Verruculotoxin potentiation of twitch tension in skeletal muscle.

Verruculotoxin [1-oxo-3-benzyl-octahydro-2H-pyrido(1,2-α)pyrazinel, a mycotoxin, was shown to act directly on both isolated mammalian and amphibian skeletal muscles to potentiate twitch tension. After 10 min exposure to a concentration of 0.4 mm, the twitch tensions of the rat diaphragm and frog sartorius muscles were enhanced to 152 and 150% of controls, respectively. In the isolated frog sartorius muscle, 10 min exposure to verruculotoxin (VTX, 0.4 mm) significantly increased the rate of contraction ($\text{dP}\text{dt}$, 120%), contraction time (CT, 127%), and half-relaxation time ($\text{1}\text{2}\text{RT}$, 126%) without significantly changing the twitch duration; in the rat diaphragm preparation, 10 min exposure to VTX (0.4 mm) significantly increased both $\text{dP}\text{dt}$ (141%) and CT (112%) without altering $\text{1}\text{2}\text{RT}$ and twitch duration. Of the C-15 substituted analogs tested, two analogs, fluoroverruculotoxin and methoxyverruculotoxin, enhanced twitch tension with a potency comparable to that of VTX, while chloroverruculotoxin increased twitch tension to only 120% of control. Hydroxyverruculotoxin and analogs lacking the C-3 benzyl group did not alter the twitch amplitude from control. VTX (0.4 mm, 10 min exposure) reduced twitch tension in the isolated cat papillary muscle to 33% of control. VTX (0.4 mm) was nondepolarizing in endplate and nonendplate regions. Thirty minute exposure to VTX irreversibly increased both the rising phase (sodium influx, 115% of control) and the repolarization phase (115% of control) of the muscle action potential. The results of this study indicate that VTX is a new muscle potentiator with properties similar to caffeine and the other Type A muscle potentiators.