The role of cholinergic and noncholinergic mechanisms in the cardiorespiratory failure produced by N-methylcarbamate cholinesterase inhibitors in rabbits

We investigated the relative contribution of several cardiorespiratory comp onents to acute lethality produced by N-methylcarbamate cholinesterase (ChE ) inhibitors physostigmine, 2-sec-butylphenyl methylcarbamate (BPMC), and 2 -isopropoxyphenyl methylcarbamate (PHC) in halothane-anesthetized rabbits. Intravenous injection of these compounds produced dose-dependent presser an d/or depressor responses related to each compound. A lethal dose of physost igmine resulted in cardiovascular collapse after a presser response. That o f PHC produced cardiovascular collapse after biphasic effects on blood pres sure, a transient decrease followed by an increase. Unlike these compounds, BPMC elicited a rapidly developing depressor response followed by cardiova scular collapse. Artificial ventilation prevented cardiovascular collapse a nd lethal actions to physostigmine and PHC, but not BPMC. A degree of acute lethality to physostigmine and PHC depended on their anti-ChE activity, wh ereas BPMC exhibited a low degree of lethality relative to its anti-ChE act ivity. While the presser response to physostigmine and PHC was ascribed to an atropine-sensitive increase in cardiac contractility, the depressor resp onse to PHC and BPMC was attributed to an atropine-insensitive decrease in cardiac contractility and/or vascular resistance. Similar to the order for eliciting the depressor response in vivo, an three compounds inhibited cont raction of the isolated cardiac and aortic smooth muscles with the order of their inhibition in terms of anti-ChE activity, i.e., BPMC > PHC > physost igmine. Thus, the primary cause of death with physostigmine and PHC is resp iratory arrest subsequent to ChE inhibition, whereas BPMC exhibiting the lo w degree of lethality causes cardiovascular collapse mediated through direc t inhibitory effects on cardiac and vascular smooth muscle contraction. (C) 2000 Academic Press.