Effects of S-isopropyl isothiourea, a potent inhibitor of nitric oxide synthase, in severe hemorrhagic shock

We characterized the response to intravenous S-isopropyl isothiourea (IPTU), a novel potent nitric oxide synthase (NOS) inhibitor, in rodent and porcine models of hemorrhagic shock (HS). IPTU (at 300 micrograms/kg, administered as 3 subsequent bolus injections), in anesthetized rats hemorrhaged to a mean arterial blood pressure (MAP) of 35 mmHg, increased MAP and improved survival over 120 min. In anesthetized pigs hemorrhaged to a MAP of 45 mmHg, IPTU (0.3 mg/kg plus 1 mg.kg-1.h-1) increased MAP and systemic vascular resistance. IPTU did not alter the cardiac index, renal blood flow, arterial and portal oxygen content, or splanchnic oxygen consumption or extraction. In contrast, infusion of norepinephrine (100 micrograms.kg-1.h-1) did not alter MAP and increased mortality in the rat model, whereas it caused a transient increase in MAP and a tachycardia in the porcine model of HS without significantly affecting the other parameters studied. Inhibition of the endothelial NOS in early severe HS may have beneficial effects on blood pressure and survival without altering cardiac output and splanchnic and renal perfusion.