L-CARNITINE AS A BASIS OF CHOLINOMIMETIC SUBSTANCES

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  • 1 January 1976
    • journal article
    • research article
    • Vol. 35  (5) , 645-656
Abstract
Acetylcarnitine has the same configuration as acetylcholine and acetyl-.beta.-methylcholine but is devoid of cholinomimetic properties if the carboxylic group is free. Contradictions were explained by lack of uniformity of the test substance caused by carboxylic group substitution and intramolecular cleavage of water or acetic acid from carnitine or acetylcarnitine and by admixtures of active substances because of the formation of metabolites in vivo. Recrystallization of L-acetylcarnitine and L-carnitine salts in alcohols caused the formation of active carboxylic esters. The latter could be separated and identified by TLC from the starting substances. In the isolated frog heart (Rana esculenta), neither L-carnitine nor L-acetylcarnitine had muscarinic effects; higher concentrations (0.03-0.15 M) exerted positively inotropic effects that increased with concentration and were qualitatively and quantitatively equal for L-carnitine and lower O-acyl-L-carnitines. As betaine, L-carnitine affected the heart rate only at 42 .+-. 12 mg/ml, crotonic acid betaine at 22 .+-. 7 mg/ml, -butyrobetaine at 15 .+-. 8 mg/ml. The cholinomimetic properties increased to the level of the stimulation system choline/acetylcholine because of carboxyl substitution of betaines. The LD50 of L-acetylcarnitine for mice injected s.c. with 8.4 (7.3-9.7) mg/g body wt was within the range of LD50 of L-carnitine. Both substances, when administered in high doses, give no symptoms like the cholinomimetic substances. Carnitine carboxyl ester, acetylcarnitine carboxyl ester and other carnitine derivatives, on a molar basis, were 2 .cntdot. 101-2 .cntdot. 103-fold more toxic than carnitine and acetylcarnitine. The modes of action of carnitines and their metabolites upon the heart rate were discussed.