%0 Journal Article %A A. W. CUTHBERT %T Importance of Guanidinium Groups for Blocking Sodium Channels in Epithelia %D 1976 %J Molecular Pharmacology %P 945-957 %V 12 %N 6 %X Sodium transport in an isolated amphibian epithelium (skin of Rana temporaria) has been investigated as a function of pH. The evidence is consistent with the view that sodium entry into the epithelium is dependent on an acid grouping, which behaves as a singly ionizable grouping with a pKa of around 5. The activities of three blocking drugs which prevent sodium entry have also been investigated as a function of pH. These were amiloride, triamterene, and N-(N-benzylamidino)-3,5-diamino-6-chloropyrazine carboxamide (benzamil). The variation in affinity of these compounds with pH was predictable from mass action kinetics if it was assumed that the positively charged inhibitors interacted with a negatively charged acid grouping in the mucosal membrane. With the three inhibitors the positive charge is located on a guanidinium (or isosteric) group, suggesting similarities with compounds which block sodium channels in excitable membranes. Tetrodotoxin had only weak blocking activity in this system (K = 103 M-1) compared with amiloride (K = 5 x 106 M-1), triamterene (K = 5 x 105 M-1), and benzamil (5 x 107 M-1). Guanidine had anomalous and unexplained blocking activity in this system, while 2-guanidinobenzimidazole had both stimulating and blocking activity. The former was probably due to the imidazoline ring structure, while the latter was dependent upon the guanidinium moiety. ACKNOWLEDGMENTS I am grateful to Dr. E. J. Cragoe of Merck Sharp & Dohme for a supply of benzamil. %U https://molpharm.aspetjournals.org/content/molpharm/12/6/945.full.pdf