SELECTIVE INOS INHIBITION IS SUPERIOR TO NOREPINEPHRINE IN THE TREATMENT OF RAT ENDOTOXIC-SHOCK

S-methyl-isothiourea (SMT) is a potent inhibitor of NO synthase (NOS) with relative selectivity towards the inducible isoform (iNOS). We com pared SMT and norepinephrine for the treatment of experimental endotox ic shock. Anaesthetized rats challenged intravenously with lipopolysac charide (LPS), 10 mg/kg, were treated after 1 h with a 4-h infusion of norepinephrine (titrated to maintain blood pressure within baseline v alues), SMT at low dose (0.1 mg.kg(-1).h(-1)), or at high dose (1 mg.k g(-1).h(-1)), or an equivalent volume of saline (2 ml.kg(-1).h(-1)). I n saline-treated animals, LPS increased plasma nitrate and produced hy potension, low cardiac output (CO), lactic acidosis, and signs of live r 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-dependentl y blunted by SMT. Treatment with this agent prevented hypotension, thr ough 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. I n additional studies, we obtained evidence that, in contrast with the high dose, SMT at low dose did not interfere with the function of cons titutive NOS. These findings suggest a potential advantage of selectiv e iNOS inhibition over standard adrenergic support in the therapy of s eptic shock.