Selective inhibition of peripheral cholinergic transmission in the cat produced by AF64A.
The neuropharmacologic effects of ethylcholine aziridinium ion, AF64A, were studied in cats, using various physiological techniques, to ascertain its synaptic site of action and to determine whether it may act as a cholinergic specific neurotoxin in vivo. Nictitating membrane contractions elicited by preganglionic nerve stimulation (1-16 Hz) were diminished in a dose-dependent manner after injection of AF64A into the carotid artery. Contractions due to injection of l-norepinephrine, tetramethylammonium or acetylcholine were not changed. Postganglionic action potentials from the superior cervical ganglion evoked by preganglionic stimulation were also abolished by AF64A, whereas the postganglionic firing produced by tetramethylammonium was unchanged. Neither the nictitating membrane nor ganglionic responses on the contralateral side of the animal were affected by AF64A treatment. In the same animals, twitch tension in the tongue produced by stimulation of the ipsilateral hypoglossal nerve (1-16 Hz) was gradually reduced and in most experiments completely blocked by AF64A. Repetitive stimulation of either the autonomic or somatic nerves at high frequencies (greater than 10 Hz) magnified and accelerated the onset of neurotoxic effects of AF64A. The suppression of ganglionic and neuromuscular transmission by AF64A was irreversible during the course of the experiments (12-18 hr). From these results, we can conclude that AF64A produces in the peripheral nervous system a longlasting inhibition of cholinergic transmission, without interfering with adrenergic transmission. Moreover, because AF64A did not block the postganglionic responses elicited by cholinergic nicotinic and muscarinic agonists, the inhibitory effects of AF64A must be mediated by a presynaptic action on cholinergic nerve terminals.
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001388:Aziridines / Q000633:toxicity*; D001389:Azirines / Q000633:toxicity*; D002415:Cats; D002794:Choline / Q000031:analogs & derivatives* / Q000633:toxicity; D004558:Electric Stimulation; D005260:Female; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000502:physiology*; D007002:Hypoglossal Nerve / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000633:toxicity*; D009638:Norepinephrine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*
D001388:Aziridines; D001389:Azirines; D009466:Neuromuscular Blocking Agents; C044894:ethylcholine aziridinium; D002794:Choline; D000109:Acetylcholine; D009638:Norepinephrine