A myotoxin secreted by some piscivorous Conus species

1. Toxins isolated from the venom apparatus of Conus magus and Conus achatinus have the same pharmacological properties, but differ from the toxins of several other piscivorous species of cone shells.2. C. magus and C. achatinus toxins are heat labile at pH 8.5. A single lethal component with an approximate molecular weight of 10,000 was isolated from C. achatinus toxin by exclusion chromatography.3. Animals died from a characteristic spastic paralysis after intravenous injection of the toxin.4. Nerve transmission was unaffected by the toxin; skeletal muscle appeared to be the primary site of action. The toxin caused a persistent contracture of rat diaphragm muscle, and a dose-dependent decline in twitch tension. The contracture was potentiated by caffeine.5. The decline in twitch tension was associated with depolarization of the cell membrane. Action potential height and the maximum rate of rise declined, and spike propagation failed when the resting potential had declined to approximately 60 mV. The muscle recovered very slowly on washout of the toxin. The depolarization could be reversed by exposure of the preparation to 5 mM Na(+) solution or tetrodotoxin or saxitoxin.6. Miniature end-plate potential frequency in the rat diaphragm decreased, as did the quantal content of the end-plate potential. The acetylcholine-induced contraction and depolarization of the chronically denervated rat diaphragm were increased by low doses of toxin and reduced by higher, depolarizing toxin doses. The K(+)-induced contraction and depolarization of innervated diaphragm were similarly affected by the toxin.7. Cardiac and smooth muscle were relatively resistant to the toxin. The isotonic contraction of the isolated perfused guinea-pig heart was increased by the toxins from both Conidae. The heart rate decreased. Guinea-pig atrial cells showed a small decrease in action potential height and maximum rate of rise. Rabbit sino-atrial cells showed increases in action potential height, maximum diastolic potential and maximum rate of rise of the spike at low toxin levels, and no change in any of these parameters at high levels. There was a decrease in the rate of the spontaneously beating atrium. Atrioventricular nodal potentials showed no change other than a slight increase in the maximum rate of rise of the action potential.8. It is postulated that the action of the toxin may be related to a change in the Ca(++) permeability of the excitable membrane, which makes it unstable, leading to a secondary, depolarizing entry of Na(+). The effects of the toxin are compared with those of batrachotoxin, which it somewhat resembles.