Tissue selective inhibition of cyclic nucleotide phosphodiesterase by denbufylline

The effects of the novel alkylxanthine denbufylline (1,3-d-n-butyl-7-(2'-oxopropyl)-xanthine), theophylline and 3-isobutyl-1-methyl-xanthine (IBMX), on the breakdown of cyclic AMP in homogenates of rat erythrocytes, abdominal aorta, adipocytes and cardiac and skeletal muscle were studied. Theophylline and IBMX inhibited cyclic nucleotide phosphodiesterase in all tissue extracts. In contrast, denbufylline was a tissue selective inhibitor of cyclic nucleotide phosphodiesterase. In skeletal muscle and erythrocytes, denbufylline (10 mumol/l) inhibited cyclic nucleotide phosphodiesterase activity by at least 80%. In these tissues, denbufylline was 10-30 and 100-300fold more potent than IBMX and theophylline, respectively. In adipocytes and cardiac and smooth muscle, denbufylline was not an effective inhibitor of cyclic AMP breakdown. Hofstee analysis of phosphodiesterase activity revealed that denbufylline selectively inhibited high affinity cyclic AMP phosphodiesterase in erythrocytes and skeletal muscle. In adipocytes, cardiac and vascular smooth muscle, denbufylline did not effectively inhibit the composite cyclic nucleotide phosphodiesterase activities either with high or with low affinity for cyclic AMP.