STUDY OF PHOSPHODIESTERASE INHIBITORS ON LIPOLYSIS, PHOSPHODIESTERASE ACTIVITY AND CYCLIC 3', 5'-ADENOSINE MONOPHOSPHATE LEVELS IN ISOLATED FAT CELLS

¹ Department of Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana

Papaverine, 1-ethyl-4-(isopropylidenehydrazine)-1H-pyrazole-(3,4-b)-pyridine-5-carboxylic acid, ethylester-HCl (SQ 20,009) and theophylline were compared as phosphodiesterase inhibitors at two different substrate concentrations of cyclic 3' , 5'-adenosine monophosphate (cyclic AMP). At both concentrations of cyclic AMP, papaverine and SQ 20,009 were found to be more potent than theophylline. However, only theophylline was capable of stimulating lipolysis in the isolated fat cell preparation. All three compounds augmented the lipolytic response to both epinephrine and corticotropin. Theophylline alone was able to cause a small but significant increase in the intracellular levels of cyclic AMP in isolated fat cells whereas papaverine and SQ 20,009 were without effect. In addition, theophylline greatly augmented the ability of epinephrine to elevate cyclic AMP levels in fat cells whereas the other two compounds produced no change. Theophylline produced no stimulation in adipose tissue glycogen phosphorylase activity. In fact, high concentrations of this methylxanthine were inhibitory. These results demonstrate a lack of correlation between phosphodiesterase inhibition and stimulation of lipolysis or increases in tissue levels of cyclic AMP. It is concluded that great care should be taken in assuming that the effects of theophylline on adipose tissue metabolism are secondary to inhibition of cyclic nucleotide phosphodiesterase.