TYROSINE METABOLISM 315 



by a-methyldopa. 5-Hydroxytryptoplian causes bronchoconstriction in 

 guinea pigs and central excitation in mice (if brain monoamine oxidase is 

 blocked), these effects being due to serotonin, and pretreatment of the 

 animals with a-methyldopa prevents these actions (Westermann et al., 

 1958). 



Decarboxylase inhibition should lead to a decrease in the tissue concen- 

 trations of certain amines and this has been demonstrated. The degree 

 of reduction will depend on the relative rates of formation and metabolism 

 of the amines, as well as on the magnitude of the decarboxylase inhibition 

 (which will depend in part on the penetration of the analogs into the tis- 

 sues), since we are dealing with steady-state multienzyme systems. Injec- 

 tion of a-methyldopa (200 mg/kg) into dogs leads to a lowering of serotonin 

 in the caudate nucleus (1.03 to 0.43 //g/g at 3 hr), a more prolonged lowering 

 of norepinephrine (2.41 to 1.77 /ngjg at 24 hr) (Goldberg et al., 1960), and 

 a fall of total catecholamines in the brain stem (0.17 ^- 0.08 //g/g), heart 

 (0.59 -^ 0.26 //g/g), and spleen (0.94 -^ 0.43 //g/g) (Stone et al, 1962). In 

 the mouse, brain serotonin is reduced but norepinephrine is unaffected 

 (S. E. Smith, 1960 a). The urinary amines in four hypertensive patients 

 were decreased by a-methyldopa (1-4 g per day): the reductions were 

 81% for t>Tamine, 63% for serotonin, and 55% for tryptamine (Gates 

 et al, 1960). 



Altering these amine levels should produce physiological disturbances. 

 It has been found that a-methyldopa lowers the blood pressure and causes 

 sedation in the dog (Goldberg et al, 1960), decreases coordinated activity 

 and produces miosis in mice (S. E. Smith, 1960 a), and in a variety of animals 

 induces a syndrome similar to that produced by reserpine (including hy- 

 pothermia), a drug releasing amines from the tissues (S. E. Smith, 1960 b). 

 a-Methyldopa is being studied clinically for the reduction of hypertension 

 and a preliminary report (Gates et al., 1960) indicated its effectiveness, 

 doses of 1-4 g/day for 1 week leading to a fall in supine blood pressure 

 from 187.0/115.4 to 173.4/108.1 and in standing blood pressure from 177.7/ 

 119.3 to 138.6/98.0, the controls being given a placebo in a double-blind 

 study. 



It is thus clear that a-methyl-dopa can inhibit certain amino acid de- 

 carboxylases in vivo, can alter amine levels in tissues, and can produce 

 physiological disturbances that could reasonably be attributed to the in- 

 hibition. Recently, however, more detailed studies of tissue amines have 

 indicated that other mechanisms are possibly operative. Injections of 

 a-methyl-3-hydroxyphenylalanine into guinea pigs lead to a reduction 

 in brain amines (Fig. 2-4), the degree of lowering and the duration of the 

 effect depending on the amine. a-Methyldopa acts similarly but is slightly 

 more potent. Simultaneously there is an inhibition of amino acid decar- 

 boxylase (Fig. 2-5). Cardiac norepinephrine is even more potently reduced 



