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Pharmacological Characterization of Stably Transfected Na+/H+ Antiporter Isoforms Using Amiloride Analogs and a New Inhibitor Exhibiting Anti-Ischemic Properties

Pharmacological Characterization of Stably Transfected Na+/H+ Antiporter Isoforms Using Amiloride Analogs and a New Inhibitor Exhibiting Anti-Ischemic Properties

L Counillon, W Scholz, H J Lang, J Pouysségur

Mol Pharmacol. 1993 Nov;44(5):1041-5.

PMID: 8246907

Abstract:

A fibroblast mutant cell line devoid of Na+/H+ exchange was used to stably express cDNAs encoding the NHE1, NHE2, and NHE3 Na+/H+ antiporters. Pharmacological studies using amiloride and two of its 5-N-substituted derivatives, 5-N-dimethyl amiloride and 5-N-(methyl-propyl)amiloride (MPA), demonstrate that the NHE1 isoform is the ubiquitously expressed amiloride-sensitive Na+/H+ antiporter (Ki of 0.08 microM for MPA), whereas the NHE2 and NHE3 isoforms exhibit a lower affinity for these inhibitors (Ki of 0.5 microM and 10 microM, respectively, for MPA) and are therefore likely to be members of the epithelial Na+/H+ exchanger's family. In addition, we have used this system to test a new Na+/H+ exchanger inhibitor possessing anti-ischemic properties on myocardial cells [(3-methylsulphonyl-4-piperidinobenzoyl) guanidine methanesulphonate]. This compound inhibits competitively NHE1 (Ki of 0.16 microM) with a much greater affinity than NHE2 and NHE3 (Ki of 5 microM and 650 microM, respectively) and therefore appears to be much more discriminative between these two classes of antiporter isoforms than the amiloride-related molecules. These results suggest an explanation for the observed difference of physiological effects between amiloride and HOE694, and identify this new inhibitor as a useful tool for studies of Na+/H+ exchange.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1458011	Amiloride Related Compound A		1458-01-1	Price

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