Physostigmine has a life-saving effect in rats subjected to prolonged respiratory arrest

We have previously reported that centrally-acting cholinomimetic drugs have a prompt and sustained resuscitating effect in pre-terminal conditions of hemorrhagic shock in rats. Here we have studied the effect of physostigmine in another experimental condition of hypoxia in anesthetized rats, which were endotracheally intubated and subjected to prolonged (5 min) interruption of ventilation. This led to a dramatic fall in mean arterial pressure (MAP), pulse pressure (PP), heart rate (HR), pH, PO2, SO2 and base excess, while PCO2 increased; the electroencephalogram (EEG) became isoelectric, and the electrocardiogram (ECG) showed marked bradycardia, P-wave inversion, partial atrio-ventricular block and S-T segment elevation; all saline-treated rats died of cardiac arrest within 7.01 +/- 0.85 min of ventilation being resumed. When ventilation resumption was associated with the simultaneous intravenous (i.v.) injection of physostigmine (70 microg/kg) there was an almost immediate and impressive increase in MAP, PP and HR, with normalization of ECG within 4 min and full recovery of EEG after 30-50 min. This was associated with a normalization of blood gases and pH. Fifteen days later 40% of treated animals were still alive and apparently in normal health, the mean survival time of the remaining 60% animals being 22.67 +/- 10.19 h. Pretreatment with atropine sulfate or hemicholinium-3 did not modify the response to physostigmine, which, however, was strongly antagonized by the intracerebroventricular injection of mecamylamine. These results suggest that centrally-acting cholinomimetic agents may have a resuscitating effect in pre-terminal conditions produced by prolonged asphyxia, probably through the direct activation of nicotinic receptors in the central nervous system.