K+-SPARING DIURETIC ACTIONS OF TRIMETHOPRIM - INHIBITION OF NA+ CHANNELS IN A6 DISTAL NEPHRON CELLS

被引:44
作者
SCHLANGER, LE
KLEYMAN, TR
LING, BN
机构
[1] EMORY UNIV,SCH MED,DEPT MED,DIV RENAL,ATLANTA,GA 30322
[2] VET AFFAIRS MED CTR,ATLANTA,GA 30033
[3] UNIV PENN,DEPT MED,DIV RENAL & ELECTROLYTE,PHILADELPHIA,PA 19104
[4] UNIV PENN,DEPT PHYSIOL,PHILADELPHIA,PA 19104
[5] VET AFFAIRS MED CTR,PHILADELPHIA,PA
关键词
D O I
10.1038/ki.1994.143
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Hyperkalemia complicates trimethoprim-sulfamethoxazole (TMP-SMX) therapy in over 20% of HIV-infected patients. TMP is a heterocyclic weak base, similar to amiloride, a ''K+-sparing'' diuretic and Na+ channel blocker. Apical TMP is known to inhibit amiloride-sensitive short circuit current in A6 cells, a tissue culture model for mammalian cortical collecting tubule principal cells [1]. We used cell-attached patch clamp techniques to investigate the effect of TMP on the 4 pS, highly selective Na+ channel in the apical membrane of A6 cells grown on permeable supports in the presence of 1.5 mu M aldosterone. Baseline channel activity at resting membrane potential, measured as NPo (N of channels x open probability), was 1.09 +/- 0.50 (N = 18). NPo (0.92 +/- 0.38; N = 9) was unchanged when 10(-3) M TMP was added to the basolateral bath for 30 minutes. However, apical exposure with pipettes containing 10(-3) or 10(-5) M TMP reduced NPo approximate to tenfold (0.12 +/- 0.08; N = 7 and 0.18 +/- 0.14; N = 12, respectively). Kinetic analysis revealed the appearance of a new closed state after apical TMP treatment. Another group of A6 cells were pretreated with 10(-3) M apical TMP for 30 minutes prior to patching with pipettes filled with TMP-free saline. NP, progressively rose from 0.07 +/- 0.09 to 0.87 +/- 0.23 (N = 5) as the residual TMP was diluted within the pipette. Apical or basolateral pretreatment (30 min) with 10(-3) M SMX did not change Na+ channel activity. In conclusion, in A6 distal nephron cells: (1) TMP reversibly blocks highly selective Na+ channels; (2) direct interaction with the outer channel pore is required since inhibition was observed with apical, but not basolateral TMP; (3) the SMX component of TMP-SMX preparations has no direct effect on Na+ channel activity; (4) This K+-sparing diuretic effect likely contributes to the hyperkalemia associated with TMP therapy in HIV-infected patients.
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页码:1070 / 1076
页数:7
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