Molecular Pharmacology, Vol 12, 945-957, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Importance of Guanidinium Groups for Blocking Sodium Channels in Epithelia

¹ Department of Pharmacology, University of Cambridge Medical School, Cambridge, England

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 pK_a 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.

Note:
ACKNOWLEDGMENTS I am grateful to Dr. E. J. Cragoe of Merck Sharp & Dohme for a supply of benzamil.

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