STUDIES ON THE MECHANISM OF TRIMETHOPRIM-INDUCED HYPERKALEMIA

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 bod y 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 w ere normal, bur a natriuresis, bicarbonaturia, and decreased urinary p otassium excretion occurred. Na-K-ATPase activity in microdissected se gments from these animals was decreased by 36 +/- 0.9% in proximal con voluted tubule (PCT) (P < 0.005); decreases of 50 +/- 2.1% and 40 +/- 1.1% were seen in cortical and medullary collecting tubules (CCT and M CT), respectively (P < 0.005). Na-K-ATPase activity was unaffected in medullary thick ascending limb (MTAL). H-ATPase (in PCT and collecting duel) and H-K-ATPase (in CCT and MCT) activities were not changed. Fo llowing chronic TMP administration, plasma potassium increased as comp ared 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 wer e 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-X-ATPase activity in MTAL and H-K-ATPase activity in CCT an d MCT were unchanged. H-ATPase activity in PCT and MTAL was normal, bu t in the collecting tubule (CCT and MCT) it was decreased by approxima tely 25% (P < 0.05). TMP inhibited Na-K-ATPase activity in a dose-depe ndent fashion in PCT, CCT, and MCT when tubules from normal animals we re incubated ill vitro with the drug; TMP in vitro did not affect H-AT Pase or H-K-ATPase activity. These results suggest that TMP-induced hy perkalemia may result from decreased urinary potassium excretion cause d by inhibition of distal Na-K-ATPase in the face of intact H-K-ATPase activity.