Limitation of the alpha-methylnorepinephrine hypothesis in the hypotensive effect of alpha-methyldopa

To test the hypothesis that alpha-methylnorepinephrine (MNE) is the principal active metabolite involved in the hypotensive action of alpha-methyldopa (MD), we determined the relationship between MD's depressor response and tissue levels of MD metabolites in critical sites. After administration of 250 mg/kg MD intraperitoneally to Sprague-Dawley rats (300 +/- 50 g), we studied both heart (left ventricle) and brainstem MD, MNE and endogenous NE levels using HPLC with electrochemical detection. We also measured systolic blood pressure before and during MD (25-250 mg/kg i.p.) treatment using the tail-cuff method. Our results indicate that: (1) peak MD hypotensive response was dose-dependent. (2) Central NE concentration was maximally reduced by 2 hours whereas peripheral NE was maximally reduced by 18 hours. The maximal hypotensive effect was closer to the central peak distribution of MNE than MD. (3) The MD concentrations and NE concentrations in brainstem and heart showed counterclockwise hysteresis while MNE showed clockwise hysteresis. Furthermore, the area of MNE hysteresis in brainstem was larger than that of NE. We conclude that MD's depressor effect can not be completely explained by the assumption that MNE is the sole active metabolite; alternate metabolites or mechanisms would appear to be operative.