Sales N, Dutriez I, Maziere B, Ottaviani M, Roques B P
U334 INSERM, Hôpital d'Orsay, France.
Regul Pept. 1991 Apr 25;33(2):209-22. doi: 10.1016/0167-0115(91)90215-3.
The neutral endopeptidase 24.11 (NEP) also called 'enkephalinase' thanks to its inactivation of enkephalins in the brain, was also recently shown to be involved in the degradation of the circulating atrial natriuretic peptide (ANP). Inhibitors of NEP are therefore under clinical trials as new analgesics or antidiarrheal agents, protecting centrally or peripherally released opioid peptides and as novel antidiuretics and anti-hypertensives in prolonging the renal and vascular actions of NEP. It was therefore important from a clinical point of view to investigate the distribution in peripheral tissue of a systemically administered NEP blocker. Different concentrations of the radiolabelled inhibitor [3H]HACBO-Gly have been intravenously injected in rat and the distribution studied using whole-body sections at different times by 'ex vivo' and 'in vitro' autoradiography to investigate differences in tissue accessibility of NEP to a circulating inhibitor. In vivo [3H]HACBO-Gly binding was fully prevented by an excess of unlabelled inhibitor and disappeared rapidly mainly through renal elimination. NEP labelling was prominent in kidney, liver, lung, fat deposits in the neck region, the flat bones of the skull, the mandibula, the vertebrae, the long bones of the limbs, articular cartilages and synoviae. A lower labelling was found in the intestine, the glomeruli and the submaxillary glands. [3H]HACBO-Gly binds also to a limited number of peripheral tissues in which the presence of NEP was yet unknown (bones, parts of adipose tissues. Some tissues, not labelled in vivo, exhibited various degrees of labelling under in vitro conditions (the brain, some portions of the gut, the testes, the prostate). Interestingly, few lobules of the submaxillary glands were much more densely labelled suggesting the possible occurrence of NEP heterogeneity. Except for the brain, the physiological function of NEP in various tissues remains largely unknown, but this ectoenzyme is likely involved in inactivation of regulatory peptides such as: ANP (partially in the kidney), SP in the lung and possibly somatostatin and ANP in bone, ANP in adipose tissue, enkephalin in testes, immune peptidic factors in bone marrow. A part of NEP in bone marrow corresponds probably to the common acute lymphoblastic antigen, CALLA, densely expressed on pre-B cells. Finally, it is important to notice that several tissues containing important concentrations of NEP (brain, testes, prostate, eye, gut, brush border) are inaccessible to the i.v. injected inhibitor thanks to the presence of functional barriers.
中性内肽酶24.11（NEP）由于其在脑内使脑啡肽失活，也被称为“脑啡肽酶”，最近还被证明参与循环中的心房利钠肽（ANP）的降解。因此，NEP抑制剂正在作为新型镇痛药或止泻药进行临床试验，它们可保护中枢或外周释放的阿片肽，并且作为新型抗利尿药和抗高血压药来延长NEP的肾和血管作用。因此，从临床角度来看，研究全身给药的NEP阻滞剂在外周组织中的分布很重要。已将不同浓度的放射性标记抑制剂[3H]HACBO-Gly静脉注射到大鼠体内，并在不同时间通过“离体”和“体外”放射自显影术使用全身切片研究其分布，以研究NEP对循环抑制剂的组织可及性差异。体内[3H]HACBO-Gly结合可被过量的未标记抑制剂完全阻断，并且主要通过肾脏清除而迅速消失。NEP标记在肾脏、肝脏、肺、颈部脂肪沉积、颅骨扁骨、下颌骨、椎骨、四肢长骨、关节软骨和滑膜中很明显。在肠道、肾小球和颌下腺中发现的标记较低。[3H]HACBO-Gly也与数量有限的外周组织结合，而这些组织中NEP的存在尚不清楚（骨骼、部分脂肪组织）。一些在体内未标记的组织在体外条件下表现出不同程度的标记（脑、肠道的某些部分、睾丸、前列腺）。有趣的是，颌下腺的少数小叶标记密集得多，这表明可能存在NEP异质性。除了脑之外，NEP在各种组织中的生理功能在很大程度上仍然未知，但这种外切酶可能参与调节肽的失活，例如：ANP（部分在肾脏中）、肺中的P物质以及可能在骨骼中的生长抑素和ANP、脂肪组织中的ANP、睾丸中的脑啡肽、骨髓中的免疫肽因子。骨髓中的一部分NEP可能对应于常见的急性淋巴细胞抗原，即CALLA，在B前细胞上密集表达。最后，重要的是要注意，由于存在功能屏障，静脉注射的抑制剂无法进入含有高浓度NEP的几个组织（脑、睾丸、前列腺、眼睛、肠道、刷状缘）。
