Botulinum toxin type A: kinetics of calcium dependent paralysis of the neuromuscular junction and antagonism by drugs and animal toxins.
The effect of botulinum Toxin (BoTx), which blocks the mechanism of release of acetylcholine at neuromuscular junctions and induces paralysis of muscles stimulated by nerves, is known to be Ca2+-dependent. Amplitude of muscular contractions evoked by nerve impulse was studied in BoTx poisoned preparations. The present report notes that an increase in Ca2+ concentration in vitro delays paralysis of muscular contractions of the frog evoked by nerve impulse. The restorative effect of different drugs on this paralysis has been tested: 4-aminopyridine, ATXII (toxin isolated and purified from the sea anemone Anemonia sulcata tentacles) and a crude venom isolated from the scorpion Androctonus australis antagonize the BotX induced paralysis at physiological concentrations of Ca2+ (Cao2+ = 2 mM), whereas the restorative effect observed with tetra-ethylammonium or guanidine occurs at higher concentrations of Ca2+ (Cao2+ = 4 mM), as in mammals. ATXII restores in vivo the activity of a BoTx paralysed muscle of guinea pig and this effect is more efficient if the interval between the injection of BoTx and ATXII is shortened. These results on the frog and guinea pig are in agreement with those obtained on other biological preparations by several investigators. Moreover it is suggested that the antagonism of BoTx induced paralysis is a consequence of the increase in Ca2+ at the nerve ending. The efficiency of 4-aminopyridine and animal toxins is explained by an action on the nerve ending, by increasing Ca2+ from an interval compartment of the cell, whereas antagonism produced by guanidine and tetraethylammonium involves uptake of Ca2+ from the external medium. The bathing medium must be at a higher concentration of Ca2+ than usual. This explains the differences in antagonism obtained by these drugs and toxins in vitro and in vivo.
D000818:Animals; D001904:Botulinum Antitoxin; D001905:Botulinum Toxins / Q000633:toxicity*; D002118:Calcium / Q000502:physiology*; D003064:Cnidarian Venoms / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D009469:Neuromuscular Junction / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D010243:Paralysis / Q000139:chemically induced*; D011893:Rana esculenta; D012604:Scorpion Venoms / Q000494:pharmacology; D013997:Time Factors; D014118:Toxins, Biological / Q000494:pharmacology*
D001904:Botulinum Antitoxin; D003064:Cnidarian Venoms; D009498:Neurotoxins; D012604:Scorpion Venoms; D014118:Toxins, Biological; C028800:toxin II (Anemonia sulcata); D001905:Botulinum Toxins; D002118:Calcium