Differential effects of alpha-methyldopa, clonidine and hydralazine on norepinephrine and epinephrine synthesizing enzymes in the brainstem nuclei of spontaneously hypertensive rats.
Repeated administrations of clonidine to spontaneously hypertensive rats (SHR) markedly lowered dopamine beta-hydroxylase (DBH) activity in the locus coeruleus (LC) and increased it in the spinal intermediolateral cell column (IML), while alpha-methyldopa tended to lower the enzyme activity in the medullary nucleus tractus solitarii (NTS) and A1 cell areas. Clonidine-induced inhibition of 3H-norepinephrine binding to crude cerebral membranes of SHR or Kyoto Wistar rats (KWR) as a measure of alpha-receptor agonist activity was 7 times greater than that of (+/-)alpha-methyl-(+/-)-norepinephrine. Clonidine and hydralazine significantly lowered phenylethanolamine N-methyltransferase (PNMT) activity elevated in the nucleus hypothalamicus posterior (NHP) of SHR to the level of KWR, and both drugs or alpha-methyldopa consistently increased PNMT in the nucleus paraventricularis (NPA). Peripherally active hydralazine also increased PNMT activity in the NTS, and antagonized the activity elevated in the A1 cell area of SHR to the level of KWR. In conclusion, clonidine selectively lowers DBH activity in the LC, while alpha-methyldopa appears to decrease the enzyme activity in the medullary NTS and A1 cell areas, suggesting different sites of action of both drugs. The decreased DBH activity in these nuclei may be related to stimulation of respective alpha-noradrenergic receptors. Elevating effects of all three drugs on PNMT activity in the NPA may be due to decreased baroreceptor afferent impulses to the nucleus after a fall in blood pressure.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D001933:Brain Stem / Q000201:enzymology*; D003000:Clonidine / Q000494:pharmacology*; D003864:Depression, Chemical; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology*; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D008750:Methyldopa / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010625:Phenylethanolamine N-Methyltransferase / Q000378:metabolism*; D051381:Rats; D013116:Spinal Cord / Q000201:enzymology
D006830:Hydralazine; D008750:Methyldopa; D004299:Dopamine beta-Hydroxylase; D010625:Phenylethanolamine N-Methyltransferase; D003000:Clonidine; D009638:Norepinephrine