Effect of Trimethoprim-Sulfamethoxazole on Na⁺ and K⁺ Transport Properties in the Rabbit Cortical Collecting Duct Perfused in vitro

Abstract

Background: In this study, the membrane mechanisms of hyperkalemia caused by trimethoprim-sulfamethoxazole (TMP-SMX) combination antibiotics were assessed in the cortical collecting duct (CCD). Methods: We used the microelectrode technique and flux measurements, and examined the effects of TMP and SMX on electrical properties of the apical and basolateral membranes in the rabbit CCD perfused in vitro. Results: TMP in the lumen caused increases in apical membrane voltage, fractional apical membrane resistance (fR_A), and transepithelial resistance (R_T), all effects which were completely inhibited by luminal amiloride, but not by luminal Ba²⁺. The luminal TMP inhibited both net Na⁺ reabsorption and K⁺ secretion in the CCD. TMP in the bath slightly but significantly depolarized transepithelial voltage and basolateral membrane voltage without influencing fR_A or R_T. SMX in the lumen or bath had no effect on barrier voltages or resistances. Conclusion: TMP mainly acts on the apical membrane of the CCD, inhibits the amiloride-sensitive macroscopic Na⁺ conductance in this membrane, and thereby decreases the net driving force for K⁺ exit across the membrane, resulting in an inhibition of K⁺ secretion. SMX in the lumen or bath had no effect on the CCD.

Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron

“…All these data converged with an inhibitory action on the ENaC channel, which was confirmed by Muto et al. using microperfusion of rabbit CDs [ 116 ], with a similar effect to amiloride, which is a specific ENaC blocker used as a potassium‐sparing diuretic treatment.…”

“…Using animal models, it was demonstrated that treatment with trimethoprim inhibited Na + transport in frog skin [115] and, when injected in rats, increased natriuresis and decreased K + secretion [112]. All these data converged with an inhibitory action on the ENaC channel, which was confirmed by Muto et al using microperfusion of rabbit CDs [116], with a similar effect to amiloride, which is a specific ENaC blocker used as a potassium-sparing diuretic treatment.…”

Plasma Potassium Concentration Changes Associated with Trimethoprim used for Urinary Tract Infections

“…[2][3][4][5] Experimental animal models suggest that the mechanism by which trimethoprim increases plasma potassium concentration may involve a potassium sparing effect in the cortical distal nephron; an effect similar to that observed with amiloride. [6][7][8][9] Most studies reporting trimethoprim-induced hyperkalaemia involve HIV-infected patients prescribed high-dose trimethoprim with sulfamethoxazole or dapsone for Pneumocystis jiroveci infection. 10,11 Hyperkalaemia has also been reported in patients treated with standard doses of trimethoprim+sulfamethoxazole.…”