Relationships between the cardiovascular effects of alpha-methyldopa and its metabolism in pontomedullary noradrenergic neurons of the rabbit.
We compared the biotransformation of equipotent intracisternal (i.c., 600 micrograms/kg) and intravenous (i.v., 50 mg/kg) doses of alpha-methyldopa (alpha-MD) to alpha-methylnorepinephrine (alpha-MeNE) in the five major (A1, A2, A5, A6, and A7) noradrenergic nuclei of the rabbit brain, in relation to their cardiovascular effects. Peak effects on blood pressure and heart rate occurred 2-3 h after administration and persisted for 8 h. Three hours after i.v. alpha-MD, norepinephrine (NE) content throughout the five cell group regions was greatly reduced. However, total catecholamine (CA) content (NE plus alpha-MeNE) in the five cell groups increased by up to 300% due to accumulated alpha-MeNE. Eight hours after the i.v. dose, CA content throughout all five cell groups remained elevated. Following i.c. alpha-MD, a similar pattern of effect was observed in the A1, A2, and A5 regions. In the A6 and A7 regions, the effects were small and transient. Three hours after the i.c. dose, there was some biotransformation of alpha-MD but CA content was not affected. By 8 h, alpha-MeNE accounted for only a small fraction of the CA content. These results suggest that A1, A2, and A5 areas could be contributing to alpha-MD's cardiovascular effects. The elevation in CA content may be responsible for the activation of noradrenergic depressor pathways and blood pressure reduction.
Bobik
A
A
Clinical Research Unit, Alfred Hospital, Prahran, Victoria, Australia.
Oddie
C
C
Scott
P
P
Mill
G
G
Korner
P
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008750:Methyldopa / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000502:physiology*; D009647:Normetanephrine / Q000494:pharmacology; D011149:Pons / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors
D009647:Normetanephrine; D008750:Methyldopa; D009638:Norepinephrine