SEROTONIN IS INVOLVED IN THE ACTH-INDUCED REVERSAL OF HEMORRHAGIC-SHOCK IN ANESTHETIZED RATS

In a rat model of volume-controlled hemorrhagic shock (mean arterial p ressure = 20-24 mm Hg) causing the death of all saline-treated animals within 30 min, the i.v. bolus injection of ACTH-(1-24) (160 mu g/kg) produced an almost complete and sustained reversal of the shock condit ion, with recovery of arterial blood pressure, pulse pressure and resp iratory rate, and with 100% survival at the end of the experiment (2 h ). The serotonin-depleting agent p-chlorophenylalanine (316 mg/kg i.p. , administered 66-70 h before hemorrhage) almost completely prevented the effect of ACTH. The 5-HT1/5-HT2 receptor antagonist, methysergide, prevented the effect of ACTH completely when injected i.v. (5 mg/kg), but only in part when injected into a brain ventricle (i.c.v.) (15 mu g/rat); the 5-HT2 antagonist, ketanserin, prevented the effect of ACT H completely when injected i.c.v. (1.5 mu g/rat), but only in part whe n injected i.v. (0.5 mg/kg); the 5-HT3 antagonist, MDL 72222, largely prevented the effect of ACTH when injected i.c.v. (10 mu g/rat), but h ad no influence at all when injected i.v. (3 mg/kg); finally, the 5-HT 4 antagonist, GR 125487, had no effect when injected i.v. (5 mu g/kg) or when injected i.c.v. (30 ng/rat). Overall, these data indicate that both CNS and peripheral serotonin play an important role in the compl ex mechanism of the ACTH-induced hemorrhagic shock reversal.