STEROIDOGENIC AND GLYCOLYTIC RESPONSES TO NUCLEOTIDES, NUCLEOSIDES AND STEROIDS IN RODENT ADRENAL GLANDS: OPPOSING, SPECIES-DEPENDENT EFFECTS OF CYCLIC GMP

Abstract

The effects of nucleotides and nucleosides on steroidogenesis and aerobic lactic-acid production were examined in unsectioned mouse adrenal glands preincubated for 1 h and then incubated for 2 h in Krebs–Ringer bicarbonate and 0·01 m-glucose medium equilibrated with 95% O2:5% CO2. Of all the compounds tested, at a concentration of 10 mmol/l (cyclic AMP, cyclic GMP, AMP, ADP, ATP, GMP, IMP, adenosine, guanosine and inosine), only cyclic AMP was capable of stimulating steroidogenesis and induced a nine- to 12-fold increase in corticosterone production. Cyclic GMP inhibited corticosterone production by 40–55%. The nucleotides and nucleosides, except for ATP, all increased lactic-acid production. Cyclic AMP caused a three- to fivefold stimulation, cyclic GMP an increase of only 20–30%, and GMP, AMP and ADP increases of 80–100%. Cyclic GMP, protected from hydrolysis, may thus inhibit lactic-acid as well as steroid production in the mouse adrenal gland. By contrast, cyclic GMP was nearly as effective as cyclic AMP in stimulating glycolysis and steroidogenesis of rat adrenal glands. The proportion of corticosterone to 18-hydroxydeoxycorticosterone (18-OH-DOC) obtained with cyclic GMP was, however, always lower than that obtained with cyclic AMP. Cyclic AMP, as opposed to cyclic GMP, increased the formation of corticosterone and lactic acid in the presence of exogenous deoxycorticosterone (DOC) beyond that expected from an additive response. Lactic-acid production was inhibited by 18-OH-DOC, a major secretory product of the rat but not the mouse adrenal. This steroid, furthermore, greatly reduced the stimulation of glycolysis evoked by added DOC, 11β-hydroxyprogesterone and corticosterone, facts that could account for the greater glycolytic activity of mouse compared with rat adrenals. The yield of corticosterone in the presence of added 11β-hydroxyprogesterone, but not of DOC, was also reduced by 18-OH-DOC, denoting a selective inhibition of 21-hydroxylation. A structural analogue of 18-OH-DOC, 18,20-cyclo-20,21-dihydroxypregn-4-en-3-one, added by itself stimulated lactic-acid production. Added in combination with other steroids, it specifically counteracted the inhibitory effect of 18-OH-DOC, a steroid of potentially adverse biological properties. Our results are compatible with the concept that adrenal aerobic glycolysis is to a significant extent, but not exclusively, steroid-mediated. The glycolytically active but steroidogenically inert nucleotides and nucleosides offer examples of a dissociation between the two events.