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Published ahead of print on June 7, 2004, doi:10.1164/rccm.200309-1311OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 6, September 2004, 647-655

A more recent version of this article appeared on September 15, 2004
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Submitted on September 24, 2003
Accepted on May 28, 2004

Dexamethasone Blocks Hypoxia-induced Endothelial Dysfunction in Organ-cultured Pulmonary Arteries

Takahisa Murata1*, Masatoshi Hori1, Kenichi Sakamoto1, Hideaki Karaki1, and Hiroshi Ozaki1

1 Department of Veterinary Pharmacology, University of Tokyo, Graduate School of Agriculture and Life Sciences, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: murata{at}mail.vm.a.u-tokyo.ac.jp.

We assessed the effects of dexamethasone on hypoxia-induced dysfunction of the pulmonary endothelium using organ-cultured rabbit intrapulmonary arteries. Three µM dexamethasone inhibited the 7 day-hypoxia (5% oxygen)-induced impairments of endothelial dependent relaxation, cGMP accumulation, and increase in intracellular Ca2+ level under substance P-stimulated conditions. Treatment with dexamethasone over the final 3 days of the 7-day hypoxic exposure period also restored the decreased endothelium dependent relaxation. Although chronic hypoxia did not change the mRNA expression of endothelial nitric oxide synthase (eNOS), 3 µM dexamethasone increased eNOS mRNA expression both in the hypoxic and normoxic (20% oxygen) pulmonary endothelium. On the other hand, eNOS protein expression was not changed in any of the arteries. We next assessed the effects of dexamethasone on the eNOS activation pathway. Chronic hypoxia impaired eNOS-phosphorylation and Akt-phosphorylation under both the non-stimulated and substance P-stimulated conditions, and 3 µM dexamethasone restored these phosphorylations. Morphological study revealed that 3 µM dexamethasone inhibited chronic hypoxia-induced atrophy of endothelial cells and eNOS protein condensation into plasma membranes. These results suggest that dexamethasone exerts beneficial effects on chronic hypoxia-induced impairments of NO-mediated arterial relaxation by increasing eNOS mRNA expression and inhibiting hypoxia-induced impairments in eNOS activation pathway with atrophy of endothelial cells.
Key words: Hypoxia, Organ-culture, Endothelium-dependent relaxation, dexamethasone




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