Cardiorespiratory effects of O-isobutyl S-[2-(diethylamino)-ethyl] methylphosphonothioate -- a structural isomer of VX.

Abstract

O-Isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate (VR) is a structural isomer of a more well-known chemical warefare agent, O-ethyl S-[2(diisopropylamino)ethyl]methylphosphonothioate (code designation VX). In this study, cardiorespiratory and central nervous system (CNS) effects of VR (2LD50 or 22.6 microg kg(-1); s.c.) were evaluated in urethane-anesthetized (Group 1) and unanesthetized (Group 2) guinea pigs instrumented for concurrent recordings of electrocorticogram (ECoG) and a variety of cardiorespiratory activities. The first sign of intoxication was a state of progressive bradycardia, vascular hypotension and arrhythmia (Group 1, approximately 13 min post-VR; Group 2, approximately 6 min post-VR). Bradypnea, excessive salivation and compensatory changes in blood pressure typically did not emerge until 3-5 min prior to apnea (Group 1, approximately 28 min post-VR; Group 2, approximately 15 min post-VR). An idioventricular rhythm, which signalled a failing myocardium, appeared at the same time or shortly after the development of a bradypneic profile. Another notable toxicity component of VR, based on arterial pH, pO2/pCO2 and bicarbonate (HCO3-) level data, was a state of combined hypercapnia, acidemia and hypoxemia during the development of bradypnea. Taken together, findings from this study indicated that changes in medullary respiratory unit activity and ECoG data displayed little, if any, notable signs of CNS perturbation prior to the terminal stage (approximately 1 min prior to respiratory failure). Thus, in addition to displaying a greater sensitivity to perturbation by VR, the peripheral cardiorespiratory system components also appeared to play a more important role in precipitating a progressively dysfunctional cardiorespiratory status that ultimately led to collapse of central respiratory mechanisms and death.