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1 Cardiovascular Pulmonary Research Laboratory and 2 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262; and 3 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129
Endothelial nitric
oxide (NO) synthase (eNOS) mRNA and protein and NO production are
increased in hypoxia-induced hypertensive rat lungs, but it is
uncertain whether eNOS gene expression and activity are increased in
other forms of rat pulmonary hypertension. To investigate these
questions, we measured eNOS mRNA and protein, eNOS immunohistochemical
localization, perfusate NO product levels, and NO-mediated suppression
of resting vascular tone in chronically hypoxic (3-4 wk at
barometric pressure of 410 mmHg),
monocrotaline-treated (4 wk after 60 mg/kg), and fawn-hooded (6-9
mo old) rats. eNOS mRNA levels (Northern blot) were greater in hypoxic
and monocrotaline-treated lungs (130 and 125% of control lungs,
respectively; P < 0.05) but not in
fawn-hooded lungs. Western blotting indicated that eNOS protein levels
increased to 300 ± 46% of control levels in hypoxic
lungs (P < 0.05) but were decreased
by 50 ± 5 and 60 ± 11%, respectively, in monocrotaline-treated
and fawn-hooded lungs (P < 0.05).
Immunostaining showed prominent eNOS expression in small
neomuscularized arterioles in all groups, whereas perfusate NO product
levels increased in chronically hypoxic lungs (3.4 ± 1.4 µM;
P < 0.05) but not in
either monocrotaline-treated (0.7 ± 0.3 µM) or fawn-hooded (0.45 ± 0.1 µM) lungs vs. normotensive lungs (0.12 ± 0.07 µM).
All hypertensive lungs had increased baseline perfusion pressure in
response to nitro-L-arginine but
not to the inducible NOS inhibitor aminoguanidine. These results
indicate that even though NO activity suppresses resting vascular tone in pulmonary hypertension, there are differences among the groups regarding eNOS gene expression and NO production. A better
understanding of eNOS gene expression and activity in these
models may provide insights into the regulation of this vasodilator
system in various forms of human pulmonary hypertension.
hypoxia; pulmonary circulation; fawn-hooded rat; monocrotaline; nitric oxide
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