Activation of the l-Arginine-Nitric Oxide Pathway Is Involved in Vascular Hyporeactivity Induced by Endotoxin

Summary: The possible implication of a nitric oxide (NO)-like relaxing substance in endotoxin-induced vascular hyporeactivity to norepinephrine (NA) was investigated in rats, under three different experimental conditions: ex vivo in aortic rings removed from rats injected with E. coli endotoxin lipopolysaccharide (LPS, 20 mg/kg i.p.), in vitro in aortic rings incubated with LPS (100 ng/ml) for 5 h, and in vivo on pressure responsiveness in rats infused with LPS (5 mg/kg/h, 50 min). In all conditions, responses to NA were reduced by LPS. Both ex vivo and in vitro, this effect was observed whether functional endothelium was present or not, it was increased by l- but not d-arginine, and it was associated with a three- to fourfold increase in cyclic GMP content. Addition of methylene blue (2 μM), a guanylate cyclase inhibitor, restored NA-induced contraction. In all cases, inhibitors of NO formation from l-arginine abolished LPS-induced hyporeactivity to NA. These results suggest that increased NO production in blood vessels underlies hyporeactivity to NA in endotoxemia.