INHIBITION OF NITRIC-OXIDE SYNTHASES ENHANCES THE EFFECT OF ACTH IN HEMORRHAGIC-SHOCK

In a model of volume-controlled hemorrhagic shock in rats, invariably leading to death within 30 min of bleeding termination, the intravenou s (i.v.) bolus injection of ACTH-(1-24) at the dose of 0.16 mg/kg rest ored cardiovascular and respiratory functions and greatly prolonged su rvival. I.v. or intracerebroventricular (i.c.v.) treatment with N-G-ni tro-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. o r 0.015-0.135 mg/kg i.c.v., as well as i.v. treatment with S-methyliso thiourea (SMT), a selective inhibitor of the inducible isoform of NOS, at the doses of 0.001-3 mg/kg, dose-dependently improved cardiovascul ar and respiratory functions and potentiated the effect of a subthresh old dose (0.02 mg/kg) of ACTH-(1-24). On the other hand, either intrap eritoneal or i.c.v. pretreatment with L-arginine, the substrate of NOS s, prevented the effect of ACTH-(1-24). These data suggest that inhibi tion of NO overproduction is involved in the mechanism of action of AC TH-(1-24) in shock reversal.