イオンチャネルに作用する海産生物毒の薬理学的研究
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Ciguatoxin (CTX), the principal toxin in ciguateric fish, produced a marked potentiation of contractile responses to agonists in the vas deferens. CTX markedly elevated the Na content of the vas deferens treated with ouabain. These effects of CTX were abolished by tetrodotoxin. These data suggest that CTX causes an increasing Na^+ permeability across Na channels of smooth muscle cells, and this may play an important role in its mechanism of potentiation. We have shown for the first time that maitotoxin (MTX), the most potent marine toxin known from ciguateric fish, produces a Ca^<2+>-dependent release of norepinephrine (NE) from a rat pheochromocytoma cell line, PC12 or adrenergic nerve terminals of the vas deferens and Ca^<2+>-dependent contraction of smooth or cardiac muscle. These effects of MTX may be due to an increase in Ca^<2+> permeability which possibly occurred through Ca channels in muscle and nerve membranes. MTX has been widely used as a valuable tool, since Ca^<2+> plays an important role in the regulation of many cellular functions. We have isolated geographutoxin II (GTX II) from the venom extract of Conus geographus. Our pharmacological and electrophysiological results show that GTX II has the novel action of blocking skeletal muscle Na channels without effect on nerve Na channels. GTX II inhibited [^3H] saxitoxin binding to Na channels of skeletal muscles but not of nerves. These results indicate that GTX II is the first to discriminate between the tetrodotoxin/saxitoxin receptor site on nerve and muscle Na channels. Anthopleurin-B (AP-B), a cardiotonic polypeptide isolated from Anthopleura xanthogramica, caused powerful excitatory and inhibitory actions in the ileum, taenia caeci and vas deferens. The AP-B-induced contractions of intestinal smooth muscles are due to the excitation of cholinergic nerves, while that of the vas deferens is caused by the NE release from adrenergic nerve endings. The AP-B-induced relaxation of the taenia caeci is due to the excitation of adrenergic nerves, while the relaxation of the ileum is mediated through non-adrenergic inhibitory mechanisms. Palytoxin (PTX) caused a first rapid contraction followed by the slow phasic contraction of the vas deferens. Our results reveal that the first component is the result of a direct action of PTX on smooth muscle site, whereas the second phase is the result of an indirect action mediated through the NE release from adrenergic nerve endings. Na^+, K^+-adenosine triphosphatase may be involved in the promotion of the first contraction of PTX. AP-B and PTX provide useful probes to study the neurotransmitter release.
- 1987-07-25
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