Trimethoprim, a dihydrofolate reductase inhibitor, is used as a therapeutical agent in combination with sulfamethoxazole. Studies of the interaction of trimethoprim with membrane transport are rare. This paper presents a study of the effect of trimethoprim on the short-circuit current (Isc) and on the transepithelial total conductance (Gt) of the isolated frog skin. We found a fast drop (less than 1 min) of Isc (50%) and Gt (30%) after the addition of the drug to the outside medium (mucosa). A dose-response curve of the effect of the drug has shown that trimethoprim has no effect for concentrations below 0.01 mM and reaches a half-maximum inhibition at 0.5 mM. Trimethoprim induces a decrease in the sodium radioactive tracer fluxes that parallel the decrease of the observed Isc. It induces a hyperpolarization of the mucosal barrier in the same way that amiloride does. A comparative study of the effect of trimethoprim and amiloride has shown that trimethoprim acts on the amiloride-sensitive sodium channels of the mucosal barrier and behaves as a competitive inhibitor of amiloride with a dissociation constant KTRIM of 53 x 10(-5) M while KAMIL = 46 x 10(-8) M.
Amiloride Animals