Respective contributions of alpha-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs.
The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central alpha2-adrenoceptors (alpha2ARs). However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline-like drugs with no alpha2-adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an alpha2ARs agonist alpha-methylnoradrenaline (alpha-MNA). We selected S23515 and S23757, two imidazoline-like drugs with negligible affinities and activities at alpha2ARs but with high affinities for non-adrenergic imidazoline binding sites (IBS). S23515 decreased BP dose-dependently (-27+/-5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 microg kg(-1) i.c.) was prevented by S23757 (1 mg kg(-1) i.c.) and efaroxan (10 microg kg(-1) i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of alpha-MNA (3 and 30 microg kg(-1) i.c.). Moreover, the alpha2ARs antagonist rauwolscine (3 microg kg(-1) i.c.) did not prevent the effect of S23515. Finally, whilst 3 microg kg(-1) of S23515 or 0.5 microg kg(-1) of alpha-MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (-23+/-2%). These results indicate that an imidazoline-like drug with no alpha2-adrenergic properties lowers BP and interacts synergistically with an alpha(ARs agonist.
Bruban
V
V
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université Louis Pasteur, 11 rue Humann, 67000 Strasbourg, France.
Feldman
J
J
Greney
H
H
Dontenwill
M
M
Schann
S
S
Jarry
C
C
Payard
M
M
Boutin
J
J
Scalbert
E
E
Pfeiffer
B
B
Renard
P
P
Vanhoutte
P
P
Bousquet
P
P
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002417:Cattle; D002946:Cisterna Magna; D000242:Cyclic AMP / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D019073:HT29 Cells; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007267:Injections; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*
C431512:2-(2-fluoro-5-methylphenyl)-4,5-dihydro-1H-imidazole; C431511:5-(2-bnromophenoxy)methyl-2-amino-4,5-dihydro-1,3-oxazole; D000959:Antihypertensive Agents; D007093:Imidazoles; D010080:Oxazoles; D011942:Receptors, Adrenergic, alpha; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP