Mechanism of Action of Methyldopa in the Rat

Role of 3-O-Methylated Metabolites

ZAVISCA, FRANK G.
BREAU, ALAN P.
WURTMAN, RICHARD J.

From the Laboratory of Neuroendocrine Regulation, Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.

These studies were supported in part by U.S. Public Health Service Grant AM-14228.

Dr. Zavisca was a Research Fellow at the Massachusetts General Hospital, Boston, Massachusetts, during the performance of this work. This material was submitted as part of a Ph.D. Thesis at the Massachusetts Institute of Technology, Cambridge, Massachusetts.

Address for reprints: Frank G. Zavisca, M.D., Ph.D., Department of Anesthesiology, West Virginia University Medical Center, Morgantown, West Virginia 26506.

Received April 24, 1979; accepted for publication June 27, 1979.

Circulation Research 45(5):p 684-690, November 1979.

SUMMARY

We studied the effect of 3-O-methyl-methyldopa (OMMD), the 3-O-methylated metabolite of the antihypertensive drug methyldopa (a-methyldopa, AMD), on blood pressure in the spontaneously hypertensive rat. OMMD lowered blood pressure in a dose-related manner when given orally or intraperitoneally. Its action lasted longer than that of AMD, and daily oral administration produced a cumulative fall in blood pressure. Oral and intraperitoneal OMMD produced similar reductions of blood pressure and similar tissue OMMD levels. After intraperitoneal injection of different doses, levels of OMMD measured in brain, spinal cord, and plasma correlated with the magnitude of the antihypertensive effect. No AMD was detected in tissues after either route of administration, which suggests that the antihypertensive effect was not based on demethylation of OMMD to AMD. Peripheral inhibition of the enzyme, aromatic amino acid decarboxylase (AAAD), failed to suppress OMMD's effect on blood pressure; in contrast, central inhibition of AAAD did decrease OMMD's antihypertensive effect. These observations suggest that 3-O-methylated metabolites may participate in the antihypertensive effect of AMD. Ore Res 45: 684-690, 1979