Cardiorespiratory and Neuromuscular Effects of O-Ethyl S-[2- (Diisopropylamino) Ethyl] Methylphosphonothioate (VX) in Rats

Abstract

The exposure to chemical warfare agents is not restricted to the battlefield but as humans may be poisoned with nerve gases either from a chemical warfare stockpile or even in a public place. The recent use of nerve gas Sarin in a subway of Japan by a fanatic group has triggered global consternation about the extremists and homemade weapons of mass destruction. Nerve agents are organophosphorus (OP) compounds that exert acute toxic manifestations principally by inhibiting the enzyme acetylcholinesterase (AChE) resulting in a variety of physiological alterations and ultimately death from respiratory failure (Brimblecombe 1977). However, pharmacological studies indicate that nerve agents have plethora of actions other than inhibition of AChE (Worek and Szinicz 1995, Corbier and Robineau 1989, Robineau and Guittin 1987.Several studies have revealed that acute intravenous (i.v.) administration of an OP agent increased blood pressure in cat, dog and rat (Brezenoff and Giuliano 1982, Lang andRush 1973), while subcutaneous (s.c.) administration produced marked hypotension (Preston and Heath 1972). In a recent communication from this laboratory, it has been reported that i.v. administration of DFP/sarin produced a dose-dependent hypertension involving cholinergic-catecholaminergic interaction in rats. Subcutaneous administration of DFP/ sarin was found to produce a dose-responsive hypotension mediated through muscarinic receptors (Dube et al 1993). However, the mechanism of cardiovascular toxicity induced by nerve agents still remains obscure. Therefore, the effects on blood pressure, heart rate, tracheobronchial response, neuromuscular transmission, and modulatory role of various pharmacological agents were studied after systemic administration of VX (O-ethyl S-[2-(diisopropylamino) ethyl ] methyl phosphonothioate) to delineate the distinction in mechanism of action from other OP compounds.