[Selectivity of a new antihypertensive agent, rilmenidine, for imidazoline receptors in the human brain].
The involvement of the central nervous system in the global hypotensive effect of rilménidine (R) was already suspected after experiments on cats and dogs. Indeed, the injection of this drug in the vertebral artery provoked a decrease in the arterial blood pressure in these two species. Recently, we showed that intracisternal injections of cumulative doses (1 to 300 micrograms/kg) in anaesthetized rabbits significantly lowered the blood pressure. In that protocol the efficient dose 20% was 1.5 micrograms/kg when it was 70 micrograms/kg for intravenous injections. The hypotension was always associated with bradycardia. Thus we confirmed that the drop in the arterial blood pressure induced by R was, at least partially, due to a central inhibition of the vasomotor tone. When we pretreated anaesthetized rabbits, always by intracisternal injections, with identical doses of yohimbine or idazoxan (5 nmoles/kg), we observed that idazoxan prevented much more the hypotensive effects of R than yohimbine. This study demonstrated that R whose chemical structure is close to that of imidazolines was much better antagonized by a substance with an imidazoline-like structure than by a classical alpha 2-antagonist. These results were confirmed by binding studies realized with human brain membranes. Tritiated clonidine was bound to cortical membrane preparations, containing mainly alpha 2-adrenoceptors, as well as to medullary membrane preparations, containing mainly imidazoline receptors. We observed that R selectivity for the medullary imidazoline preferring receptors was 2.5 times higher than that of the reference substance, clonidine. So, it seems that the central hypotensive effect of R might be related to its interaction with imidazoline specific receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Bricca
G
G
Institut de pharmacologie, faculté de médecine, CNRS URA 589, université Louis-Pasteur, Strasbourg.
Dontenwill
M
M
Feldman
J
J
Belcourt
A
A
Bousquet
P
P
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology; D006801:Humans; D019329:Idazoxan; D054755:Imidazoline Receptors; D010080:Oxazoles / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011817:Rabbits; D011955:Receptors, Drug / Q000378:metabolism*; D000077769:Rilmenidine; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D004146:Dioxanes; D054755:Imidazoline Receptors; D010080:Oxazoles; D011955:Receptors, Drug; D015016:Yohimbine; D000077769:Rilmenidine; D019329:Idazoxan