Pendleton R G, Gessner G, Sawyer J
Eur J Pharmacol. 1980 Nov 21;68(2):117-27. doi: 10.1016/0014-2999(80)90312-x.
After 7 day dosing with SK & F 64139, an inhibitor of adrenal and CNS PNMT, a stoichiometric relationship is observed between epinephrine decrease and norepinephrine increase in adrenal tissue. However, this relationship is not found with the adrenal PNMT inhibitor, SK & F 29661. SK & F 64139 was found to possess significant adrenal MAO inhibitory activity, but SK & F 29661 does not. Three factors are presented which argue against MAO inhibition as the cause of the catecholamine profile difference. We then performed various studies with SK & F 29661 and 64139 to examine whether enzymes in the norepinephrine biosynthetic pathway are differentially affected by these drugs and found that they were not. However. when rats were dosed with either SK & F 29661 or 64139 over 24 h and the adrenal catecholamine stores were then radioactively labeled with a tracer dose of 3H-norepinephrine, the rate of 3H-norepinephrine disappearance was reduced in the SK & F 64139-treated animals as compared with those given SK & F 29661. A similar result was observed in the heart. These results suggest that SK & F 64139 may reduce norepinephrine turnover in the adrenal gland and heart via an effect not related to peripheral PNMT inhibition. These findings also demonstrate quite clearly that in intact animals all PNMT inhibitors do not produce identical endogenous catecholamine profiles.
在用肾上腺和中枢神经系统苯乙醇胺 - N - 甲基转移酶（PNMT）抑制剂SK & F 64139给药7天后，在肾上腺组织中观察到肾上腺素减少与去甲肾上腺素增加之间存在化学计量关系。然而，肾上腺PNMT抑制剂SK & F 29661并未发现这种关系。发现SK & F 64139具有显著的肾上腺单胺氧化酶（MAO）抑制活性，但SK & F 29661没有。提出了三个因素，反对将MAO抑制作为儿茶酚胺谱差异的原因。然后我们用SK & F 29661和64139进行了各种研究，以检查去甲肾上腺素生物合成途径中的酶是否受到这些药物的不同影响，结果发现并非如此。然而，当大鼠在24小时内用SK & F 29661或64139给药，然后用示踪剂量的3H - 去甲肾上腺素对肾上腺儿茶酚胺储存进行放射性标记时，与给予SK & F 29661的动物相比，SK & F 64139处理的动物中3H - 去甲肾上腺素的消失速率降低。在心脏中也观察到了类似的结果。这些结果表明，SK & F 64139可能通过与外周PNMT抑制无关的作用来降低肾上腺和心脏中去甲肾上腺素的周转。这些发现也清楚地表明，在完整动物中，所有PNMT抑制剂不会产生相同的内源性儿茶酚胺谱。
