Selective iNOS Inhibition Is Superior to Norepinephrine in the Treatment of Rat Endotoxic Shock

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Abstract
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.