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

Abstract

1. The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central α2-adrenoceptors (α2ARs). 2. However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. 3. This work aims (i) to check whether imidazoline-like drugs with no α2adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an α2ARs agonist α-methylnoradrenaline (α-MNA). 4. We selected S23515 and S23757, two imidazoline-like drugs with negligible affinities and activities at α2ARs but with high affinities for non-adrenergic imidazoline binding sites (IBS). 5. S23515 decreased BP dose-dependently (-27±5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 μg kg-1 i.c.) was prevented by S23757 (1 mg kg-1 i.c.) and efaroxan (10 μgkg-1 i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of α-MNA (3 and 30 μg kg-1 i.c.). Moreover, the α2ARs antagonist rauwolscine (3 μg kg-1 i.c.) did not prevent the effect of S23515. 6. Finally, whilst 3 μg kg-1 of S23515 or 0.5 μg kg-1 of α-MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (-23±2%). 7. These results indicate that an imidazoline-like drug with no α2-adrenergic properties lowers BP and interacts synergistically with an α22ARs agonist.