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Departments of Internal Medicine, Pharmacology, and Physiology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242; and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
We examined the
hypotheses that responses to acetylcholine are impaired and responses
to NO are enhanced in carotid artery from mice made deficient in
endothelial nitric oxide synthase (eNOS) by gene targeting
(eNOS-deficient mice). We also tested the hypothesis that deletion of
one copy of the eNOS gene is sufficient to alter vascular responses.
Vessels were studied in vitro from heterozygous (+/
) and
homozygous (/) eNOS-deficient mice as well as wild-type
[eNOS(+/+)] littermates. After precontraction with
prostaglandin F2
, acetylcholine
produced marked relaxation of carotid arteries in eNOS(+/+) mice, with
impaired vasorelaxation in eNOS(+/) mice. For example, 1 µM
acetylcholine relaxed carotid arteries by 55 ± 5% (mean ± SE)
in eNOS(+/) mice (n = 13)
compared with 83 ± 3% in eNOS(+/+) mice
(n = 14, P < 0.001 vs. +/). In contrast, acetylcholine caused no relaxation in carotid arteries from
eNOS(/) mice (P < 0.001 vs. +/+ and +/). Relaxation of the carotid artery in
response to nitroprusside [a nitric oxide (NO) donor] was
enhanced (P < 0.001) in
eNOS-deficient mice. For example, in response to 10 nM nitroprusside,
the carotid artery relaxed by 18 ± 2% in eNOS(+/+) mice
(n = 14), 33 ± 2% in
eNOS(+/) mice (n = 13), and 47 ± 4% in eNOS(/) mice
(n = 5). Thus relaxation of the
carotid artery is impaired with acetylcholine and enhanced with the NO
donor nitroprusside in eNOS-deficient mice. Enhanced responses to NO
may represent a compensatory response expressed in the absence of eNOS.
The findings that vascular responses to acetylcholine and NO are
altered in eNOS(+/) mice compared with those observed in
eNOS(+/+) mice suggest a "gene-dosing" effect.
gene targeting; nitric oxide; acetylcholine; nitroprusside; soluble guanylate cyclase; NG-nitro-L-arginine; endothelial nitric oxide synthase
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