EFFECTS OF ANTISENSE OLIGONUCLEOTIDE TO INOS ON HEMODYNAMIC AND VASCULAR CHANGES INDUCED BY LPS

Lipopolysaccharide (LPS) causes impaired vascular contractility propos ed to be mediated by induction of nitric oxide synthase (iNOS). Antise nse (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 hyporeac tivity to norepinephrine (NE). Three groups of conscious male Wistar r ats received one of the following: saline, AS, or mismatch (MM) oligon ucleotide 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 he art rate (KR) were continuously recorded before and 6 h after LPS or s aline administration. Aorta, lung lavage, and lung tissue were collect ed for determination of iNOS protein expression and NOS activity. Smal l mesenteric arteries (approximate to 250 mu m) 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 oligonucl eotide, reduced the accumulation of cGMP, the increase in conversion o f L-[H-3]arginine to L-[H-3]citrulline, and iNOS protein expression in tissue from LPS-treated rats. Small mesenteric arterial contraction t o NE was significantly impaired in vessels from LPS-treated rats and w as restored by AS, but not MM, oligonucleotide. In a rat model of sept ic shock, AS oligonucleotide to iNOS mRNA inhibits NOS activity and iN OS protein expression and prevents the vascular hyporeactivity to NE, which may contribute to hypotension in shock.