S-ethylisothiourea, a nonamino acid inhibitor of nitric oxide synthase, reverses septic vasodilation in sheep

Abstract

S-ethylisothiourea (3936W92) is a nonamino acid antagonist of nitric oxide synthase. Its selectivity for the inducible form of nitric oxide synthase is twice as high as for the constitutive form of the enzyme. We tested 3936W92 in 20 sheep, which were surgically prepared for chronic study. In all sheep, a hyperdynamic sepsis was induced by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, nine sheep received a continuous infusion of 3936W92 over the next 24 h, whereas the control group (n = 9) received saline instead. Two sheep died within the first 24 h of sepsis. 3936W92 caused a complete reversal of the hyperdynamic circulation, while sheep in the control group remained hyperdynamic. Although the cardiac index decreased significantly during treatment with 3936W92 (7.9 +/- .8 vs. 6.0 +/- .7 l/min/m2), a simultaneous increase in oxygen extraction prevented oxygen consumption from falling.