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Paul Ernsberger - One of the best experts on this subject based on the ideXlab platform.
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the i1 Imidazoline receptor and its cellular signaling pathwaysa
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul ErnsbergerAbstract:ABSTRACT: Two primary questions are addressed. First, do I1-Imidazoline binding sites fulfill all the essential criteria for identification as a true receptor? Second, what are the cellular signaling pathways coupled to this novel receptor? I1-Imidazoline binding sites show specificity in binding assays, linkage to physiologic functions, appropriate anatomic, and cellular and subcellular localization. Most important, binding affinities correlate with functional drug responses. I1-Imidazoline binding sites meet several additional criteria identified with functional receptors: they show physiologic regulation and endogenous ligands and, most crucially, are coupled to cellular signaling events. A series of studies have identified cellular events triggered by I1-Imidazoline receptor occupancy. This receptor is not coupled to conventional pathways downstream of heterotrimeric G-proteins, such as activation or inhibition of adenylyl or guanylyl cyclases, stimulation of inositol phospholipid hydrolysis, or induction of rapid calcium fluxes. The I1-Imidazoline receptor is coupled to choline phospholipid hydrolysis, leading to the generation of diacylglyceride, arachidonic acid, and eicosanoids. Additional cellular responses include inhibition of Na+/H+ exchange and induction of genes for catecholamine synthetic enzymes. The signaling pathways linked to the I1-Imidazoline receptor are similar to those of the interleukin family, implying that I1-receptors may belong to the family of neurocytokine receptors.
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the i1 Imidazoline receptor from binding site to therapeutic target in cardiovascular disease
Journal of Hypertension, 1997Co-Authors: Paul Ernsberger, Jacob E Friedman, Richard J KoletskyAbstract:Objective To review previous work and present additional evidence characterizing the I1-Imidazoline receptor and its role in cellular signaling, central cardiovascular control, and the treatment of metabolic syndromes. Second-generation centrally-acting antihypertensives inhibit sympathetic activity mainly via Imidazoline receptors, whereas first-generation agents act viaα2-adrenergic receptors. The I1 subtype of Imidazoline receptor resides in the plasma membrane and binds central antihypertensives with high affinity. Methods and results Radioligand binding assays have characterized I1-Imidazoline sites in the brainstem site of action for these agents in the rostral ventrolateral medulla. Binding affinity at I1-Imidazoline sites, but not at other classes of Imidazoline binding sites, correlates closely with the potency of central antihypertensive agents in animals and in human clinical trials. The antihypertensive action of systemic moxonidine is eliminated by the I1/α2-antagonist efaroxan, but not by selective blockade of α2-adrenergic receptors. Until now, the cell signaling pathway coupled to I1-Imidazoline receptors was unknown. Using a model system lacking α2-adrenergic receptors (PC12 pheochromocytoma cells) we have found that moxonidine acts as an agonist at the cell level and I1-Imidazoline receptor activation leads to the production of the second messenger diacylglycerol, most likely through direct activation of phosphatidylcholine-selective phospholipase C. The obese spontaneously hypertensive rat (SHR; SHROB strain) shows many of the abnormalities that cluster in human syndrome X, including elevations in blood pressure, serum lipids and insulin. SHROB and their lean SHR littermates were treated with moxonidine at 8 mg/kg per day. SHROB and SHR treated with moxonidine showed not only lowered blood pressure but also improved glucose tolerance and facilitated insulin secretion in response to a glucose load. Because α2-adrenergic agonists impair glucose tolerance, I1-Imidazoline receptors may contribute to the multiple beneficial effects of moxonidine treatment. Conclusion The I1-Imidazoline receptor is a specific high-affinity binding site corresponding to a functional cell-surface receptor mediating the antihypertensive actions of moxonidine and other second-generation centrally-acting agents, and may play a role in countering insulin resistance in an animal model of metabolic syndrome X.
