1. Metyrosine (l-α-methyl-p-tyrosine, Demser), an inhibitor of tyrosine hydroxylase, has moderate antihypertensive activity in spontaneously hypertensive rats (20–40 mmHg fall in mean arterial pressure) at 20–80 mg/kg intraperitoneally or 80 mg/kg orally. The maximal effect is reached at 4 h after treatment and the duration of action exceeds 12 h.
2. A peripheral inhibitor of amino acid decarboxylase, carbidopa ([—]-l-α-hydrazino-3,4-dihydroxy-α-methylbenzenepropanoic acid monohydrate), (25 mg/kg intraperitoneally) has little or no antihypertensive activity alone but if administered 5 min before metyrosine, it greatly enhances the antihypertensive potency of metyrosine. The relative potency of metyrosine + carbidopa (both intraperitoneally), as compared with metyrosine alone, was 74 with 95% confidence limits of 31 and 142.
3. In another series of experiments, the antihypertensive activity of metyrosine (80 mg/kg orally) was enhanced and prolonged by carbidopa, (25 mg/kg intraperitoneally). This effect was independent of the interval between administration of the two drugs (5 or 45 min).
4. Metyrosine (20 mg/kg intraperitoneally), reduced brain and heart noradrenaline concentrations in spontaneously hypertensive rats as determined 6 h after treatment. Carbidopa (25 mg/kg intraperitoneally) slightly enhanced the noradrenaline-depleting effect of metyrosine in the whole brain but not in the heart.
5. After metyrosine or carbidopa + metyrosine, low concentrations of α-methyldopamine were found in the brain of spontaneously hypertensive rats. Methyldopa at the same dose (20 mg/kg intraperitoneally) produced a 10 times greater increase in α-methyldopamine concentrations.
6. The inhibition by carbidopa of noradrenaline synthesis in sympathetic nerve endings in the heart and in peripheral blood vessels may be at least partially responsible for the carbidopa-induced enhancement of the antihypertensive action of metyrosine.