Contribution of central and peripheral mechanisms to the antihypertensive effects of alpha-methyldopa in the rabbit.
We compared the effects of one intracisternal (0.6 mg/kg i.c.) and two intravenous (25 and 50 mg/kg i.v.) doses of alpha-methyldopa (alpha-MD) on blood pressure, heart rate, and plasma catecholamines in rabbits before and 2-3 weeks after intracisternal administration of 6-hydroxydopamine (6-OHDA). Intracisternally administered alpha-MD lowered heart rate, blood pressure, and plasma noradrenaline levels. Peak effects on heart rate and blood pressure were observed 2-3 h after administration. Three hours after intracisternally administered alpha-MD, plasma noradrenaline levels were reduced by 58%. Two to three weeks after 6-OHDA administration, the central mechanism responsible for the falls in heart rate, blood pressure, and plasma noradrenaline levels was abolished. The effects of intravenously administered alpha-MD (50 mg/kg) on heart rate, blood pressure, and plasma noradrenaline levels were attenuated but not completely abolished by destruction of central catecholaminergic neurons with 6-OHDA. These residual effects of alpha-MD most probably represent the peripheral effects of alpha-methylnoradrenaline at sympathetic terminals. The relative magnitudes of central to peripheral effects of alpha-MD on heart rate and blood pressure are dose dependent. After the lower intravenous dose (25 mg/kg), which achieves plasma alpha-MD concentrations similar to those found in humans, central mechanisms predominant. At higher doses, central and peripheral mechanisms contribute equally to these effects.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood; D002490:Central Nervous System / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine; D011817:Rabbits; D013997:Time Factors
D002395:Catecholamines; D006892:Hydroxydopamines; D016627:Oxidopamine; D009638:Norepinephrine