Dafnis E, Kurtzman N A, Sabatini S
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock.
J Pharmacol Exp Ther. 1992 May;261(2):701-6.
In humans and animals, the administration of Li or amiloride results in a defect in urinary acidification. Both agents are thought to cause this by a voltage-dependent mechanism in the distal nephron. This study was designed to determine the effects of chronic Li and amiloride administration on the two main transport enzymes in rat nephron collecting tubule, the Na-K-adenosine triphosphatase (ATPase) and the H(+)-ATPase. We also examined the effects of both agents on these enzymes in vitro. Amiloride administration resulted in a decrease in Na-K-ATPase and H(+)-ATPase activities in cortical collecting tubule and medullary collecting tubule. Therapeutic concentrations of amiloride in vitro inhibited Na-K-ATPase activity, but only in cortical collecting tubule. The effects of Li administration were different; it decreased Na-K-ATPase and H(+)-ATPase in both cortical collecting tubule and medullary collecting tubule. In cortical collecting tubule, the inhibitory effect on H(+)-ATPase activity was seen in vitro at a Li concentration similar to that found in urine. In contrast to the effect of Li on the H(+)-ATPase, in vitro Li stimulated Na-K-ATPase activity. These results suggest that the mechanism of action whereby these two agents result in distal renal tubular acidosis in humans and animals are different. In the collecting tubule, amiloride appears to act solely through a voltage-dependent mechanism by inhibiting cortical collecting tubule Na-K-ATPase. Li, by contrast, appears to have an additional effect in the cortical collecting tubule to inhibit the H(+)-ATPase. The biochemical differences seen with these drugs may explain the more severe acidemia universally found in animals after chronic Li administration.
在人类和动物中，给予锂或氨氯吡咪会导致尿液酸化功能缺陷。人们认为这两种药物都是通过远端肾单位中的电压依赖性机制导致这种情况的。本研究旨在确定长期给予锂和氨氯吡咪对大鼠肾单位集合管中两种主要转运酶——钠钾三磷酸腺苷酶（ATP酶）和氢离子ATP酶的影响。我们还在体外研究了这两种药物对这些酶的影响。给予氨氯吡咪导致皮质集合管和髓质集合管中的钠钾ATP酶和氢离子ATP酶活性降低。氨氯吡咪在体外的治疗浓度可抑制钠钾ATP酶活性，但仅在皮质集合管中。给予锂的影响则不同；它降低了皮质集合管和髓质集合管中的钠钾ATP酶和氢离子ATP酶活性。在皮质集合管中，在体外锂浓度与尿液中相似时即可观察到对氢离子ATP酶活性的抑制作用。与锂对氢离子ATP酶的作用相反，体外锂刺激钠钾ATP酶活性。这些结果表明，这两种药物在人类和动物中导致远端肾小管酸中毒的作用机制不同。在集合管中，氨氯吡咪似乎仅通过抑制皮质集合管钠钾ATP酶的电压依赖性机制起作用。相比之下，锂似乎在皮质集合管中还有额外作用，即抑制氢离子ATP酶。这些药物所表现出的生化差异可能解释了长期给予锂后动物普遍出现的更严重酸血症。
