Presynaptic imidazoline receptors and non‐adrenoceptor[³H]‐idazoxan binding sites in human cardiovascular tissues

Abstract

1 In segments of human right atrial appendages and pulmonary arteries preincubated with [3 H]-noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, the involvement of imidazoline receptors in the modulation of [ 3 H]-noradrenaline release was investigated. 2 In human atrial appendages, the guanidines aganodine and DTG (1,3-di(2-tolyl)guanidine) which activate presynaptic imidazoline receptors, inhibited electrically-evoked [ 3 H]-noradrenaline release. The inhibition was not aected by blockade of a 2 -adrenoceptors with 1 mM rauwolscine, but antagonized by extremely high concentrations of this drug (10 and/or 30 mM; apparent pA 2 against aganodine and DTG: 5.55 and 5.21, respectively). 3 In the presence of 1 mM rauwolscine, [3 H]-noradrenaline release in human atrial appendages was also inhibited by the imidazolines idazoxan and cirazoline, but not by agmatine and noradrenaline. The inhibitory eects of 100 mM idazoxan and 30 mM cirazoline were abolished by 30 mM rauwolscine. 4 In the atrial appendages, the rank order of potency of all guanidines and imidazolines for their inhibitory eect on electrically-evoked [3 H]-noradrenaline release in the presence of 1 mM rauwolscine was: aganodine5BDF 6143 [4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline]4DTG5clonidine4cira-zoline4idazoxan (BDF 6143 and clonidine were previously studied under identical conditions). This potency order corresponded to that previously determined at the presynaptic imidazoline receptors in the rabbit aorta. 5 When, in the experiments in the human pulmonary artery, rauwolscine was absent from the superfusion¯uid, the concentration-response curve for BDF 6143 (a mixed a 2 -adrenoceptor antagonist/ imidazoline receptor agonist) for its facilitatory eect on electrically-evoked ]-idazoxan (de®ned by cirazoline 0.1 mM) to membranes of human atrial appendages was concentration-dependently inhibited by several imidazolines and guanidines, but not by rauwolscine and agmatine. In most cases, the competition curves were best ®tted to a two-site model. 7 The rank order of anity for the high anity site (in a few cases for the only detectable site; cirazoline=idazoxan4BDF 61434DTG5clonidine) is compatible with the pharmacological properties of I 2 -imidazoline binding sites, but is clearly dierent from the rank order of potency for inhibiting evoked noradrenaline release from sympathetic nerves in the same tissue. 8 It is concluded that noradrenaline release in the human atrium and, less well established, in the pulmonary artery is inhibited via presynaptic imidazoline receptors. These presynaptic imidazoline receptors appear to be related to those previously characterized in rabbit aorta and pulmonary artery, but dier clearly from I 1 and I 2 imidazoline binding sites.

Effects of imidazoline receptor ligands on monoamine synthesis in the rat brain in vivo

“…Presynaptic imidazoline receptors modulate the release of noradrenaline from peripheral, but not central, noradrenergic neurones (Göthert et al 1995;Molderings et al 1997). However, a stimulatory effect of imidazoline receptor ligands on noradrenaline release was observed in the cerebral cortex which was mediated by an indirect extra-cortical mechanism (Meana et al 1997).…”

Presynaptic Imidazoline Receptors: New Developments in Characterization and Classificationa

“…In the meantime, presynaptic imidazoline receptors have also been found on the sympathetic axon terminals of rats, 9 guinea pigs, 10 and man. 11,12 Several isoindoline derivatives substituted with aminoimidazoline (BDF 6100, BDF 6143, and BDF 7572) or guanidine (BDF 7579 and aganodine; for chemical structures, see our previous reviews 1,13) played a key role as pharmacologic tools in the identification of presynaptic imidazoline receptors.…”

Experimental Physiology –Research Paper: Modulation of N‐type calcium currents by presynaptic imidazoline receptor activation in rat superior cervical ganglion neurons

“…The I 1 receptors are mainly located in the ventrolateral medulla and are known to play a role in the exertion of central control over vascular tone (Ernsberger & Haxhiu, 1997; Bousquet & Feldman, 1999; Bruban et al 2001). The I 2 receptors are found in atrial appendages, vascular smooth muscle cells, carotid bodies, and prostate and cerebral cortices (Renouard et al 1993; Regunathan et al 1995; Youngson et al 1995; Molderings et al 1997). To date, no clear functional role has been discovered for these I 2 receptors, although they are thought to be associated with eating behaviour in rats (Polidori et al 2000) and various mental disorders, such as major depression (Meana et al 1993; Sastre et al 1995) and Alzheimer's disease (Ruiz et al 1993).…”

“…To date, no clear functional role has been discovered for these I 2 receptors, although they are thought to be associated with eating behaviour in rats (Polidori et al 2000) and various mental disorders, such as major depression (Meana et al 1993; Sastre et al 1995) and Alzheimer's disease (Ruiz et al 1993). More recently, a non‐I 1 /non‐I 2 new presynaptic‐modulating imidazoline receptor has been found in blood vessels and hearts of rabbits, rats, guinea‐pigs and humans (Molderings & Göthert, 1995, 1998; Likungu et al 1996; Molderings et al 1997). This presynaptic imidazoline receptor (R i‐pre ) is located in the sympathetic axon terminal and regulates blood pressure by modulating peripheral NA release (Göthert et al 1999).…”