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.
The I 1 subtype of imidazoline receptors (I 1 R) is a plasma membrane protein that is involved in diverse physiological functions. Available radioligands used so far to characterize the I 1 R were able to bind with similar affinities to ␣ 2 -adrenergic receptors (␣ 2 -ARs) and to I 1 R. This feature was a major drawback for an adequate characterization of this receptor subtype. New imidazoline analogs were therefore synthesized and the present study describes one of these compounds, 2-(2-chloro-4-iodophenylamino)-5-methyl-pyrroline (LNP 911), which was of high affinity and selectivity for the I 1 R. LNP 911 was radioiodinated and its binding properties characterized in different membrane preparations. Saturation experiments with [
The 2 -receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of 2 receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac 2 receptors in the regulation of cardiac K ϩ channel conductances and ii) to check whether 2 -receptor agonists exhibit class III antiarrhythmic properties. , and 1,3-di(2-tolyl)guanidine were used to discriminate the effects linked to 2 receptors from those of the 1 subtype, induced by (Ϯ)-N-allylnormetazocine (SKF-10,047). The 2 -receptor antagonist 3-␣-tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize 2 -mediated effects in patchclamp experiments. In rabbits, all 2 -receptor agonists reduced phenylephrine-induced cardiac arrhythmias. They prolonged action potential duration in rabbit Purkinje fibers and reduced human ether-a-go-go-related gene (HERG) K ϩ currents. (ϩ)-SKF-10,047 was completely inactive in the last two tests. The effects of threoifenprodil were not antagonized by SM-21. In HERG-transfected COS-7 cells, SM-21 potentiated the ifenprodil-induced blockade of the HERG current. These data suggest that 2 -receptor ligands block I Kr and that this effect could explain part of the antiarrhythmic properties of this ligands family. Nevertheless, an interaction with HERG channels not involving 2 receptors seems to share this pharmacological property. This work shows for the first time that particular caution has to be taken toward ligands with affinity for 2 receptors. The repolarization prolongation and the earlyafterdepolarization can be responsible for "torsades de pointe" and sudden cardiac death.
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