Losert W, Bittler D, Buse M, Casals-Stenzel J, Haberey M, Laurent H, Nickisch K, Schillinger E, Wiechert R
Arzneimittelforschung. 1986 Nov;36(11):1583-600.
The ability of a series of 15,16-methylene-spirolactones in comparison to known antimineralocorticoids to inhibit the renal actions of aldosterone was tested in adrenalectomized, glucocorticoid-treated rats. The standard procedure involved continuous i.v. infusion with an isotonic solution of low sodium content (0.05% NaCl + 5.2% glucose, 3 ml/rat/h) supplemented with d-aldosterone [1 micrograms/(kg X h)] resulting in a long-lasting reduction of renal sodium excretion, increase of renal potassium excretion and hence decrease of the urinary Na/K-ratio. In some experiments sodium input was increased (0.2% NaCl + 4.3% glucose or 0.9% NaCl, respectively). The test drugs either were administered orally 1 h before start of the infusion or were added to the infused solution. With the exception of two steroids which could only be tested at single doses, all compounds were administered at three doses ranging from 2.2 to 40 mg/kg (p.o.) or from 0.83 to 6.7 mg/kg/h (i.v.). Spironolactone or spirorenone (oral administration) and potassium canrenoate (i.v. infusion) served as reference compounds. The antimineralocorticoid activity of the steroids was judged by the increase in the aldosterone-lowered Na/K-ratio in urine which was collected at hourly intervals for 15 or 21 h, respectively. Adrenalectomized, glucocorticoid-treated rats receiving an i.v. infusion without aldosterone were used as controls. To obtain preliminary information on potential antiandrogenic and progestogenic (side-)effects, binding of the test-compounds to androgen receptors (rat prostate cytosol) and progestogen receptors (rabbit uterus cytosol) was measured in vitro using 3H-dihydrotestosterone (DHT) and 3H-progesterone (prog.) as tracer and unlabelled DHT and prog. as references. All steroids tested exhibited antimineralocorticoid activity. For compounds tested at three doses levels the potency relative to the standard used was evaluated using regression analysis based on the Na/K-ratio or the log (Na X 100)/K-ratio. The relative potency of the other compounds was estimated by comparing the biological effect of single doses of test drug and standard drug, respectively, using nonparametric statistical tests.(ABSTRACT TRUNCATED AT 400 WORDS)
在肾上腺切除并接受糖皮质激素治疗的大鼠中，测试了一系列15,16-亚甲基-螺内酯与已知抗盐皮质激素相比抑制醛固酮肾脏作用的能力。标准程序包括持续静脉输注低钠含量的等渗溶液（0.05% NaCl + 5.2%葡萄糖，3 ml/大鼠/小时），并补充d-醛固酮[1微克/（千克×小时）]，导致肾钠排泄长期减少、肾钾排泄增加，从而使尿钠/钾比值降低。在一些实验中，增加了钠的输入量（分别为0.2% NaCl + 4.3%葡萄糖或0.9% NaCl）。受试药物要么在输注开始前1小时口服给药，要么添加到输注溶液中。除了两种只能以单剂量测试的类固醇外，所有化合物均以2.2至40 mg/kg（口服）或0.83至6.7 mg/kg/小时（静脉注射）的三种剂量给药。螺内酯或螺瑞酮（口服给药）和坎利酸钾（静脉输注）用作参考化合物。通过醛固酮降低的尿钠/钾比值的增加来判断类固醇的抗盐皮质激素活性，分别在15或21小时内每小时收集尿液。接受无醛固酮静脉输注的肾上腺切除并接受糖皮质激素治疗的大鼠用作对照。为了获得关于潜在抗雄激素和孕激素（副作用）的初步信息，使用3H-二氢睾酮（DHT）和3H-孕酮（prog.）作为示踪剂，未标记的DHT和prog.作为参考，在体外测量受试化合物与雄激素受体（大鼠前列腺胞质溶胶）和孕激素受体（兔子宫胞质溶胶）的结合。所有测试的类固醇均表现出抗盐皮质激素活性。对于以三种剂量水平测试的化合物，使用基于钠/钾比值或log（钠×100）/钾比值的回归分析来评估相对于所用标准的效力。通过分别使用非参数统计检验比较单剂量受试药物和标准药物的生物学效应，估计其他化合物的相对效力。（摘要截断于400字）
