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- W2113300234 abstract "The relationship between the ability of a compound to antagonize the escape of cyclic AMP from cultured cells and its cyclic 3':5'-nucleotide phosphodiesterase (EC [3.1.4.17][1]) inhibitory activity was investigated using 1-methyl-3-isobutylxanthine (MIX) and three MIX analogs, i.e., 7-benzyl MIX, 8- t -butyl MIX, and 1-isoamyl-3-isobutylxanthine. The addition of 30 µM MIX, 7-benzyl MIX, 8- t -butyl MIX, or 1-isoamyl-3-isobutylxanthine to the incubation media of WI-38 fibroblasts exposed to 5.7 µM prostaglandin E1 (PGE1) increased the intracellular cyclic AMP levels and decreased the release of cyclic AMP from the cells after 6 and 24 mm. Concentration-response studies showed that cyclic AMP escape from PGE1-stimulated WI-38 fibroblasts was most sensitive to inhibition by 7-benzyl MIX and 8- t -butyl MIX. At 30 µM, the highest concentration tested, only 1-isoamyl-3-isobutylxanthine potentiated the effects of 5.7 µM PGE1 on cyclic AMP accumulation in SV40-transformed WI-38 (VA13) cells. None of the compounds at 30 µM affected cyclic AMP escape from PGE1-treated VA13 cultures. WI-38- and VA13-soluble and DEAE-cellulose peak I phosphodiesterase activities were most effectively inhibited by 7-benzyl MIX and 8- t -butyl MIX when either 1 µM cyclic AMP or cylcic GMP was the substrate. In contrast, 1-isoamyl-3-isobutylxanthine was the most potent inhibitor of WI-38 and VA13 DEAE-cellulose peak II phosphodiesterase activities. These results suggested that there are similar structural requirements of the xanthines for antagonism of cyclic AMP escape from WI-38 cultures and inhibition of the fibroblast peak I phosphodiesterase activities. The data also appear to indicate that the ability of the xanthines to alter cyclic AMP metabolism in VA13 cells cannot be predicted solely on the basis of their potencies as phosphodiesterase inhibitors.ACKNOWLEDGMENTS The authors thank Richard H. Chamberlain, Peter S. Ciano, Cynthia A. Eaton, and Chih-Fang Wu for their excellent technical assistance. [1]: pending:yes" @default.
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- W2113300234 date "1980-07-01" @default.
- W2113300234 modified "2023-10-03" @default.
- W2113300234 title "Inhibition of fibroblast cyclic AMP escape and cyclic nucleotide phosphodiesterase activities by xanthines." @default.
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