Involvement Of Imidazoline Receptors Research Articles

Neuroprotective effect of agmatine in mouse spinal cord injury model: Modulation by imidazoline receptors

Objective: The involvement of imidazoline receptors in the effect of agmatine was studied in locomotor recovery following experimental SCI (ESCI) in mice. Methods: ESCI was induced in mice using compression method. Locomotor function score (0–10) was measured on day 14 following ESCI. Results: Agmatine (2.5, 5, and 10 mg/kg) treatment through intraperitoneal route for 14 days following ESCI, dose-dependently improved the motor function score. Clonidine (0.1 mg/kg; imidazoline I1 receptor agonist) or moxonidine (0.5 mg/kg; I2 receptor agonist) treatment 15 min before agmatine (2.5 mg/kg) daily for 14 days, following ESCI, significantly potentiated the effect of per se agmatine. On the other hand, 15 min before treatment of efaroxan (1 mg/kg; imidazoline I1 receptor antagonist) or idazoxan (3 mg/kg; imidazoline I2 receptor antagonist) significantly blocked the motor function score of agmatine (10 mg/kg). Conclusion: These data suggest that imidazoline receptors may modulate the locomotor recovery following ESCI in agmatine treated mice, perhaps through I1/I2 receptors.

Imidazoline Antihypertensive Drugs: Selective I1‐Imidazoline Receptors Activation

Involvement of imidazoline receptors (IR) in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensives has received tremendous attention. To date, pharmacological studies have allowed the characterization of three main imidazoline receptor classes, the I(1) -imidazoline receptor which is involved in central inhibition of sympathetic tone to lower blood pressure, the I(2) -imidazoline receptor which is an allosteric binding site of monoamine oxidase B (MAO-B), and the I(3) -imidazoline receptor which regulates insulin secretion from pancreatic β-cells. All three imidazoline receptors represent important targets for cardiovascular research. The hypotensive effect of clonidine-like centrally acting antihypertensives was attributed both to α(2) -adrenergic receptors and nonadrenergic I(1) -imidazoline receptors, whereas their sedative action involves activation of only α(2) -adrenergic receptors located in the locus coeruleus. Since more selective I(1) -imidazoline receptors ligands reduced incidence of typical side effects of other centrally acting antihypertensives, there is significant interest in developing new agents with higher selectivity and affinity for I(1) -imidazoline receptors. The selective imidazoline receptors agents are also more effective in regulation of body fat, neuroprotection, inflammation, cell proliferation, epilepsy, depression, stress, cell adhesion, and pain. New agonists and antagonists with high selectivity for imidazoline receptor subtypes have been recently developed. In the present review we provide a brief update to the field of imidazoline research, highlighting some of the chemical diversity and progress made in the theoretical studies of imidazoline receptor ligands.

Involvement of imidazoline receptors in the centrally acting muscle-relaxant effects of tizanidine

The centrally acting muscle relaxant tizanidine has an imidazoline structure and binds not only to α 2-adrenoceptors but also to imidazoline receptors. The role of imidazoline receptors in the muscle-relaxant effect of tizanidine was studied using the α 2-adrenoceptor/imidazoline receptor antagonist idazoxan and the α 2-adrenoceptor antagonist yohimbine. Tizanidine decreased the spinal mono- and polysynaptic reflexes in intact rats, and the inhibitory effects were antagonized by idazoxan but not by yohimbine. After pretreatment with prazosin, tizanidine decreased the mono- and polysynaptic reflexes in spinalized rats. While yohimbine partly inhibited tizanidine-induced depression of the polysynaptic reflex, idazoxan completely abolished tizanidine-induced depression of spinal reflexes. Furthermore, tizanidine-induced muscle relaxation in the traction test was significantly inhibited by idazoxan but not by yohimbine. From these results, it is suggested that imidazoline receptors, but not α 2-adrenoceptors, are involved in the supraspinal inhibitory effects of tizanidine on spinal reflexes, and at the spinal level, α 2-adrenoceptors and imidazoline receptors are involved in the inhibitory effects of tizanidine.

Involvement of imidazoline receptors in the baroreflex effects of rilmenidine in conscious rabbits.

It has been suggested that imidazoline receptors rather than alpha2-adrenoceptors are involved in the sympathoinhibitory action of centrally acting antihypertensive drugs such as rilmenidine. In the present study, we examined the relative importance of alpha2-adrenoceptors and imidazoline receptors in modulating the renal sympathetic and heart rate (HR) baroreflex in response to central administration of rilmenidine in conscious normotensive rabbits. In seven conscious rabbits, chronically instrumented with a fourth ventricular (4V) catheter, aortic and vena caval cuff occluders and a renal nerve electrode, we continuously recorded renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and HR and assessed baroreflex MAP-RSNA and MAP-HR relationships with balloon-induced ramp rises and falls in MAP. Rabbits were treated with 4V rilmenidine (22 microg/kg) followed by 4V idazoxan (30 microg/kg; a mixed alpha2-adrenoceptor and imidazoline receptor antagonist) or 4V 2-methoxy-idazoxan (1 microg/kg; an alpha2-adrenoceptor antagonist with little affinity for imidazoline receptors). Rilmenidine lowered blood pressure by 24% and reduced both upper and lower plateaus of the renal sympathetic baroreflex curve, such that the RSNA range (difference between plateaus) was reduced by 40% (-32 +/- 10 normalized units). Curves were shifted to the left with the fall in MAP. Idazoxan restored MAP, maximum RSNA and the RSNA baroreflex range. By contrast the alpha2-adrenoceptor antagonist 2-methoxy-idazoxan caused only a partial recovery of MAP and RSNA baroreflex upper plateau and range (-9 +/- 2 mmHg, 29 and 33% lower than control). Both antagonists partially restored the HR baroreflex. These findings suggest that in conscious rabbits, both imidazoline receptors and alpha2-adrenoceptors are involved in the central antihypertensive and baroreflex actions of rilmenidine, but that activation of imidazoline receptors is more important for its renal sympathoinhibitory action.