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a novel mechanism of action for hypertension control moxonidine as a selective i1 Imidazoline agonist
Cardiovascular Drugs and Therapy, 1994Co-Authors: Paul Ernsberger, Musa A Haxhiu, Lynette M Graff, Laura A Collins, Ismail A Dreshaj, Danette L Grove, Marilyn E Graves, Siegfried G Schafer, Marie O ChristenAbstract:Sympathoadrenal inhibition by a direct action within the central nervous system is an advantageous route to blood pressure control. Stimulation of brain alpha 2-adrenergic receptors is one mechanism for sympathoadrenal suppression, but comes at the cost of nonspecific depression of CNS function, including sedation and decreased salivary flow. Evidence is accumulating for a second pathway for pharmacological control of sympathoadrenal outflow, mediated by a novel receptor specific for Imidazolines. First-generation central antihypertensive agents, which are Imidazolines such as clonidine, act primarily to stimulate these I1-Imidazoline receptors in the rostral ventrolateral medulla oblongata (RVLM) to lower blood pressure, but have sufficient agonism at alpha 2-adrenergic receptors to produce side effects. Second-generation centrally acting antihypertensive agents, such as moxonidine and rilmenidine, are selective for I1 relative to alpha 2 receptors. The reduced alpha 2 potency of these agents correlates with reduced severity of side effects. In this study we further established the selectivity of moxonidine for I1-Imidazoline sites by characterizing the direct interaction of [3H]moxonidine with these receptors in the RVLM and in adrenomedullary chromaffin cells. [3H]Moxonidine preferentially labeled I1-Imidazoline sites relative to alpha 2-adrenergic sites, only a small portion of which were labeled in the RVLM. [3H]Moxonidine binding to I1-Imidazoline sites was modulated by guanine nucleotides, implying that I1-Imidazoline sites may be membrane receptors coupled to guanine nucleotide binding regulatory proteins (G proteins). Receptor autoradiography with [125I]p-iodoclonidine confirmed the presence of I1-Imidazoline sites in the RVLM and other areas of the brainstem reticular formation. In contrast, alpha 2-adrenergic sites were mainly localized to the nucleus of the solitary tract. Moxonidine selectively displaced [125I]p-iodoclonidine binding from reticular areas, including the RVLM. In vivo studies in SHR rats confirmed the ability of moxonidine to normalize hypertension by an action within the RVLM and confirmed the correspondence of I1 binding affinity and antihypertensive efficacy. We also discuss prior literature on the cardiovascular pharmacology of Imidazolines, reinterpreting previous studies that only considered alpha-adrenergic mechanisms.
Sandra L. Burke - One of the best experts on this subject based on the ideXlab platform.
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i1 Imidazoline receptors in cardiovascular regulation the place of rilmenidine
American Journal of Hypertension, 2000Co-Authors: Geoffrey A. Head, Sandra L. BurkeAbstract:From the very earliest suggestion of a distinction between Imidazoline receptors and a2adrenoceptors, there has been much debate as to their contribution to the antihypertensive actions of clonidine-like agents. However, with the development of drugs such as rilmenidine that are more selective for I1 Imidazoline receptors, their role and also their close relationship with a2adrenoceptors has become clearer. We have examined this question using a range of Imidazoline and a2-adrenoceptor antagonists given centrally and peripherally to conscious rabbits. We found that second-generation agents such as rilmenidine preferentially act via Imidazoline receptors but that a2-adrenoceptors are important for the hypotension produced by the firstgeneration agents clonidine and a-methyldopa. In addition to the hypotension, rilmenidine facilitates cardiac vagal baroreflexes and inhibits cardiac sympathetic baroreflexes and diminishes the increase in renal sympathetic activity produced by environmental stress. In other studies using anesthetized rabbits and direct measures of sympathetic nerve activity, we confirmed that the major site of sympathoinhibitory actions and sympathetic baroreflex effects of rilmenidine is the rostral ventrolateral medulla. Our results also suggest that a2-adrenoceptors are activated as a consequence of Imidazoline receptor activation by rilmenidine. Thus, though Imidazoline receptors appear to be the primary target of rilmenidine, “downstream” a2-adrenoceptors within the brainstem are also involved and need to be considered in developing pharmacologic strategies for antihypertensive treatment involving Imidazoline agents. Am J Hypertens 2000; 13:89S‐98S © 2000 American Journal of Hypertension, Ltd.
Pascal Bousquet - One of the best experts on this subject based on the ideXlab platform.
