INHIBITION OF ALDOSTERONE RELEASE BY HYPOXIA IN-VITRO - INTERACTION WITH CARBON-MONOXIDE

We have demonstrated that the aldosteronogenic pathway of the zona glo merulosa is unusually sensitive to modest changes in PO2 (Michaelis co nstant for O-2 approximate to 95 Torr). The current study evaluated th e interaction of CO (the classic ligand for P-450 enzymes) and the dec reases in O-2 on aldosteronogenesis in vitro. Bovine adrenocortical zo na glomerulosa cells were incubated for 2 h and stimulated with either adenosine 3',5'-cyclic monophosphate (cAMP) or angiotensin II. Ten an d 20% CO led to significant decreases in cAMP- and angiotensin II-stim ulated aldosteronogenesis. The combination of 20% CO and moderate decr eases in PO2 (from similar to 140 to similar to 100 Torr) led to an in teractive decrease in aldosterone production. The conversion of cortic osterone to aldosterone catalyzed by aldosterone synthase, which is th e site of O-2 sensitivity, was not significantly inhibited by CO. We c onclude that the aldosterone pathway is not exceptionally sensitive to CO compared with other steroidogenic pathways. This observation sugge sts that the unique O-2-sensitive properties of the aldosterone pathwa y located primarily within aldosterone synthase may not reside in its CO binding site (i.e., heme).