Peripheral and central effects of naphazoline on ocular hydrodynamics. Involvement of imidazoline receptors, ANP, and Gi proteins.

Annals of the New York Academy of SciencesVolume 881, Issue 1 p. 388-391 Peripheral and Central Effects of Naphazoline on Ocular Hydrodynamics: Involvement of Imidazoline Receptors, ANP, and Gi Proteinsa MILLER J. OGIDIGBEN, MILLER J. OGIDIGBEN Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310–1495, USASearch for more papers by this authorT. C. CHU, T. C. CHU Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310–1495, USASearch for more papers by this authorD. E. POTTER, D. E. POTTER Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310–1495, USASearch for more papers by this author MILLER J. OGIDIGBEN, MILLER J. OGIDIGBEN Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310–1495, USASearch for more papers by this authorT. C. CHU, T. C. CHU Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310–1495, USASearch for more papers by this authorD. E. POTTER, D. E. POTTER Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310–1495, USASearch for more papers by this author First published: 06 February 2006 https://doi.org/10.1111/j.1749-6632.1999.tb09387.xCitations: 2 a This work was supported by National Institutes of Health Grant EY06338. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume881, Issue1IMIDAZOLINE RECEPTORS AND THEIR ENDOGENOUS LIGANDS: CURRENT CONCEPTS AND THERAPEUTIC POTENTIALJune 1999Pages 388-391 RelatedInformation

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

1 In segments of human right atrial appendages and pulmonary arteries preincubated with [3H]-noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, the involvement of imidazoline receptors in the modulation of [3H]-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 [3H]-noradrenaline release. The inhibition was not affected by blockade of alpha 2-adrenoceptors with 1 microM rauwolscine, but antagonized by extremely high concentrations of this drug (10 and/or 30 microM; apparent pA2 against aganodine and DTG: 5.55 and 5.21, respectively). 3 In the presence of 1 microM rauwolscine, [3H]-noradrenaline release in human atrial appendages was also inhibited by the imidazolines idazoxan and cirazoline, but not by agmatine and noradrenaline. The inhibitory effects of 100 microM idazoxan and 30 microM cirazoline were abolished by 30 microM rauwolscine. 4 In the atrial appendages, the rank order of potency of all guidelines and imidazolines for their inhibitory effect on electrically-evoked [3H]-noradrenaline release in the presence of 1 microM rauwolscine was: aganodine > or = BDF 6143 [4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline] > DTG > or = clonidine > cirazoline > idazoxan (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 fluid, the concentration-response curve for BDF 6143 (a mixed alpha 2-adrenoceptor antagonist/imidazoline receptor agonist) for its facilitatory effect on electrically-evoked [3H]-noradrenaline release was bell-shaped. In the presence of 1 microM rauwolscine, BDF 6143 and cirazoline concentration-dependently inhibited the evoked [3H]-noradrenaline release. 6 In human atrial appendages, non-adrenoceptor [3H]-idazoxan binding sites were identified and characterized. The binding of [3H]-idazoxan was specific, reversible, saturable and of high affinity (KD: 25.4 nM). The specific binding of [3H]-idazoxan (defined 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 fitted to a two-site model. 7 The rank order of affinity for the high affinity site (in a few cases for the only detectable site; cirazoline = idazoxan > BDF 6143>DTG> or = clonidine) is compatible with the pharmacological properties of I2-imidazoline binding sites, but is clearly different 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 differ clearly from I1 and I2 imidazoline binding sites.

The stimulatory effect of clonidine on locus coeruleus neurons of rats with inactivated alpha 2-adrenoceptors: involvement of imidazoline receptors located in the nucleus paragigantocellularis.

