The effect of alkylxanthines and other phosphodiesterase inhibitors on adenosine-receptor mediated decrease in...

Cyclic AMP accumulation and glycerol release were studied in isolated rat fat cells. Both processes were inhibited by R-site specific adenosine analogues (L-PIA greater than NECA greater than 2-chloro-adenosine greater than D-PIA), but poorly or not at all by the P-site selective analogue SQ 22,536. The effect of a series of xanthine derivatives and of some structurally unrelated phosphodiesterase inhibitors as inhibitors of 2-chloro-adenosine induced inhibition of NA stimulated cyclic AMP accumulation and lipolysis was subsequently examined. The 2-chloroadenosine effect on cyclic AMP accumulation was antagonized by the xanthines with the following order of potency: DPX greater than 8-phenyl-theophylline greater than 8-p-sulpho-phenyl-theophylline greater than verrophylline greater than IBMX greater than theophylline greater than HWA 285 greater than pentoxiphylline greater than caffeine greater than 7-benzyl IBMX greater than theobromine greater than enprofylline greater greater than ZK 62,711. The rank order potency of xanthines against the antilipolytic effect of 2-chloro-adenosine was the same with two notable exceptions: the two potent phosphodiesterase inhibitors 7-benzyl-IBMX and ZK 62,711 were more than 20 times more potent as inhibitors of the antilipolytic effect of 2-chloro-adenosine. The results show that antagonism of adenosine analogue-induced antilipolytic effects is a convenient assay for adenosine antagonistic potency of drugs, except for drugs with a high potency as phosphodiesterase inhibitors. The lipolytic potency of the xanthine derivatives was also studied. The ability of the xanthines to stimulate basal and noradrenaline stimulated lipolysis was generally in agreement with their potency as adenosine antagonists. Adenosine deaminase induced lipolysis was stimulated by potent phosphodiesterase inhibitors.