title: Competitive blocking of epithelial sodium channels by organic cations: the relationship between macroscopic and microscopic inhibition constants.
abstract: 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.
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002024:Bufo marinus; D004848:Epithelium / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D007700:Kinetics; D008954:Models, Biological; D011743:Pyrimidines / Q000494:pharmacology; D011895:Rana ridibunda; D012964:Sodium / Q000378:metabolism*; D014223:Triamterene / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D011743:Pyrimidines; C012070:2,4,6-triaminopyrimidine; C050820:5H-amiloride; C050819:5,6-dichloroamiloride; D000584:Amiloride; D012964:Sodium; D014223:Triamterene