| Potentiation of acute lethality occurs when a reversible, peripherally-acting cholinesterase inhibitor, pyridostigmine bromide (PB), is combined with a personal insect repellent, N,N-diethyl-m-toluainide (DEET). This interaction is important because recent reports suggested that these agents may have been involved in Gulf War illnesses. Continued widespread use of cholinesterase inhibitors and DEET in agriculture and medicine raises concern over the potential for future toxic interactions to occur. Whole body plethysmography was used to measure respiratory function in conscious freely-moving rats while cardiovascular activity was monitored simultaneously through an arterial catheter, in an effort to elucidate the mechanism(s) of acute lethality following intraperitoneal administration of PB (2 mg/kg) and/or DEET (300 or 500 mg/kg). PB administered alone increased blood pressure, respiratory rate, tidal volume and minute volume. Arterial pH was decreased, while pO2 and pCO2 were unaltered. Pretreatment with atropine methyl nitrate (AMN) reduced the effects of PB. Administration of DEET, by itself, increased tidal volume and reduced blood pressure. Blood gases and pH were unaltered. The higher dose of DEET decreased respiratory and heart rate. Pretreatment with AMN reduced the DEET-induced decrease in blood pressure and tidal volume. Coadministration of PB and DEET increased tidal volume, but respiratory rate and minute volume were unaltered. Coexposure also decreased arterial pH, and elevated pCO 2. Heart rate and blood pressure progressively declined after drug coadministration. AMN prevented bradycardia and significantly increased survival. DEET did not alter PB-induced inhibition of cholinesterase activity in the periphery, but may have played a role in facilitating the entry of PB into the brain at the highest dose combination. This inhibition of brain cholinesterase activity was not likely to have been life-threatening. While respiratory depression contributed to lethality, it was concluded that the primary cause of death was circulatory failure. DEET may have depressed central cardiorespiratory control mechanisms and sympathetic outflow from the brain. PB-induced accumulation of ACh at peripheral cholinergic receptor sites resulted in bradycardia, and further reduced cardiac output, causing progressive circulatory shock. Pretreatment with AMN protected against circulatory collapse by preventing PB-induced bradycardia. |
