Administration of
lipopolysaccharide to anaesthetised rats produced a reduction in mean arterial pressure, an increase in heart rate, and death at 4-6 h.
Intravenous infusion of
NG-nitro-L-arginine methyl ester (50 mg/kg), an inhibitor of constitutive and inducible
nitric oxide (
NO) synthase, 60 min after challenge with
lipopolysaccharide, caused an immediate increase in blood pressure followed by a precipitous fall in pressure, and death. In contrast,
intravenous infusion of L-
canavanine (100 mg/kg), reported to be a selective inhibitor of inducible
NO synthase in vitro, 60 min and 180 min after
lipopolysaccharide challenge, produced an increase in mean arterial pressure and reversed the
lipopolysaccharide induced hypotension. However, in
lipopolysaccharide challenged animals protected from
hypotension by administration of L-
canavanine (60 min post challenge),
intravenous infusion of
NG-nitro-L-arginine methyl ester at 180 min post challenge caused an immediate rise in mean arterial pressure, followed by a rapid fall in blood pressure and heart rate, and
sudden death. In contrast, a second dose of L-
canavanine at 180 min post challenge maintained blood pressure for the duration of the experiment. These findings indicate that inhibition of both constitutive and inducible
NO synthase during endotoxaemia is lethal. However, the use of a selective inhibitor of inducible
NO synthase restores mean arterial pressure to baseline, and offers a therapeutic approach to managing
hypotension in
shock.