An imidazoline-specific mechanism for the hypotensive effect of clonidine: a study with yohimbine and idazoxan.
Our previous in vivo electrochemical studies in the normotensive rat have shown that there was a positive correlation between the hypotensive effect of low doses of clonidine (8-40 nmol/kg i.v.) and the inhibition of the metabolic activity of catecholaminergic neurons within the nucleus reticularis region in the brain stem. Higher doses of the drug (200 nmol/kg i.v.) were required to decrease the metabolic activity in the locus ceruleus, which is involved in the sedative effect of clonidine. To investigate further the pharmacological mechanism involved in the hypotensive effect of imidazolines, low doses of antagonists were injected centrally in the cisterna magna (5 nmol/kg intracisternal): idazoxan, an imidazoline that labels nonadrenergic imidazoline-preferring sites and yohimbine, which is a classical alpha-2 adrenergic antagonist. Our results show that idazoxan very potently antagonizes both the hypotensive effect of clonidine and neuronal inhibition on the nucleus reticularis lateralis region but not in the locus ceruleus. The opposite effect is observed with yohimbine, i.e., neither the hypotensive effect nor the neuronal inhibition produced by clonidine on the nucleus reticularis lateralis region were affected but it prevented the inhibitory effect of clonidine on locus ceruleus neuronal metabolic activity. In conclusion, we confirm the hypothesis that the hypotensive action of imidazoline is due to an interaction of these substances with imidazoline-preferring receptors in the ventrolateral medulla oblongata whereas its sedative effect is related to an action on alpha-2 adrenoceptors.
Tibiriça
E
E
Laboratoire de Pharmacologie Cardiovasculaire et Rénale, CNRS URA 589, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.
Feldman
J
J
Mermet
C
C
Gonon
F
F
Bousquet
P
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D019329:Idazoxan; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D015102:3,4-Dihydroxyphenylacetic Acid; D015016:Yohimbine; D003000:Clonidine; D019329:Idazoxan