Application of chemical ionization mass spectrometry and stable isotopes in studies of α-methyldopa metabolism

Abstract

Following the definitive clinical studies of Oates and co-workers (Oates et al.,1960) on the antihypertensive properties of α-methyldopa (I), a number of investigators have attempted to establish the mechanistic features underlying the pharmacological properties of this clinically useful drug. The most widely accepted theory was advanced a few years ago by Henning (1968), who proposed that α-methyldopa is transported into the brain, where it undergoes metabolism to α-methyldopamine (II) which is subsequently converted to α-methylnorepinephrine (III). The α-methylnorepinephrine and/or α-methyldopamine displace the endogenous central catecholamines dopamine (IV) and norepinephrine (V) and act as ‘false neurotransmitters’, leading to the attenuation of sympathetic outflow from the central nervous system and to a decrease in blood pressure. A number of key experiments have contributed to the development of this theory and include the observations that the antihypertensive properties of α-methyldopa are associated exclusively with the S-enantiomer (S-I) (Gillespie et al., 1962) and that peripheral decarboxylase inhibitors do not block the antihypertensive effects of the drug whereas central decarboxylase inhibitors do (Jaju, Tangri and Bhargava, 1966).