Direct and indirect effects of ciguatoxin on guinea-pig atria and papillary muscles

The mode of action of ciguatoxin (CTX) on the isolated atrial and papillary muscle of the guinea-pig heart was investigated using conventional methods for the measurement of mechanical and electrophysiological parameters. CTX induced positive inotropic and positive klinotropic responses in atrial and papillary muscles. Each response consisted of two phases. The initial positive inotropic response developed rapidly and resulted from the previously reported indirect action of CTX. The second phase of positive inotropy developed more slowly and was well maintained at doses of CTX up to 0.15 mouse units/ml in atria and up to 0.8 M.U./ml in papillary muscles. This phase was found to result from a direct action of CTX on the myocardium which was not reversed by washing. Tetrodotoxin (TTX) reversed the positive inotropic effects stemming from the direct action of CTX. The (-) and (+) enantiomers of propranolol were equally effective in inhibiting the direct effect of CTX. These antagonists did not displace CTX from the myocardium. CTX induced a TTX-sensitive depolarization of stimulated or quiescent atrial cells. All the effects of CTX on the atrial action potential were reversed by TTX. It was therefore concluded that CTX opens voltage dependent Na+ channels. CTX bound equally to resting and K+-depolarized Na+ channels but there were indications that electrical stimulation enhanced the rate of CTX binding. CTX overrides the positive staircase effect of increasing stimulation frequency. Na+ channels found in the atria which were particularly sensitive to TTX did not play a prominent role in mediating the CTX effect. CTX appeared to have little effect on the normal Na+ channel inactivation process. CTX did not restore contractions in the K+-depolarized cardiac muscles examined. The sensitivity of CTX action to TTX distinguished it from cardiac glycoside activity. Established mechanisms of Na+/Ca2+ exchange and Ca2+-induced release of Ca2+ can explain the link between CTX-induced increase of intracellular [Na+] and the positive inotropic response.