Central and peripheral autonomic mechanisms involved in the circulatory actions of methyldopa.
Intracisternal (i.c.) and intravenous (i.v.) administration of methyldopa in conscious rabbits produced closely similar changes in hemodynamics, heart rate, and falls in plasma norepinephrine levels. Two weeks after giving i.c. 6-hydroxydopamine (6-OHDA), when there is widespread destruction of central noradrenergic neurons, the effects of i.c. methyldopa virtually were abolished. This suggests that noradrenergic neurons are the major central site of biotransformation into active metabolites. The circulatory and norepinephrine effects of i.v. methyldopa were attenuated but not completely abolished after giving i.c. 6-OHDA. Hence, in the rabbit about 70% of the action of methyldopa was central and about 30% was peripheral in the human therapeutic range of methyldopa concentrations. Preliminary lesion experiments suggest that the A5 nucleus plays an important role in the bradycardia. Two weeks after giving 5,6-dihydroxytryptamine (5,6-DHT) to destroy serotonergic (5HT) neurons the effects of i.c. methyldopa on mean arterial pressure (MAP) and heart rate were attenuated to approximately 50% of control effects. Therefore, some of the central effects of methyldopa apparently are mediated through 5HT pathways. We also compared the effects of i.c. methyldopa with those of i.c. clonidine (an alpha 2-adrenergic receptor agonist) and with the effects of transmitter release from the endings of noradrenergic and 5HT neurons during the first few hours after either 6-OHDA or 5,6-DHT administration. Our findings suggest that after biotransformation of methyldopa its active metabolites increase the activity of the bulbospinal noradrenergic neurons that control MAP and heart rate and reduce the activity of bulbospinal 5HT neurons.
D015115:5,6-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000502:physiology; D003000:Clonidine / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D008750:Methyldopa / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology; D009638:Norepinephrine / Q000097:blood / Q000502:physiology; D016627:Oxidopamine; D010525:Peripheral Nerves / Q000378:metabolism; D011149:Pons / Q000502:physiology; D011817:Rabbits; D012701:Serotonin / Q000502:physiology; D013116:Spinal Cord / Q000502:physiology; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology
D006892:Hydroxydopamines; D012701:Serotonin; D008750:Methyldopa; D016627:Oxidopamine; D003000:Clonidine; D015115:5,6-Dihydroxytryptamine; D009638:Norepinephrine