Importance of guanidinium groups of blocking sodium channels in epithelia
Cuthbert, A.W.
Molecular Pharmacology 12(6): 945-957
1976
ISSN/ISBN: 0026-895X PMID: 12462 Document Number: 105856
Na transport in an isolated amphibian epithelium (skin of Rana temporaria) was investigated as a function of pH. The vidence is consistent with the view that Na entry into the epithelium is dependent on an acid grouping, which behaves as a singly ionizable grouping with a pK.alpha. of around 5. The activities of 3 blocking drugs which prevent Na entry were also 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 3 inhibitors the positive charge is located on a guanidinium (or isosteric) group, suggesting similarities with compounds which block Na channels in excitable membranes. Tetrodotoxin had only weak blocking activity in this system (K = 103 M-1) compared with amiloride (K = 5 .times. 106 M-1), triamterene (K = 5 .times. 105 M-1) and benzamil (5 .times. 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 on the guanidinium moiety.