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

Abstract

1 The hypotensive e ect of imidazoline-like drugs, such as clonidine, was ®rst attributed to the exclusive stimulation of central a 2 -adrenoceptors (a 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-like drugs with no a 2 -adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an a 2 ARs agonist a-methylnoradrenaline (a-MNA). 4 We selected S23515 and S23757, two imidazoline-like drugs with negligible a nities and activities at a 2 ARs but with high a nities for non-adrenergic imidazoline binding sites (IBS). 5 S23515 decreased BP dose-dependently (727+5% maximal e ect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 mg kg 71 i.c.) was prevented by S23757 (1 mg kg 71 i.c.) and efaroxan (10 mg kg 71 i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive e ect of a-MNA (3 and 30 mg kg 71 i.c.). Moreover, the a 2 ARs antagonist rauwolscine (3 mg kg 71 i.c.) did not prevent the e ect of S23515. 6 Finally, whilst 3 mg kg 71 of S23515 or 0.5 mg kg 71 of a-MNA had weak hypotensive e ects, the sequential i.c. administration of these two drugs induced a marked hypotension (723+2%). 7 These results indicate that an imidazoline-like drug with no a 2 -adrenergic properties lowers BP and interacts synergistically with an a 2 ARs agonist.

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

“…However, most drugs that are ligands for these receptors are also á 2 -adrenoceptor agonists and it has been difficult to secure definitive evidence for I 1 involvement in blood pressure control (32,43). Recent work with the I 1 selective compound S23515, (±)5-(2-bromophenoxyl)methyl-2-amino-4,5-dihydro-1,3 oxazole, suggests that I 1 receptor ligands are hypotensive and that, in this respect, they act synergistically in combination with á 2 -adrenoceptor agonists (7).…”

Evidence for Synergy Between α 2 -Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation

“…This hypotensive action was prevented by S23757, an antagonist highly selective for I 1 BS. 22 LNP 509 also caused hypotension when administered in the 4 th V of WT and D79N mice. These in vivo data demonstrate (1) that LNP 509 is capable of reducing BP in 2 different species and (2) that this activity is independent of any action at ␣ 2 ARs.…”

“…The hypotensive response to 100 g/kg LNP 509 was prevented by an intracisternal injection of 1 mg/kg S23757, an antagonist highly selective for I 1 BS. 22 Figure 3). The HR was not affected in either strain: 382Ϯ22 versus 407Ϯ25 bpm (WT mice) and 423Ϯ25 versus 433Ϯ24 bpm (D79N mice).…”

“…Studies were performed on normotensive male rabbits (Zika strain, Wendling, Wasselonne, France), weighing 2.5 to 3.5 kg, prepared as described previously, 22 and on 10-to 20-week-old B6.129S2-Adra2a tm1Lel mice, ie, D79N mice. These mice were kindly provided by Dr L. Limbird (Vanderbilt University, Medical Center, Nashville, Tenn).…”

“…22 Membranes of CHO cells (clone 1E5) transfected with human ␣ 2A ARs were incubated with 0.2 nmol/L [ 35 S]GTP␥S and drugs for 1 hour at 25°C. Nonspecific binding was defined by 10 mol/L cold GTP␥S.…”