Kleyman T R, Roberts C, Ling B N
University of Pennsylvania School of Medicine, Philadelphia.
Ann Intern Med. 1995 Jan 15;122(2):103-6. doi: 10.7326/0003-4819-122-2-199501150-00004.
To determine whether pentamidine directly affects the transport of renal ions and thus provides a mechanism for hyperkalemia, which develops in as many as 100% of patients with the acquired immunodeficiency syndrome (AIDS) who receive pentamidine for more than 6 days.
Transepithelial and single-channel electrical measurements were made on two models of distal-nephron ion transport: an amphibian distal-nephron cell line (A6) and primary cultures of rabbit cortical collecting tubules.
Luminal bath application of pentamidine to A6 monolayers inhibited the amiloride-sensitive, short-circuit current with a 50% inhibitory concentration of 700 microM (five experiments). In the principal cell apical membranes of cortical collecting tubule primary cultures, amiloride-sensitive, 4-picosiemen Na+ channels in cell-attached patches were also identified. When the luminal membrane was directly exposed to 1.0 microM of pentamidine in the patch pipette solution, channel activity decreased by 40% (11 experiments). Channel inhibition rapidly reversed with washout of intrapipette pentamidine (four experiments). In contrast, replacement of either the luminal bath outside the patch pipette (four experiments) or the serosal bath (five experiments) with pentamidine did not significantly affect Na+ channel activity in the patches.
Luminal or "urinary" pentamidine inhibits distal nephron reabsorption of Na+ by blocking apical Na+ channels in a manner similar to "potassium-sparing" diuretics (for example, amiloride and triamterene). This results in a decrease in the electrochemical gradients that drive secretion of distal nephron K+. Because pentamidine is eliminated through urinary excretion, this renal tubular effect provides a mechanism for pentamidine-induced hyperkalemia.
确定喷他脒是否直接影响肾离子转运，从而为高钾血症提供一种机制。高钾血症在接受喷他脒治疗超过6天的多达100%的获得性免疫缺陷综合征（AIDS）患者中出现。
对两种远端肾单位离子转运模型进行跨上皮和单通道电测量：一种是两栖类远端肾单位细胞系（A6），另一种是兔皮质集合管原代培养物。
将喷他脒应用于A6单层细胞的管腔浴中可抑制氨氯地平敏感的短路电流，其半数抑制浓度为700微摩尔（五项实验）。在皮质集合管原代培养物的主细胞顶端膜中，还鉴定出细胞贴附式膜片中的氨氯地平敏感的4皮西门子钠通道。当在膜片吸管溶液中管腔膜直接暴露于1.0微摩尔喷他脒时，通道活性降低了40%（十一项实验）。随着吸管内喷他脒的洗脱，通道抑制迅速逆转（四项实验）。相比之下，用喷他脒替代膜片吸管外的管腔浴（四项实验）或浆膜浴（五项实验）对膜片中的钠通道活性没有显著影响。
管腔或“尿中”喷他脒通过阻断顶端钠通道来抑制远端肾单位对钠的重吸收，其方式类似于“保钾”利尿剂（例如氨氯地平和氨苯蝶啶）。这导致驱动远端肾单位钾分泌的电化学梯度降低。由于喷他脒通过尿液排泄消除，这种肾小管效应为喷他脒诱导的高钾血症提供了一种机制。
