Cardiorespiratory Effects Following Acute Exposure to Pyridostigmine Bromide and/or N,N-Diethyl-m-toluamide (DEET) in Rats

The acute lethal interaction that occurs in rodents when high doses of a peripherally restricted cholinesterase inhibitor, pyridostigmine bromide (PB), and the insect repellent N,N-diethyl-m-toluamide (DEET) are combined was first described during studies of chemical mixtures that were targeted as potential causative agents of Gulf War illnesses. This study was intended to provide insight into possible mechanisms of that lethal interaction. Following a single intraperitoneal injection of PB (2 mg/kg) and/or DEET (300 or 500 mg/kg), respiratory activity was measured in conscious freely moving rats using whole-body plethysmography. Cardiovascular function was also monitored simultaneously through an arterial catheter. PB (2 mg/kg) given alone stimulated respiration and increased blood pressure. Arterial pH levels were decreased, whereas pO₂ and pCO₂ remained at control levels. Administration of DEET (300 mg/kg) alone increased tidal volume and decreased blood pressure. Blood gases and pH levels were unaltered. A higher dose of DEET (500 mg/kg) also decreased respiratory and heart rate. Coadministration of PB (2 mg/kg) and DEET (300 mg/kg) increased tidal volume, decreased arterial pH, and elevated pCO₂. Heart rate and blood pressure declined progressively after drug coadministration. Pretreatment with atropine methyl nitrate (AMN), a peripherally selective competitive antagonist at nicotinic and muscarinic receptor sites, reduced the individual effects of PB or DEET, and significantly increased survival after co-exposure to these agents. Although changes in respiratory function may have contributed to the lethal interaction, it was concluded that the primary cause of death was circulatory failure.