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

1 The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central aa-adrenoceptors (alpha (2)ARs). 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-llike drugs with no alpha (2)-adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an alpha (2)ARs agonist alpha -methylnoradrenaline (alpha -MMA). 4 We selected S23515 and S23757, two imidazoline-like drugs with negligible affinities and activities at alpha (2)ARs 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 mug kg i.c.) was prevented by S23757 (1 mg kg(-1) i.c.) and efaroxan (10 mug 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 mug kg(-1) i.c.). Moreover, the alpha (2)ARs antagonist rauwolscine (3 mug kg(-1) i.c.) did not prevent the effect of S23515. 6 Finally, whilst 3 mug kg(-1) of S23515 or 0.5 mug kg(-1) of a-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 alpha (2)-adrenergic properties lowers BP and interacts synergistically with an alpha (2)ARS agonist.