Comparative action of three major ciguatoxins on guinea-pig atria and ilea

The actions of pure ciguatoxin-1, ciguatoxin-2 and ciguatoxin-3 were assessed on the contractile activity of isolated guinea-pig left atria and ilea. Low concentrations of each ciguatoxin caused transient positive inotropy, whereas moderate concentrations induced transient and sustained positive inotropic phases. The transient positive inotropic phase was inhibited by tetrodotoxin or atenolol, indicating this phase stems from indirect effects of the ciguatoxins via the stimulation of intrinsic adrenergic nerves. On atria pretreated with atropine and alpha- and beta-adrenoceptor antagonists to block neural actions of the ciguatoxins, moderate concentrations of each ciguatoxin induced only slowly developing, sustained positive inotropy. ED50s for the indirect positive inotropic phase were 2.7 x 10(-11), 1.6 x 10(-10) and 1.4 x 10(-11) M and for the direct positive inotropic phase were 1.6 x 10(-10), 1.4 x 10(-9) and 1.5 x 10(-9) M for ciguatoxin-1, -2 and -3, respectively, indicating that their effects on neurons are 10-fold (ciguatoxin-1 and -2) to 100-fold (ciguatoxin-3) more potent than those directly on the myocardium. High concentrations of each ciguatoxin additionally induced sustained negative inotropy which could be reversed by lidocaine. On guinea-pig ilea, each ciguatoxin induced a transient contracture which could be abolished by atropine. Each ciguatoxin significantly reduced the contractile response of ilea to nicotine, without affecting the contractile response to acetylcholine. We conclude that ciguatoxin-1, -2 and -3 activate similarly the voltage-dependent Na+ channels in neuronal and myocardial tissues, but vary in their relative affinity for the Na+ channels in these tissues.