Application of chemical ionization mass spectrometry and stable isotopes in studies of α-methyldopa metabolism
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).
KeywordsCaudate Nucleus Chemical Ionisation Mass Spectrometry Endogenous Dopamine Deuterated Internal Standard Intraventricular Administration
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