Hnatowich M, Labella F
Eur J Pharmacol. 1984 Nov 27;106(3):567-75. doi: 10.1016/0014-2999(84)90060-8.
Endogenous substances that modulate the activity of (Na+ + K+)-ATPase through interaction at the cardiac glycoside site have been postulated. Reports of digitalis-like biological and immunological activity exhibited by certain ACTH/MSH peptides and 14-OH steroids make these compounds potential candidates as endogenous digitalis-like factors. We tested several ACTH/MSH peptides and 14 alpha-OH steroids in four in vitro assays and detected no significant cardiac glycoside-like activity. On the other hand, chlormadinone acetate, a progesterone derivative shown to bind with high affinity to the digitalis receptor, was nearly equipotent to digoxigenin in a [3H]ouabain radioreceptor assay. In a [3H]digoxin radioimmunoassay, however, digoxigenin and digoxin were equipotent but chlormadinone acetate was inactive. A clear dissociation between radioreceptor assay and radioimmunoassay activity was also observed using 15 beta-OH-progesterone. Our findings indicate that (a) ACTH/MSH peptides and 14 alpha-OH steroids are not viable candidates as endogenous digitalis-like factors, (b) digoxin antibodies are not necessarily directed at molecular determinants critical for biological activity, and (c) among the compounds reported to exhibit digitalis-like activity and postulated to share structural features with an endogenous steroidal digitalis-like factor, only chlormadinone acetate and its congeners appear to constitute tenable models.
有人推测，内源性物质可通过与强心苷位点相互作用来调节（Na⁺ + K⁺）-ATP酶的活性。某些促肾上腺皮质激素/促黑素细胞激素肽和14-羟基类固醇所表现出的类洋地黄生物活性和免疫活性的报告，使这些化合物成为内源性类洋地黄因子的潜在候选物。我们在四种体外试验中测试了几种促肾上腺皮质激素/促黑素细胞激素肽和14α-羟基类固醇，未检测到明显的类强心苷活性。另一方面，醋酸氯地孕酮是一种已证明与洋地黄受体具有高亲和力的孕酮衍生物，在[³H]哇巴因放射受体测定中，其效力与洋地黄毒苷几乎相当。然而，在[³H]地高辛放射免疫测定中，洋地黄毒苷和地高辛效力相当，但醋酸氯地孕酮无活性。使用15β-羟基孕酮时，在放射受体测定和放射免疫测定活性之间也观察到明显的解离。我们的研究结果表明：（a）促肾上腺皮质激素/促黑素细胞激素肽和14α-羟基类固醇不是内源性类洋地黄因子的可行候选物；（b）地高辛抗体不一定针对对生物活性至关重要的分子决定因素；（c）在报告显示有类洋地黄活性并假定与内源性甾体类洋地黄因子具有共同结构特征的化合物中，只有醋酸氯地孕酮及其同系物似乎构成合理的模型。
