Am. J. Respir. Crit. Care Med., Vol 157, No. 1, 01 1998, 162-170.
Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock [In Process Citation]
A Rosselet, F Feihl, M Markert, A Gnaegi, C Perret and L Liaudet
Institute of Pathophysiology and Central Laboratory for Clinical Chemistry, University Hospital, Lausanne, Switzerland.
S-methyl-isothiourea (SMT) is a potent inhibitor of NO synthase (NOS) with
relative selectivity towards the inducible isoform (iNOS). We compared SMT
and norepinephrine for the treatment of experimental endotoxic shock.
Anesthetized rats challenged intravenously with lipopolysaccharide (LPS),
10 mg/kg, were treated after 1 h with a 4-h infusion of norepinephrine
(titrated to maintain blood pressure within baseline values), SMT at low
dose (0.1 mg x kg-1 x h-1), or at high dose (1 mg x kg-1 x h-1), or an
equivalent volume of saline (2 ml x kg- 1 x h-1). In saline-treated
animals, LPS increased plasma nitrate and produced hypotension, low cardiac
output (CO), lactic acidosis, and signs of liver and kidney dysfunction.
Norepinephrine maintained blood pressure (BP) and reduced the fall in CO,
without affecting lactic acidosis, organ dysfunction, and nitrate
accumulation. The latter was dose-dependently blunted by SMT. Treatment
with this agent prevented hypotension, through systemic vasoconstriction
with the high dose and a maintained CO with the low dose. Low, but not
high, dose SMT blunted lactic acidosis. Both doses reduced the signs of
renal, but not liver, dysfunction. In additional studies, we obtained
evidence that, in contrast with the high dose, SMT at low dose did not
interfere with the function of constitutive NOS. These findings suggest a
potential advantage of selective iNOS inhibition over standard adrenergic
support in the therapy of septic shock.
