Respective contributions of alpha-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs.

Abstract

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.

• Authors: V Bruban, J Feldman, H Greney, M Dontenwill, S Schann, C Jarry, M Payard, J Boutin, E Scalbert, B Pfeiffer, P Renard, P Vanhoutte, P Bousquet
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 133 Issue 2 Pg. 261-6 (May 2001) ISSN: 0007-1188 [Print] England
• PMID: 11350862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-fluoro-5-methylphenyl)-4,5-dihydro-1H-imidazole
• 5-(2-bnromophenoxy)methyl-2-amino-4,5-dihydro-1,3-oxazole
• Antihypertensive Agents
• Imidazoles
• Oxazoles
• Receptors, Adrenergic, alpha
• Guanosine 5'-O-(3-Thiotriphosphate)
• Cyclic AMP

Topics

• Animals
• Antihypertensive Agents (administration & dosage, pharmacology)
• Blood Pressure (drug effects)
• Cattle
• Cisterna Magna
• Cyclic AMP (metabolism)
• Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
• HT29 Cells
• Hemodynamics (drug effects)
• Humans
• Imidazoles (administration & dosage, pharmacology)
• In Vitro Techniques
• Injections
• Male
• Oxazoles (pharmacology)
• Rabbits
• Radioligand Assay
• Receptors, Adrenergic, alpha (drug effects)