[L-carnitine as a basis of cholinomimetic substances]

Acetylcarnitine, though having the same configuration as acetylcholine and Acetyl-beta-methylcholine, is devoid of cholinomimetic properties as long as the carboxylic group is free. Contrary findings are explainable by the lack of uniformity of the test substance, caused by substitution of the carboxylic group and intramolecular cleavage of water or acetic acid from carnitine or acetylcarnitine and by admixtures of active substances, and are attributable to the formation of metabolites in vivo. Already the recrystallization of salts of L-acetylcarnitine and L-carnitine in alcohols causes the formation of active carboxylic esters. The latter can be separated and identified by t.l.c. from the starting substances. At the isolated frog heart (Rana esculenta), neither L-carnitine nor L-acetylcarnitine have muscarine-like effects; higher concentrations of them (0.03-0.15 M) exert positively inotropic effects that increase with concentration and are qualitatively and quantitatively equal for L-carnitine and lower O-acyl-L-carnitines. As betaine, L-carnitine affects the heart rate only at 42 +/- 12 mg/ml, crotonic acid betaine at 22 +/- 7 mg/ml, gamma-butyrobetaine at 15 +/- 8 mg/ml. As a result of carboxyl substitution of betaines, the cholinomimetic properties increase to the level of the stimulation system choline/acetylcholine. The LD50 of L-acetylcarnitine for mice injected s.c. with 8.4 (7.3-9.7) mg/g body weight is within the range of LD50 of L-carnitine. Both substances, even when administered in high doses, give no such symptoms as cholinomimetic substances. Carnitine carboxyl ester, acetylcarnitine carboxyl ester, and other carnitine derivatives, on a molar basis, are 2-10(1) to 2-10(3)-fold more toxic than carnitine and acetylcarnitine. The modes of action of carnitines and their metabolites upon the heart rate are discussed.