Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries.
We assessed the effects of dexamethasone (DEX) on hypoxia-induced dysfunction of the pulmonary endothelium using organ-cultured rabbit intrapulmonary arteries; 3-microM DEX inhibited the 7-day hypoxia (5% oxygen)-induced impairments of endothelial-dependent relaxation, cGMP accumulation, and increase in intracellular Ca(2+) level under substance P-stimulated conditions. Treatment with DEX 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 microM of DEX increased eNOS mRNA expression in both 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 DEX on the eNOS activation pathway. Chronic hypoxia impaired eNOS phosphorylation and Akt phosphorylation under both the nonstimulated and substance P-stimulated conditions, and 3-microM DEX restored these phosphorylations. Morphologic study revealed that 3-microM DEX inhibited chronic hypoxia-induced atrophy of endothelial cells and eNOS protein condensation into plasma membranes. These results suggest that DEX exerts beneficial effects on chronic hypoxia-induced impairments of nitric oxide-mediated arterial relaxation by increasing eNOS mRNA expression and inhibiting hypoxia-induced impairments in eNOS activation pathway with atrophy of endothelial cells.
Murata
Takahisa
T
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan. murata@mail.vm.a.u-tokyo.ac.jp
Hori
Masatoshi
M
Sakamoto
Kenichi
K
Karaki
Hideaki
H
Ozaki
Hiroshi
H
D000818:Animals; D001284:Atrophy; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005938:Glucocorticoids / Q000494:pharmacology*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology; D011817:Rabbits; D014652:Vascular Diseases / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology
D005938:Glucocorticoids; D003907:Dexamethasone; D019001:Nitric Oxide Synthase