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Vol. 284, Issue 2, 568-575, February 1998
Center for Experimental Therapeutics and Reperfusion Injury,
Brigham and Women's Hospital and Harvard Medical School, Boston,
Massachusetts
Decreased oxygen delivery to cells (hypoxia) is prevalent in a number
of important diseases. Little is known about mechanisms of oxygen
sensing at the cellular level or about whether functional correlates of
oxygen sensing exist. In this study, we examined the impact of hypoxia
on stimulated epithelial ion transport function. T84 cells, a model of
intestinal epithelia, were grown on permeable supports, exposed to
hypoxia (range 1-21% O2) for periods of time between 0 and 72 h and assessed for stimulated ion transport. Hypoxia evoked
a specific decrease in cyclic nucleotide-stimulated (cAMP and cGMP) but
not Ca++-stimulated ion transport. 86Rb
(K+ tracer) uptake and 125I (Cl
tracer) efflux were reduced in hypoxic cells by >50% and >40%, respectively, fluid movement was reduced by hypoxia (>50% decrease) and reoxygenation resulted in partial recovery of the ion transport responses. Stimulated and basal levels of both cAMP and cGMP were decreased in response to hypoxia, although intracellular ATP levels were unaltered under similar conditions. Exogenous addition of cobalt,
nickel or manganese, all of which compete for oxygen binding on
heme-containing proteins, mimicked hypoxia. Because guanylate cyclase
is a heme protein, we measured the influence of cobalt on activity of
guanylate cyclase in purified plasma membrane preparations and found
cobalt to inhibit stimulated cGMP levels in this cell-free system.
Finally, pharmacological lowering of intracellular cGMP (using LY83583)
resulted in decreased cAMP-stimulated Cl secretion, and
direct elevation of cGMP (using 8-bromo-cGMP or dibutyryl-cGMP)
restored this hypoxia-induced activity. We conclude that a potential
oxygen-sensing mechanism of epithelial cells involves the cooperation
of heme-containing proteins such as guanylate cyclase and that
biochemical cross-talk between cAMP- and cGMP-stimulated pathways may
be important in such responses.
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