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Research ArticleArticle

Importance of Guanidinium Groups for Blocking Sodium Channels in Epithelia

A. W. CUTHBERT
Molecular Pharmacology November 1976, 12 (6) 945-957;
A. W. CUTHBERT
Department of Pharmacology, University of Cambridge Medical School, Cambridge, England
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Abstract

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.

  • Copyright © 1976 by Academic Press, Inc.

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Molecular Pharmacology
Vol. 12, Issue 6
1 Nov 1976
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Research ArticleArticle

Importance of Guanidinium Groups for Blocking Sodium Channels in Epithelia

A. W. CUTHBERT
Molecular Pharmacology November 1, 1976, 12 (6) 945-957;

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Research ArticleArticle

Importance of Guanidinium Groups for Blocking Sodium Channels in Epithelia

A. W. CUTHBERT
Molecular Pharmacology November 1, 1976, 12 (6) 945-957;
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