PHYSOSTIGMINE HAS A LIFESAVING 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 cond itions of hemorrhagic shock in rats. Here we have studied the effect o f physostigmine in another experimental condition of hypoxia in anesth etized rats, which were endotracheally intubated and subjected to prol onged (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 electroencep halogram (EEG) became isoelectric, and the electrocardiogram (EGG) sho wed marked bradycardia, P-wave inversion, partial atrio-ventricular bl ock and S-T segment elevation; all saline-treated rats died of cardiac arrest within 7.01 +/- 0.85 min of ventilation being resumed. When ve ntilation resumption was associated with the simultaneous intravenous (i.v.) injection of physostigmine (70 mu g/kg) there was an almost imm ediate and impressive increase in MAP, PP and HR, with normalization o f 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 la ter 40% of treated animals were still alive and apparently in normal h ealth, the mean survival time of the remaining 60% animals being 22.67 +/- 10.19 h. Pretreatment with atropine sulfate or hemicholinium-3 di d not modify the response to physostigmine, which, however, was strong ly antagonized by the intracerebroventricular injection of mecamylamin e. These results suggest that centrally-acting cholinomimetic agents m ay have a resuscitating effect in pre-terminal conditions produced by prolonged asphyxia, probably through the direct activation of nicotini c receptors in the central nervous system. (C) 1997 Elsevier Science I reland Ltd.