Inhibition of nitric oxide synthases enhances the effect of ACTH in hemorrhagic shock

Abstract

In a model of volume-controlled hemorrhagic shock in rats, invariably leading to death within 30 min of bleeding termination, the intravenous (i.v.) bolus injection of ACTH-(1–24) at the dose of 0.16 mg/kg restored cardiovascular and respiratory functions and greatly prolonged survival. I.v. or intracerebroventricular (i.c.v.) treatment with N G-nitro-L-arginine methylester (L-NAME), a non-isoform-selective inhibitor of nitric oxide synthases (NOSs), at the doses of 2.5–10 mg/kg i.v. or 0.015–0.135 mg/kg i.c.v., as well as i.v. treatment with S-methylisothiourea (SMT), a selective inhibitor of the inducible isoform of NOS, at the doses of 0.001–3 mg/kg, dose-dependently improved cardiovascular and respiratory functions and potentiated the effect of a subthreshold dose (0.02 mg/kg) of ACTH-(1–24). On the other hand, either intraperitoneal or i.c.v. pretreatment with L-arginine, the substrate of NOSs, prevented the effect of ACTH-(1–24). These data suggest that inhibition of NO overproduction is involved in the mechanism of action of ACTH-(1–24) in shock reversal.