HYPOXIA IN-VIVO INHIBITS ALDOSTERONE SYNTHESIS AND ALDOSTERONE SYNTHASE MESSENGER-RNA IN RATS

Hypoxia leads to a decrease in aldosterone that cannot be entirely exp lained by extrinsic controllers of adrenal function. We have shown tha t acute hypoxia attenuates aldosterone synthesis via a direct inhibiti on of the function of the aldosterone enzyme pathway. The mechanism of the sustained decrease in aldosterone during chronic hypoxia is unkno wn. The present study evaluated the hypothesis that chronic hypoxia le ads to a decrease in the expression of the steroidogenic enzyme P-450c 11AS unique to the aldosterone pathway. Rats were exposed to 3 days of normoxia, moderate hypoxia (12% O-2), or severe hypoxia (10% O-2) Adr enal glands were removed and prepared for biochemical analysis of ster oidogenesis in vitro (dispersed capsular cells) and for measurement of steady-state enzyme mRNA levels by reverse-transcription competitive polymerase-chain reaction (RT-cPCR) and by in situ hybridization histo chemistry (ISHH). Moderate hypoxia had no effect on steroidogenesis. A drenal cells from rats exposed to severe hypoxia demonstrated a decrea sed conversion of corticosterone to aldosterone (late pathway catalyze d by P-450c11AS) without a change in the other mitochondrial cytochrom e P-450 enzyme activities. Adrenal cells from rats exposed to hypoxia also demonstrated a three- to fourfold decrease in P-450c11AS mRNA wit hout a change in the other mitochondrial cytochrome P-450 enzymes mRNA s, as determined by either RT-cPCR or ISHH. We conclude that relativel y short-term chronic hypoxia in rats leads to a decrease in aldosteron ogenesis by decreasing the expression of the gene for the late-pathway enzyme unique to the aldosterone pathway (P-450c11AS).