Actions of various methylxanthines and papaverine on the synthesis of corticosterone in vitro.
Actions of various methylxanthines (theophylline, theobromine, caffeine) and papaverine, i.e. drugs which are known to inhibit phosphodiesterase (PDE), were studied on the basal and stimulated synthesis of corticosterone in vitro by using rat adrenal slices. When slices were incubated with methylxanthines, the synthesis of corticosterone was slightly increased. The order of potency, expressed as the efficacy (intrinsic activity) was: theophylline greater than caffeine greather than theobromine. Papaverine did not stimulate the synthesis. The synthesis stimulated by ACTH or the dibutyryl derivative of c-AMP (DBA) was reduced by all of the inhibitors of phosphodiesterase. The molar concentration of the inhibitors which reduced the stimulated steroidogenesis by 50% was lowest for papaverine, higher for theobromine and theophylline and highest for caffeine. Papaverine was active in concentrations of about 10(-5)M, while the methylxanthines were effective in concentrations of 10(-3)--10(-2)M. When the PDE-inhibitors were added to the incubate simultaneously with the stimulant (ACTH or DBA), there was a delay of 60 min before the synthesis was completely blocked. When the stimulant was added 30 min before the administration of an inhibitor, the inhibitory action was no more evident. The inhibitory action of theophylline, but not that of papaverine, was reversed by washing adrenal slices free from the inhibitor, before adding the stimulant. The type of inhibition for papaverine as well as for methylxanthines in antagonizing both the ACTH- and DBA-stimulated synthesis of corticosterone was not competitive but of a mixed type.
D000311:Adrenal Glands / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D003345:Corticosterone / Q000096:biosynthesis* / Q000378:metabolism; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D010208:Papaverine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors; D051381:Rats; D013805:Theobromine / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology*; D013997:Time Factors
D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; D003994:Bucladesine; D000324:Adrenocorticotropic Hormone; D013806:Theophylline; D010208:Papaverine; D013805:Theobromine; D003345:Corticosterone