Inhalation of the nerve gas sarin impairs ventilatory responses to hypercapnia and hypoxia in rats

Abstract

Sarin, a highly toxic nerve gas, is believed to cause bronchoconstriction and even death primarily through respiratory failure; however, the mechanism underlying the respiratory failure is not fully understood. The goals of this study were to ascertain whether sarin affects baseline ventilation (V E ) and V E chemoreflexes as well as airway resistance and, if so, whether these changes are reversible. Four groups of F344 rats were exposed to vehicle (VEH) or sarin at 2.5, 3.5, and 4.0 mg h m −3 (SL, SM, and SH, respectively). V E and V E responses to hypercapnia (7% CO 2 ) or hypoxia (10% O 2 ) were measured by plethysmography at 2 h and 1, 2, and 5 days after VEH or sarin exposure. Total pulmonary resistance (R L ) also was measured in anesthetized VEH-and SHexposed animals 2 h after exposure. Our results showed that within 2 h after exposure 11% of the SM-and 52% of the SH-exposed groups died. Although the SM and SH significantly decreased hypercapnic and hypoxic V E to similar levels (64 and 69%), SH induced greater respiratory impairment, characterized by lower baseline V E (30%; P < 0.05), and total loss of the respiratory frequency response to hypercapnia and hypoxia. V E impairment recovered within 1-2 days after sarin exposure; interestingly, SH did not significantly affect baseline R L . Moreover, sarin induced body tremors that were unrelated to the changes in the V E responses. Thus, LC 50 sarin causes a reversible impairment of V E that is not dependent on the sarin-induced body tremors and not associated with changes in R L .

Post-exposure therapy with human butyrylcholinesterase following percutaneous VX challenge in guinea pigs

“…Peripheral muscarinic receptor overstimulation produces broncho-constriction, oedema and excess secretions, which have been demonstrated, in the case of sarin poisoning, to respond to treatment with the antimuscarinic atropine, although efficacy was limited at high challenge doses, 28,29 although studies in sarinexposed rats suggested that disruption of the central respiratory drive was responsible for respiratory failure and death. 30 A centrally mediated respiratory disorder has been shown to contribute in human OP poisoning cases, and some benefit from diazepam treatment was demonstrated. 31 In a practical poisoning scenario, personnel might not be aware that they have been exposed to nerve agent until early signs of poisoning manifest, by which time a significant degree of tissue AChE inhibition might be present.…”

Acute Changes in Pulmonary Function Following Microinstillation Inhalation Exposure to Soman in Nonatropenized Guinea Pigs

“…41,42 Chemosensory effects also proposed to contribute to CWNA-induced respiratory toxicity and may contribute to the acute effect following GD exposure. 43 With regard to the dose of GD, the most notable changes were observed in animals exposed to 841 mg/m 3 compared to 280 or 561 mg/m 3 GD exposures. Although not significant, mean MV, PIF, PEF, Ti, Te, EEP, pause, and Penh values showed dose-dependent changes with 280 or 561 mg/m 3 GD at 4 hours post-GD exposure that was reduced at 24 hours postexposure.…”

“…41,42 Chemosensory effects also proposed to contribute to CWNA-induced respiratory toxicity and may contribute to the acute effect following GD exposure. 43…”