Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway.
The involvement of L-arginine-dependent nitric oxide (NO) production in the vascular failure observed in endotoxemia was investigated in male Wistar rats treated with Escherichia coli lipopolysaccharide (LPS). Contractile responses to norepinephrine (NE) were measured ex vivo in aortas isolated from rats treated with LPS (20 mg/kg ip, 4 h before experiments) and pressor responses to NE were recorded in vivo in rats infused with LPS (5 mg.kg-1.h-1 iv). LPS pretreatment induced a rightward shift of the concentration-response curve to NE and a reduction of the maximal contraction by approximately 43% and 54% (P less than 0.05) in aortic rings with and without functional endothelium, respectively. This was not modified by the presence of indomethacin (10 microM) during the contractile experiments. In contrast, in the presence of NG-monomethyl-L-arginine (L-NMMA, 300 microM) or methylene blue (10 microM), maximal contractions to NE were restored to control values whether functional endothelium was present or not. The effects of L-NMMA were reversed by L- but not by D-arginine. Additionally, the effects of LPS pretreatment on vascular contractility were potentiated by L-arginine. In vivo, LPS infusion produced a reduction in pressor responsiveness to NE (0.1-10 mg/kg), which was also abolished by L-NMMA (30 mg/kg iv). This effect of L-NMMA was reversed by L- but not by D-arginine (100 mg/kg iv). These results demonstrate that activation of the L-arginine pathway has a major role in the production of vascular hyporeactivity in endotoxemia, ex vivo as well as in vivo. Additionally, they suggest that endothelium-independent vascular production of NO may be involved.
Julou-Schaeffer
G
G
Laboratoire de Pharmacologie Cellulaire et Moléculaire, Université Louis Pasteur de Strasbourg, France.
Gray
G A
GA
Fleming
I
I
Schott
C
C
Parratt
J R
JR
Stoclet
J C
JC
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects; D019323:omega-N-Methylarginine
D004731:Endotoxins; D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D001120:Arginine; D000109:Acetylcholine; D008751:Methylene Blue; D009638:Norepinephrine; D007213:Indomethacin