H. Raff et al., HYPOXIA IN-VIVO INHIBITS ALDOSTERONE SYNTHESIS AND ALDOSTERONE SYNTHASE MESSENGER-RNA IN RATS, Journal of applied physiology, 81(2), 1996, pp. 604-610
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).