THE TOXICITY OF ACONITINE AND ITS ANALOGUES AND THEIR EFFECTS ON CARDIAC CONTRACTIVE FUNCTION

The present paper reports on the toxicity of aconitine and its nine selected analogs, their cardiac contractive function, and their structure-toxicity and structure-activity relationships.The results showed that the toxicity in terms of iv LD₅₀ of these compounds in mice decreased in the order of aconitine(AC)>indaconitine(IA)=3-acetylaconitine(3-AAC)>3-acetylindaconitine (3-AIA)>benzoylaconine (BA)>diacetylindaconitine (DAIA)>aconine (A)>pseudaconine (PA)>tetraacetylpseudaconine (TAPA)>pentaacetylaconine(PAA). In rats the toxicity in terms of iv absolute lethal dose was found to be in a very slmilar order(AC>3-AAC>IA>3-AIA>BA>DAIA>TAPA>A PA>PAA). Thus, AC appeared as the most toxic one and the other compounds with the corresponding structural modification of AC invariably resulted in a decrease of toxicity. Our findings confirmed the previous general conclusion that the high toxicity of those aconite alkaloids is primarily associated with the presence of C-8-OCOCH₃ and C-14-OCOC₆H₅ in the molecules, while removal of these ester groups by hydrolysis caused sharp decrease in toxicity. It was noted that lowering of toxicity also manifested as a result of changes in the number and position of the free and acetylated hydroxyl groups in the molecules. Those alkaloids containing the C-14-OCOC_{6H5 moiety including AC, IA, 3-AIA, BA and DAIA all induced arrhythmia in rats, while those with deletion of such an ester group, such as A, PA, TAPA and PAA, did not. Thus, C-14-OCOC6H5 is substantiated as an essential functional group in the induction of arrhythmia.All the compounds studied caused a decline in blood pressure and an inhibition of myocardial contraction except aconitine, which showed no such activities before arrhythmia appeared. At present, no generalization could be made about the degree of the effects in relation to structures. Heart rate was not affected in all case by these compounds.The results indicated so far that AC and its related compounds showed no beneficial but harmful effect on the cardial contractive function. Hence, in case should Fu-Zi (aconite) be applied for the treatment of cardiovascular diseases. We would recommend that some new preparations be worked out which are essentially free from the aconitine-type alkaloids. A study towards this end is presently undertaking.}