Desensitization and down-regulation of brain alpha 2-adrenoceptors by centrally acting antihypertensive drugs.
Rabbits were treated with intravenous clonidine (8 mumol kg-1 day-1), guanabenz (20 mumol kg-1 day-1), rilmenidine (80 mumol kg-1 day-1) or vehicle via osmotic minipumps. After 6 days treatment mean arterial pressure (MAP), pressor responses to intravenous alpha-methyl noradrenaline and depressor responses to intracisternal clonidine were studied, and [3H]-yohimbine binding to forebrain and hindbrain examined in vitro. Clonidine, guanabenz and rilmenidine had similar effects on MAP and caused a similar attenuation of the depressor response to intracisternal clonidine, but only guanabenz attenuated pressor responses to intravenous alpha-methyl noradrenaline. Rilmenidine had no effect on [3H]-yohimbine binding to brain membranes. Clonidine treatment decreased binding in hindbrain while guanabenz treatment decreased binding in both fore- and hindbrain. Thus, the depressor effects of chronic treatment did not correlate with the effects on [3H]-yohimbine binding sites in rabbit brain suggesting that the blood pressure lowering effects of many centrally acting antihypertensive drugs are not necessarily dependent on binding to the alpha 2-adrenoceptor site labelled by [3H]-yohimbine.
Hamilton
C A
CA
University Department of Materia Medica, Stobhill General Hospital, Glasgow.
Yakubu
M A
MA
Howie
C A
CA
Jardine
E
E
Reid
J L
JL
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002490:Central Nervous System / Q000502:physiology; D003000:Clonidine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D006143:Guanabenz / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010080:Oxazoles / Q000494:pharmacology; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D000077769:Rilmenidine; D015016:Yohimbine / Q000378:metabolism / Q000494:pharmacology
D000959:Antihypertensive Agents; D010080:Oxazoles; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D006143:Guanabenz; D003000:Clonidine; D000077769:Rilmenidine