Eiam-Ong S, Kurtzman N A, Sabatini S
Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, USA.
Kidney Int. 1996 May;49(5):1372-8. doi: 10.1038/ki.1996.193.
We examined the effects of trimethoprim (TMP) on metabolic parameters and renal ATPases in rats after a 90 minute infusion (9.6 mg/hr/kg body wt, i.v.) and after 14 days (20 mg/kg body wt/day, i.p.). After one dose of TMP, plasma electrolytes, arterial pH and aldosterone levels were normal, but a natriuresis, bicarbonaturia, and decreased urinary potassium excretion occurred. Na-K-ATPase activity in microdissected segments from these animals was decreased by 36 +/- 0.9% in proximal convoluted tubule (PCT) (P < 0.005); decreases of 50 +/- 2.1% and 40 +/- 1.1% were seen in cortical and medullary collecting tubules (CCT and MCT), respectively (P < 0.005). Na-K-ATPase activity was unaffected in medullary thick ascending limb (MTAL). H-ATPase (in PCT and collecting duct) and H-K-ATPase (in CCT and MCT)-activities were not changed. Following chronic TMP administration, plasma potassium increased as compared to control (5.16 +/- 0.05 mEq/liter vs. 3.97 +/- 0.05 mEq/liter, P < 0.05), however, acid-base status and plasma aldosterone levels were normal. Na-K-ATPase activity was decreased by 45 +/- 2.6% in PCT (P < 0.005), 73 +/- 2.0% in CCT (P < 0.001), and 53 +/- 2.5% in MCT (P < 0.005). Na-K-ATPase, activity in MTAL and H-K-ATPase activity in CCT and MCT were unchanged. H-ATPase activity in PCT and MTAL was normal, but in the collecting tubule (CCT and MCT) it was decreased by approximately 25% (P < 0.05). TMP inhibited Na-K-ATPase activity in a dose-dependent fashion in PCT, CCT, and MCT when tubules from normal animals were incubated in vitro with the drug; TMP in vitro did not affect H-ATPase or H-K-ATPase activity. These results suggest that TMP-induced hyperkalemia may result from decreased urinary potassium excretion caused by inhibition of distal Na-K-ATPase, in the face of intact H-K-ATPase activity.
我们研究了甲氧苄啶（TMP）在大鼠静脉输注90分钟（9.6毫克/小时/千克体重）和14天（20毫克/千克体重/天，腹腔注射）后对代谢参数和肾脏ATP酶的影响。单次给予TMP后，血浆电解质、动脉血pH值和醛固酮水平正常，但出现了钠利尿、重碳酸盐尿和尿钾排泄减少。这些动物经显微解剖的节段中，近端曲管（PCT）的钠钾ATP酶活性降低了36±0.9%（P<0.005）；皮质和髓质集合管（CCT和MCT）分别降低了50±2.1%和40±1.1%（P<0.005）。髓质厚升支（MTAL）的钠钾ATP酶活性未受影响。H-ATP酶（在PCT和集合管中）和H-K-ATP酶（在CCT和MCT中）的活性未改变。长期给予TMP后，与对照组相比血浆钾升高（5.16±0.05毫当量/升对3.97±0.05毫当量/升，P<0.05），然而，酸碱状态和血浆醛固酮水平正常。PCT中钠钾ATP酶活性降低了45±2.6%（P<0.005），CCT中降低了73±2.0%（P<0.001），MCT中降低了53±2.5%（P<0.005）。MTAL中的钠钾ATP酶活性以及CCT和MCT中的H-K-ATP酶活性未改变。PCT和MTAL中的H-ATP酶活性正常，但在集合管（CCT和MCT）中降低了约25%（P<0.05）。当将正常动物的肾小管与该药物在体外孵育时，TMP以剂量依赖方式抑制PCT、CCT和MCT中的钠钾ATP酶活性；TMP在体外不影响H-ATP酶或H-K-ATP酶活性。这些结果表明，在H-K-ATP酶活性完整的情况下，TMP诱导的高钾血症可能是由于远端钠钾ATP酶受抑制导致尿钾排泄减少所致。
