Studies on the interrelationship between the syntheses of noradrenaline and metaraminol.

1. Experiments were conducted to determine the influence of the rate of noradrenaline synthesis on the conversion of alpha-methyl-m-tyrosine to metaraminol.2. Male Wistar rats, 175-200 g, were placed into four groups and treated with (1) alpha-methyl-p-tyrosine methyl ester, 250 mg/kg; (2) DL-alpha-methyl-m-tyrosine, 400 mg/kg; (3) alpha-methyl-p-tyrosine methyl ester, 250 mg/kg plus DL-alpha-methyl-m-tyrosine, 400 mg/kg; or (4) an equivalent volume of injection vehicle. All solutions were injected intraperitoneally.3. Immediately after treatment half of the rats were transferred to 4 degrees C with the remaining animals being kept at 27 degrees C.4. The rats were killed 4, 8 and 12 h after injection, the brains, hearts, spleens and adrenals removed and analysed for adrenaline, noradrenaline, metaraminol and alpha-methyl-m-tyramine.5. In virtually all cases, both during rest (27 degrees C) and sympathetic stress (4 degrees C), treatment of the rats with alpha-methyl-p-tyrosine methyl ester increased the amount of metaraminol formed from alpha-methyl-m-tyrosine. The only organ not containing increased quantities of metaraminol in the presence of alpha-methyl-p-tyrosine methyl ester was the adrenals, taken from the rats kept at 27 degrees C. Adrenals removed from the cold-exposed rats contained more metaraminol when alpha-methyl-p-tyrosine methyl ester was combined with alpha-methyl-m-tyrosine than when alpha-methyl-m-tyrosine was used alone.6. These results demonstrate that the inhibition of noradrenaline synthesis, by treatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine methyl ester, increased the conversion of alpha-methyl-m-tyrosine to metaraminol. It is concluded that inhibiting the formation of dopa allowed increased amounts of alpha-methyl-m-tyrosine to enter the biosynthetic pathway. These results support the false sympathetic transmitter concept advanced for metaraminol.

The formation and release of metaraminol during exposure to warm or cold environments.

1. Rats were injected intraperitoneally with alpha-methyl-m-tyrosine (400 mg/kg) and placed at either 27 degrees C or 4 degrees C. The levels of alpha-methyl-m-tyramine, metaraminol and noradrenaline were determined in heart tissue after 1, 4 and 12 hr of treatment. The excretion of metaraminol, alpha-methyl-m-tyramine, noradrenaline, adrenaline and 3-methoxy-4-hydroxyphenylglycol (MHPG) was also estimated in both treated and control rats.2. Cold exposure increased both the formation and excretion of metaraminol. Hearts removed from the cold-stressed rats 4 hr after injection contained significantly more metaraminol than hearts taken from animals maintained in the warm environment. Twelve hours after treatment, no metaraminol remained in the hearts of cold-exposed rats, whereas significant quantities of the amine still remained in the hearts of rats kept at 27 degrees C. These results support the false transmitter concept advanced for metaraminol as they demonstrate that in vivo sympathetic stimulation can increase both the formation and release of metaraminol.3. Alpha-methyl-m-tyrosine produced a greater fall in cardiac noradrenaline in the rats kept at 27 degrees C. Whereas an approximate mole-for-mole replacement of metaraminol for noradrenaline existed at 27 degrees C, no such relationships existed at 4 degrees C. Twelve hours after treatment the hearts of cold-stressed rats contained no metaraminol and only 40% of control noradrenaline levels. These results do not support the necessity for a mole-for-mole replacement of noradrenaline with metaraminol to produce a catecholamine loss.4. Alpha-methyl-m-tyrosine depressed the noradrenaline excretion for at least 24 hr in the cold-stressed rats. Excretion of 3-methoxy-4-hydroxyphenylglycol was also lower in the treated rats between 0 and 12 hr in the cold but rose abruptly between 12 and 24 hr to exceed the quantity excreted by the control animals. This increase suggests an increase in noradrenaline synthesis, which may be related to the depletion of metaraminol from the body.5. The results of this paper support the postulate that metaraminol may function as a false transmitter. They do not agree with the concept that the loss of noradrenaline from tissue sites is dependent upon a mole-for-mole replacement with metaraminol.