Competitive blocking of epithelial sodium channels by organic cations: The relationship between macroscopic and microscopic inhibition constants

Fluctuation analysis of Na current passing the apical membrane in the skin of Rana ridibunda was used to study the kinetics of Na-channel blocking by several organic cations present in the outer solution together with 60 mM Na. The ratios of the apparent off-rate and on-rate constants (the microscopic inhibition constants) thus obtained for triamterene, triaminopyrimidine (TAP), 5,6-diCl-amiloride, 5H-amiloride and amiloride itself are found to be in the mean about sevenfold smaller than the corresponding inhibition constants obtained from macroscopic dose-response curves. The apparent discrepancy is explicable by competition of the organic blocker with the channel block by Na ions (the self-inhibition effect). The type of interaction between extrinsic blockage and self-inhibition may be purely competitive or mixed. However, in case of mixed inhibition the competitive component must dominate the noncompetitive component by at least seven to one.