The Pharmacology of Phospholipases A2 Isolated from Snake Venoms, with Particular Reference to Their Effects on Neuromuscular Transmission

Abstract

The toxicity of phospholipases A2 (PLAs) purified from various snake venoms differs greatly from one preparation to another. In general, basic PLAs are more toxic than acidic or neutral PLAs. Especially, the presynaptic toxins with PLA activity such as β-bungarotoxin, crotoxin, taipoxin and notexin are highly toxic. These toxins act presynaptically at the motor nerve endings to produce a triphasic change in the evoked transmitter release: an initial inhibition followed by facilitation of acetylcholine (ACh) release and then progressive depression leading to an irreversible blockade of transmission. The PLA activity of these toxins appears to be essential for their presynaptic neurotoxicity, since inhibition of their catalytic activity either by replacement of Ca2+ with Sr2+ in the medium or by chemical modification of histidine residue of the toxin with p-bromophenacyl bromide results in a corresponding diminution or abolition of neurotoxicity. The initial decrease in ACh release appears to result from the toxin binding to a specific presynaptic site, while the facilitation followed by eventual failure of transmission has been attributed to their PLA activity. The site of toxin binding, however, appears to be different for each toxin. Besides presynaptic effects, most PLA toxins have more or less postsynaptic and musculotropic effects, leading to myonecrosis. The contracture produced by basic PLAs can be prevented by pretreatment with heparin, whereas their presynaptic effect remains little affected. Some autonomic motor transmissions are also affected by these toxins. The vagal effects on both atrial and stomach preparations of the guinea-pig are abolished by β-bungarotoxin, whereas those of the mouse, rat and rabbit are unaffected. The twitch-like response of the guinea-pig and rat vas deferens to transmural stimulation is also inhibited by β-bungarotoxin and notexin. Physostigmine decreases and atropine enhances the initial inhibitory effect of β-bungarotoxin, suggesting possible cholinergic involvement in this system. PLAs have a stimulant action on the isolated guinea-pig ileum. The ileal stimulant action is abolished by indomethacin pretreatment, suggesting involvement of prostaglandin release.