of high amounts of dihydroxyphenylglycol that was not inhibited by uptake1 blockade. The release of the lipophilic dihydroxyphenylglycol by diffusion reflects deamination of axoplasmic noradrenaline by monoamine oxidase. Since saturation of the enzyme could be excluded in this model dihydroxyphenylglycol release can be taken as a mirror of cytoplasmic noradrenaline concentration. The results obtained by these studies indicate that nonexocytotic catecholamine release is a two-step process induced by energy deficiency in the sympathetic varicosity. In a first step, noradrenaline is lost from storage vesicles, resulting in increasing axoplasmic concentrations. The second step is the rate-limiting transport of intracellular noradrenaline across the cell membrane by the uptake1 carrier that has reversed its normal net transport direction.
在大鼠离体灌流心脏中，研究了内源性去甲肾上腺素及其脱氨基代谢产物二羟基苯乙二醇在三种能量耗竭模型（缺血、缺氧和氰化物中毒）下心肌中的释放情况。缺氧和氰化物中毒在恒定灌流流量下与底物缺乏同时发生。所有三种能量耗竭程序均导致去甲肾上腺素类似的溢出，在无释放增加的情况下经过10分钟的恒定延迟后，40分钟内去甲肾上腺素溢出量超过心脏总含量的25%。在无细胞外钙的情况下，这种去甲肾上腺素溢出并未减少，并且在所有三个实验模型中均被摄取1阻滞剂地昔帕明抑制，表明存在共同的非胞吐释放机制。在有葡萄糖存在的情况下，缺氧和氰化物中毒均未导致可测量的去甲肾上腺素溢出。相反，在缺血或氰化物中毒之前阻断糖酵解或耗尽葡萄糖会加速去甲肾上腺素溢出，表明交感神经细胞的能量状态在引起非胞吐性儿茶酚胺释放中起关键作用。在有氧存在的情况下阻断能量代谢（氰化物模型）导致大量二羟基苯乙二醇溢出，该溢出不受摄取1阻断的抑制。亲脂性二羟基苯乙二醇通过扩散释放反映了轴浆中去甲肾上腺素被单胺氧化酶脱氨基。由于在该模型中可以排除酶的饱和，二羟基苯乙二醇释放可被视为细胞质去甲肾上腺素浓度的反映。这些研究获得的结果表明，非胞吐性儿茶酚胺释放是交感神经末梢能量缺乏诱导的两步过程。第一步，去甲肾上腺素从储存囊泡中丢失，导致轴浆浓度增加。第二步是细胞内去甲肾上腺素通过摄取1载体跨细胞膜的限速转运，摄取1载体已逆转其正常的净转运方向。
