The parasympathetic nervous system actively participates in the regulation of pathophysiologic responses in circulatory shock. To determine the effects of cholinergic blockade in endotoxic shock in newborn piglets, 16 chronically instrumented newborn piglets were infused with 10 mg/kg of endotoxin over 10 min. Eight animals were injected intravenously with 10 mg/kg of anisodamine, an anticholinergic drug, 10 min before endotoxin and then with escalating doses of 2, 5, 10, and 20 mg/kg every 10 min, beginning 60 min after endotoxin. The other eight animals were given saline as a control. Endotoxin infusion caused elevations in mean pulmonary artery pressure and vascular resistance index and an initial increase in systemic artery pressure followed by hypotension. Heart rate was stable for 45 min and then increased. Cardiac index fell from a baseline of 173 ± 20 (mean ± S.E.) to 136 ± 23 mL min-1.kg-1 60 min after endotoxin. Pretreatment with anisodamine increased heart rate from 163 ± 15 to 289 ± 10 beats.min-1 and cardiac index from 195 ± 15 to 238 ± 14 mL min-1-kg-1 before endotoxin infusion. These variables remained at higher levels than in the control group until 60 min after endotoxin infusion; thereafter, the two groups were similar. The changes in pulmonary and systemic artery pressures were not significantly altered by anisodamine. After 60 min, additional doses of anisodamine caused no significant hemodynamic responses, and the differences between the two groups were not significant. Arterial plasma thromboxane B2 levels rose immediately and tumor necrosis factor-a levels increased 60 min after endotoxin infusion; no significant differences were noted between groups at any time. Intestinal histopathologic examination showed massive hemorrhage and or necrosis in the lamina propria, submucosa, and/or serosa in five of seven control piglets, while six of seven anisodamine-treated animals developed only edema and/or congestion in the submucosa (p <.01). Mean survival times were 9.2 ± 2.8 h and 16.6 ± 2.6 h for the control and anisodamine groups, respectively (p =.06). The markedly reduced intestinal lesions observed in the anisodamine group suggest that cholinergic blockade may be helpful in treatment of septic shock. The phase-dependent effects of anisodamine on endotoxin-induced hemodynamic disturbances suggest that parasympathetic tone to the heart is elevated in the early phase of shock in newborn piglets and gradually decreases in the later phases and indicate that any therapeutic benefits resulting from cholinergic blockade in newborns with septic shock would likely be maximized by early use. © 1994 The Shock Society.