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Interrelation between lipophilic characters and speeds of positive inotropic effect (PIE) of cardenolides and ericaceous toxins was studied by determining both parameters of lipophilicity and inotropy speeds. The lipophilic characters of 8 kinds of cardenolides, evaluated from Rm or log k' values by means of thin layer chromatography (Rf) or high performance liquid chromatography (retention time), increased in the order of ouabain, digoxin, digitoxigenin, digitoxigenin-monodigitoxoside, digitoxigenin-bis-digitoxoside, digitoxin, alpha-acetyl-digitoxin, triacetyl-digitoxin. Lipophilic character, evaluated from Rm values of 6 kinds of ericaceous toxins, was in decreasing order of 10S-grayanotoxin II, 6-acetyl grayanotoxin I, asebotoxin I, grayanotoxin I, asebotoxin III, asebotoxin X. The speed with which PIE developed was evaluated from the time to half maximum PIE (T50) of cardenolides and ericaceous toxins at a pD2 concentration. The speed of positive inotropy of cardenolides was independent of their concentration tested in the range from half to twice the concentration of pD2, while the speeds of PIE of ericaceous toxins depended on their concentration in the same range used in case of cardenolides. Inotropy speed of these two classes of cardiotoxins correlated well with the lipophilic character: a) In the case of cardenolides, a positive and close correlation (r = 0.98) was observed between T50 and Rm. The more lipophilic the cardenolides, the more time was required to reach the fully development of PIE. b) In contrast, a negative correlation (r = -0.82, between Rm and T50) was obtained in the case of ericaceous toxins; Toxins with more lipophilic nature caused faster development of PIE. The present results can be interpreted to mean that the PIE receptor for cardenolides in myocardial cells is located on the outer surface of the sarcolemma, while that for ericaceous toxins is located on the inside of the myocardial cell.

Relationship between the inotropy speeds in guinea-pig myocardium and lipophilic character of cardenolides and ericaceous toxins.