Studies on the Metabolism and Mechanism

THE decarboxylase-inhibiting, sedative, and antihypertensive properties of amethyl-3,4-dihydroxy-DI,-phenylalanine (DL-amethyl-dopa) in man were first reported from this department in 1960.1 It was shown subsequently that these three properties of the compound reside solely in the L isomer (methyldopa, Aldomet) .2, 3 Numerous favorable reports on the use of methyldopa in the treatment of hypertension have appeared; prominent among these are the articles by Cannon et al.,4 Dollery and Harrington,5 Irvine et al.6 Smirk,7 and Hamilton and Kopelman.8 It is worth recalling that the original finding of blood pressure-lowering effects in man. was not predicted. The compound had beeni shown to have no significant cardiovascular hemodynamic effects in animals and was used solely as an investigational tool for inhibiting the decarboxylation of aromatic-L-amino acids added exogenously to in vitro or in vivo systems. It seemed doubtful that the synthesis of endogenous norepinephrine could be decreased (and blood pressure thereby lowered) even with a more potent decarboxylase inhibitor for the following reasons: formation of 3,4-dihydroxyphenylalanine (dopa) from tyrosine is the rate-limiting step in synthesis, the amounts of dopa in tissues are so small as to be generally undetectable normally and the decarboxylation of dopa to dopamine (the immediate precursor of norepinephrine) is a highly efficient process. Indeed, it was the