Target sites for anticholinesterases on the ventral surface of the medulla oblongata: hypotension elicited by organophosphorus agents.

Sensitivity of the ventral surface of the medulla oblongata to organophosphorus agents, oxime reactivators, and muscarinic antagonists was examined in order to delineate sites of cholinergic activity in the central nervous system. The exposed ventral surface of the medulla oblongata in anaesthetized cats was treated with the organophosphorus anticholinesterase agents soman and (7-nitro-2-oxa-1,3-diazole) aminopentyl methylphosphonofluoridate (NBD-AP-MFP), a fluorescent active centre-selective probe of acetylcholinesterase. Topical application of soman (1-5 micrograms) or NBD-AP-MPF (5-120 micrograms) elicited a profound (80-90 mm Hg), long-lasting (0.5-3 h), dose-dependent vasodepression with only minor changes in heart rate and respiration. The vasodepression was rapidly reversed (7-10 min) upon topical application of muscarinic antagonists (atropine methylnitrate, atropine sulphate) and the bisquaternary oxime HI-6; systemic administration was without effect. Reversal of the hypotension by HI-6 occurred irrespective of whether the organophosphorus agent was NBD-AP-MPF, which forms conjugates with acetylcholinesterase that undergo no aging, or soman, which forms conjugates that undergo extensive aging rendering the enzyme refractory to oxime reactivation. Hence, oxime efficacy for reversal of the physiologic hypotension was not dependent solely on the fraction reactivatable enzyme. By virtue of the fluorescence distribution of NBD-AP-MPF the chemosensitive sites were estimated to reside no deeper than 50 microns into the medulla oblongata, providing a direct indication for localization of the chemosensitive cells on the superficial surface.