Clonidine stimulates locus coeruleus neurons by an alpha 2-adrenoceptor-independent mechanism which probably involves imidazoline receptors. To study this effect, single-unit extracellular recordings in the locus coeruleus were performed in anaesthetised rats after complete, irreversible inactivation of alpha 2-adrenoceptors by the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (6 mg/kg i.p.; 6 h before experiments). After this pretreatment, clonidine applied into the locus coeruleus failed to produce any change in the cell firing rate. However, clonidine applied intravenously (320-2560 micrograms/kg), or locally (0.5-2.0 microliters of 0.02 M) into the nucleus paragigantocellularis, a major locus coeruleus afferent, stimulated locus coeruleus neurons (increasing the firing rate by approximately 90%). Electrical lesions of the nucleus paragigantocellularis greatly attenuated the clonidine induced stimulation of locus coeruleus neurons ipsilateral to the lesion when applied intravenously. Blood pressure which was recorded simultaneously with cell recording, remained unaffected after clonidine administration in EEDQ pretreated rats. These results indicate that the clonidine-induced stimulation of locus coeruleus neurons is an indirect effect mediated by imidazoline receptors located on paragigantocellularis neurons projecting to the locus coeruleus.

Are imidazoline receptors involved in sympathetic neurotransmission in rat vas deferens

1. 1. An involvement of imidazoline receptors in the modulation of neurotransmitter release was investigated in the prostatic portion of the rat vas deferens stimulated transmurally at 0.2 Hz or by single pulses. 2. 2. Idaxozan and yohimbine induced a concentration-dependent potentiation of the contractile response to 0.2-Hz transmural stimulation in the epididymal and prostatic portion of the vas. 3. 3. After reserpine treatment, idazoxan, but not yohimbine, still potentiated the contractile response, suggesting a possible involvement of imidazoline receptors. 4. 4. Clonidine and rilmenidine, agonists with different affinities to α 2-adrenoceptors and imidazoline receptors, inhibited with the same potency the contractile responses to a single pulse transmural stimulation. 5. 5. Yohimbine (a selective α 2-adrenoceptor antagonist) antagonized the inhibitory concentration effect curve to rilmenidine in a competitive manner. pA 2 values for idaxozan (an antagonist to α 2-adrenoceptors and imidazoline receptors) were not different when noradrenaline or rilmenidine were used as agonists. Phenoxybenzamine blocked the effect of both agonists. 6. 6. Thus, the potency relationship of agonists, as well as the effect of the antagonists, did not favor the hypothesis that imidazoline receptors are involved in the idazoxan-potentiating effect in the rat vas deferens.

Inhibitory presynaptic imidazoline receptors on sympathetic nerves in the rabbit aorta differ from I1- and I2-imidazoline binding sites

The involvement of imidazoline receptors in modulation of noradrenaline release was investigated in the rabbit aorta preincubated with [3H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol. After blockade of alpha 2-autoreceptors by rauwolscine, the electrically evoked tritium overflow was inhibited by various imidazolines and guanidines. The rank order of potency was BDF 7579 (4-chloro-2-isoindolinyl) guanidine) > or = BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline) > BDF 6100 [2-(2-imidazolin-2-ylamino)-isoindoline] > clonidine > ST587 (2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine nitrate) > or = cirazoline > tolazoline > idazoxan > phentolamine. Comparison of the potencies of these drugs with those previously found for the presynaptic imidazoline receptors in the rabbit pulmonary artery revealed a very good correlation. In contrast, no positive correlation was found with their affinities for the I1- and I2-imidazoline binding sites in bovine adrenal medullary membranes and with their lipophilicity (log P values). The electrically evoked tritium overflow was also inhibited by the recently identified endogenous imidazoline receptor ligand agmatine, but was not affected by amiloride. In further series of experiments, the ability of putative antagonist at presynaptic imidazoline receptors to counteract the inhibitory effect of imidazoline derivatives was determined. Amiloride, imidazole-4-acetic acid and 1-benzylimidazole did not attenuate the inhibitory effect of BDF 6143 on the electrically evoked tritium overflow. In contrast, rauwolscine antagonized the inhibitory effect of various imidazolines; rauwolscine was clearly less potent in antagonizing the effect of clonidine, BDF 6143 and cirazoline (apparent pA2 6.48-7.32) than in antagonizing that of oxymetazoline and moxonidine (apparent pA2 8.33 and 8.12, respectively). In a final series of experiments, BDF 6143 (under the conditions applied a selective agonist at presynaptic imidazoline receptors) proved to be considerably less potent in inhibiting tritium overflow evoked by high K+ than by electrical stimulation, whereas moxonidine (in rabbit aorta a selective agonist at presynaptic alpha 2-adrenoceptors) exhibited similar potency in inhibiting the overflow evoked by both methods of stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Section Review—Cardiovascular & Renal: Recent Advances in Imidazoline Receptor Research

The discovery of the imidazoline receptors opened up an attractive new field for investigation. Since their existence was first proposed in 1984, extensive biochemical and pharmacological studies have confirmed the involvement of imidazoline receptors in various regulatory and pathological processes, including, primarily but not uniquely, hypertension. They have also been implicated in the mechanism of action of some centrally-acting antihypertensive, clonidine-like drugs. Rilmenidine, an oxazoline chemically related to the imidazolines, is the prototype of such centrally-acting drugs, selective for imidazoline specific receptors with few undesirable side-effects. Several therapeutic applications have already been considered, whereas others are still speculative. In addition to hypertension, ventricular arrhythmia, X-syndrome, diabetes, renal function impairments and mood disorders are examples of pathological processes in which the potential beneficial effects of imidazoline-like drugs may be confirmed i...