PRESYNAPTIC SNAKE BETA-NEUROTOXINS PRODUCE TETANIC FADE AND END-PLATEPOTENTIAL RUN-DOWN DURING NEUROMUSCULAR BLOCKADE IN MOUSE DIAPHRAGM

The present study investigated the ability of a number of presynaptic snake neurotoxins (snake beta-neurotoxins) to produce nerve-evoked tra in-of-four fade, tetanic fade and endplate potential run-down during t he development of neuromuscular blockade in the isolated mouse phrenic -hemidiaphragm nerve-muscle preparation. All the snake beta-neurotoxin s tested, with the exception of notexin, produced train-of-four and te tanic fade of nerve-evoked isometric muscle contractions. Train-of-fou r fade was not present during the initial depressant or facilitatory p hases of muscle tension produced by the snake beta-neurotoxins but dev eloped progressively during the final depressant phase that precedes c omplete neuromuscular blockade. The 'non-neurotoxic' bovine pancreatic phospholipase A(2) and the 'low-toxicity' phospholipase A(2) from Naj a naja atra venom failed to elicit train-of-four fade, indicating that the phospholipase activity of the snake beta-neurotoxins is not respo nsible for the development of fade. Intracellular recording of endplat e potentials (EPPs) elicited by nerve-evoked trains of stimuli showed a progressive run-down in EPP amplitude during the train following inc ubation with all snake beta-neurotoxins except notexin. Again this run -down in EPP amplitude was confined to the final depressant phase of s nake beta-neurotoxin action. However when EPP amplitude fell to near u niquantal levels (<3 mV) the extent of toxin induced-fade was reduced. Unlike postjunctional snake alpha-neurotoxins, prejunctional snake be ta-neurotoxins interfere with acetylcholine release at the neuromuscul ar junction during the development of neuromuscular blockade. This stu dy provides further support for the hypothesis that fade in twitch and tetanic muscle tension is due to an underlying rundown in EPP amplitu de resulting from a prejunctional alteration of transmitter release ra ther than a use-dependent block of postjunctional nicotinic receptors.