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Blockade of the sodium proton antiport abolishes growth factor induced dna synthesis in fibroblasts structure activity relationships in the amiloride series



Blockade of the sodium proton antiport abolishes growth factor induced dna synthesis in fibroblasts structure activity relationships in the amiloride series



Journal of Biological Chemistry 259(7): 4313-4319



In Chinese hamster lung fibroblasts a growth factor activatable and amiloride-sensitive Na+/H+ antiport was characterized. In this report, the affinity of 28 analogs of amiloride for inhibition of the Na+/H+ antiport and inhibition of growth factor-induced DNA synthesis was compared. The guanidino moiety of amiloride must be protonated to elicit inhibition of the Na+/H+ exchange. Substitutions within this moiety by methyl, phenyl or benzyl groups reduced the activity 20- to 1000-fold. Substitution of the proton(s) of the 5-amino group of amiloride with alkyl or alkenyl groups increases potency up to 100-fold (5-N,N-diethylamiloride has a KI of 4 .times. 10-8 M). In HCO3--free medium and at lower [Na+]0 (25 or 50 mM) to reduce competition with amiloride, growth factor-stimulated DNA synthesis of G0-arrested cells is inhibited by amiloride and its analogs with the same rank order as that for Na+/H+ antiporter inhibition. Over a range of 3 logs of concentration, a tight correlation was established between IC50 [median inhibitory concentration] for the blockade of both processes, Na+/H+ exchange and percentage of cells entering the S phase upon growth factor action. In HCO3--free medium, the functioning of the Na+/H+ exchange system is required for growth factor-induced DNA synthesis.

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