Effects of antisense oligonucleotide to iNOS on hemodynamic and vascular changes induced by LPS

Azizul M. Hoque, Andreas Papapetropoulos, Richard C. Venema, John D. Catravas, Leslie C. Fuchs

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30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H1078-83
Number of pages6
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume275
Issue number3 Pt 2
StatePublished - Sep 1 1998

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Keywords

  • Antisense oligonucleotide
  • Inducible nitric oxide synthase
  • Mesenteric small arteries
  • Septic shock

ASJC Scopus subject areas

  • Physiology

Cite this

Hoque, A. M., Papapetropoulos, A., Venema, R. C., Catravas, J. D., & Fuchs, L. C. (1998). Effects of antisense oligonucleotide to iNOS on hemodynamic and vascular changes induced by LPS. American Journal of Physiology - Heart and Circulatory Physiology, 275(3 Pt 2), H1078-83.