Eisenhofer G
Clinical Neuroscience Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892.
Naunyn Schmiedebergs Arch Pharmacol. 1994 Mar;349(3):259-69. doi: 10.1007/BF00169292.
The importance of neuronal reuptake for terminating the actions of noradrenaline is well established, but the role of extraneuronal uptake is less clear. This study used plasma concentrations of the extraneuronal noradrenaline metabolite, normetanephrine, to estimate rates of extraneuronal removal of noradrenaline in rats. Animals received infusions of 3H-noradrenaline, with and without inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), to examine the extraneuronal removal of noradrenaline and formation of normetanephrine from infused and endogenous noradrenaline. Infusions of 3H-normetanephrine were also carried out to examine the plasma kinetics of normetanephrine before and after inhibition of MAO. Normetanephrine was cleared rapidly from the circulation and had a short plasma halflife (1 min). Spillover of normetanephrine into plasma (79 pmol kg-1 min-1) was a third that of noradrenaline, but increased 2.8-fold after inhibition of MAO; noradrenaline spillover remained unchanged. Combined inhibition of MAO and COMT decreased the plasma clearance of 3H-noradrenaline by 38%, reflecting removal of 3H-noradrenaline by extraneuronal uptake. Division of the rate of extraneuronal removal of 3H-noradrenaline by the specific activity of plasma 3H-normetanephrine during the 3H-noradrenaline infusion indicated that the rate of extraneuronal removal of endogenous noradrenaline was 250 pmol kg-1 min-1; this was close to the spillover of normetanephrine into plasma after inhibition of MAO (219 pmol kg-1 min-1). Forty-five% of plasma normetanephrine was derived from circulating noradrenaline and 55% from noradrenaline before entry into the circulation. Assuming that these proportions reflected the sources of noradrenaline metabolized extraneuronally indicated that the rate of extraneuronal metabolism of noradrenaline before entry into the circulation was 138 pmol kg-1 min-1. Comparison of this with the rates at which noradrenaline was recaptured by sympathetic nerves (2540 pmol kg-1 min-1) or spilled over into plasma (228 pmol kg-1 min-1), indicated that 87% of the noradrenaline released by sympathetic nerves was recaptured, 5% was metabolized extraneuronally and 8% escaped into plasma. Thus, extraneuronal uptake removes much less of the noradrenaline released by sympathetic nerves than neuronal reuptake.
神经再摄取对于终止去甲肾上腺素的作用的重要性已得到充分证实，但细胞外摄取的作用尚不清楚。本研究利用细胞外去甲肾上腺素代谢产物去甲变肾上腺素的血浆浓度来估计大鼠体内去甲肾上腺素的细胞外清除率。给动物输注3H-去甲肾上腺素，同时抑制和不抑制儿茶酚-O-甲基转移酶（COMT）和单胺氧化酶（MAO），以研究去甲肾上腺素的细胞外清除以及输注的和内源性去甲肾上腺素形成去甲变肾上腺素的情况。还进行了3H-去甲变肾上腺素的输注，以研究抑制MAO前后去甲变肾上腺素的血浆动力学。去甲变肾上腺素从循环中迅速清除，血浆半衰期较短（1分钟）。去甲变肾上腺素向血浆中的溢出量（79 pmol kg-1 min-1）是去甲肾上腺素的三分之一，但在抑制MAO后增加了2.8倍；去甲肾上腺素的溢出量保持不变。MAO和COMT的联合抑制使3H-去甲肾上腺素的血浆清除率降低了38%，这反映了细胞外摄取对3H-去甲肾上腺素的清除作用。在输注3H-去甲肾上腺素期间，将3H-去甲肾上腺素的细胞外清除率除以血浆3H-去甲变肾上腺素的比活性，表明内源性去甲肾上腺素的细胞外清除率为250 pmol kg-1 min-1；这与抑制MAO后去甲变肾上腺素向血浆中的溢出量（219 pmol kg-1 min-1）相近。血浆中45%的去甲变肾上腺素来自循环中的去甲肾上腺素，55%来自进入循环之前的去甲肾上腺素。假设这些比例反映了细胞外代谢的去甲肾上腺素的来源，表明进入循环之前去甲肾上腺素的细胞外代谢率为138 pmol kg-1 min-1。将此与交感神经重新摄取去甲肾上腺素的速率（2540 pmol kg-1 min-1）或溢出到血浆中的速率（228 pmol kg-1 min-1）进行比较，表明交感神经释放的去甲肾上腺素中87%被重新摄取，5%被细胞外代谢，8%逸入血浆。因此，与神经再摄取相比，细胞外摄取清除的交感神经释放的去甲肾上腺素要少得多。
