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Vascular Biology Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912
Lipopolysaccharide (LPS) causes impaired vascular contractility
proposed to be mediated by induction of nitric oxide synthase (iNOS).
Antisense (AS) oligonucleotide inhibits the translation of target mRNA
into functional proteins. We hypothesize that in vivo pretreatment with
AS oligonucleotide targeted to iNOS mRNA can prevent LPS-induced
hyporeactivity to norepinephrine (NE). Three groups of conscious male
Wistar rats received one of the following: saline, AS, or mismatch (MM)
oligonucleotide at 0.4 mg/kg iv at 12 and 24 h before LPS (5 mg/kg iv).
The fourth group received saline only. Mean arterial pressure (MAP) and
heart rate (HR) were continuously recorded before and 6 h after LPS or
saline administration. Aorta, lung lavage, and lung tissue were
collected for determination of iNOS protein expression and NOS
activity. Small mesenteric arteries (
250 µm) were isolated,
denuded of endothelium, and maintained at a constant intraluminal
pressure of 40 mmHg for study in vitro. LPS produced significant
tachycardia that was not altered by AS or MM oligonucleotide. AS, but
not MM oligonucleotide, reduced the accumulation of cGMP, the increase in conversion of
L-[3H]arginine
to
L-[3H]citrulline,
and iNOS protein expression in tissue from LPS-treated rats. Small
mesenteric arterial contraction to NE was significantly impaired in
vessels from LPS-treated rats and was restored by AS, but not MM,
oligonucleotide. In a rat model of septic shock, AS oligonucleotide to
iNOS mRNA inhibits NOS activity and iNOS protein expression and
prevents the vascular hyporeactivity to NE, which may contribute to
hypotension in shock.
septic shock; inducible nitric oxide synthase; antisense oligonucleotide; mesenteric small arteries
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