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I1 receptors, cardiovascular function, and metabolism
2016Co-Authors: Pascal BousquetAbstract:When injected into the medullary site of the hypotensive action of clonidine, Imidazolines and related compounds decrease blood pressure (BP), whereas no phenylethyl-amine compounds were capable of producing such an effect at the same site. There is much biochemical and pharmacologic evidence to support the involvement of Imidazoline receptors in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensive drugs. Imidazoline-specific bind-ing sites, which do not recognize catecholamines, have been described in various tissues. Functional studies using selective antagonists have confirmed that the hypotensive effects of clonidine-like drugs are mediated, at least in part, by nonadrenergic Imidazoline-specific receptors, whereas their sedative action clearly involves 2-adrener-gic receptors located in the locus coeruleus. Compared with clonidine, newer centrally acting antihypertensive drugs such as rilmenidine are more selective for imidazo-line receptors than for 2-adrenergic receptors. This selec-tivity may explain the reduced incidence of side effects of these drugs at therapeutic doses. Very recently, imidazo-line-like compounds with no affinity and no activity at 2-adrenergic receptors have become available. Some of these compounds lowered the BP when injected centrally, indicating that an action on Imidazoline I1 receptors alone is sufficient to cause hypotension. Nevertheless, imidazo-line receptors and 2-adrenoceptors cooperate in the con-trol of the vasomotor tone and in the hypotensive action of centrally acting hybrid drugs (ie, drugs that bind to both types of receptor). Additional noncardiovascular effects of Imidazoline-like drugs have also been described, such as insulin secretion stimulation and renal sodium reabsorp-tion inhibition. These effects may account for the long-term benefits of Imidazoline selective drugs, such a
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characterization of Imidazoline binding protein s solubilized from human brainstem studies with 3h idazoxan and 3h clonidine
Neurochemistry International, 1994Co-Authors: Hugues Greney, Pascal Bousquet, M. Dontenwill, Giampiero Bricca, J Stutzmann, A. BelcourtAbstract:Abstract Imidazoline binding sites from the human brainstem were solubilized with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane-sulfonate (CHAPS). [ 3 H]idazoxan and [ 3 H]clonidine were used as ligands to characterize the solubilized binding sites. In both the soluble and membrane fractions, [ 3 H]idazoxan binding was saturable, stereoselective, sensitive to Imidazolines and insensitive to (-)norepinephrine and to amiloride. The affinities of [ 3 H]idazoxan for the soluble and membrane sites were similar ( K D = 25 ± 11 nM and 20 ± 3 nM). In both soluble and membrane fractions, the α 2 -adrenoceptor binding being masked with (-)norepinephrine, [ 3 H]clonidine bound to a low affinity site which was insensitive to (-)norepinephrine and which exhibited the same selectivity for various drugs as the [ 3 H]idazoxan binding site. α 2 -adrenoceptor binding was present in the membrane and the soluble fractions although it was difficult to detect in the soluble fraction because of inhibition of [ 3 H]rauwolscine binding by the CHAPS detergent.
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selectivity of rilmenidine for the nucleus reticularis lateralis a ventrolateral medullary structure containing Imidazoline preferring receptors
European Journal of Pharmacology, 1991Co-Authors: Eduardo Tibirica, Laurent Monassier, J Feldman, Claire Mermet, Francois Gonon, Pascal BousquetAbstract:Abstract Neuronal metabolic activity was studied by in vivo electrochemistry in two brain areas of the anesthetized rat: the nucleus reticularis lateralis (NRL) region of the ventrolateral medulla oblongata - site of the hypotensive action of clonidine-like Imidazolines - and the locus coeruleus (LC), which is involved in the sedative effect of these drugs. Hypotensive doses of i.v. rilmenidine (0.3 and 1.5 mg/kg), which is structurally related to clonidine, induced a dose-related inhibition of the metabolic activity of catecholaminergic neurons in the NRL region whereas higher doses (50-fold) were required to inhibit the activity of the catecholaminergic neurons in the locus coeruleus. On the other hand azepexole, another centrally acting antihypertensive drug that is not structurally related to the Imidazolines failed to inhibit the neuronal metabolic activity of the RNL region when administered i.v. in hypotensive doses (1 mg/kg). Taken together, these findings suggest that the central hypotensive action of clonidine-like drugs requires the Imidazoline structure or pharmacologically compatible compounds like rilmenidine. Our results also show that rilmenidine is twice as selective as clonidine for the NRL region, which contains Imidazoline-preferring receptors, compared with the LC, which contains mainly α 2 -adrenoceptors. In conclusion, this study provides a functional confirmation of the dissociation between the therapeutic (hypotensive) and untoward (sedative) effects of rilmenidine.
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an Imidazoline specific mechanism for the hypotensive effect of clonidine a study with yohimbine and idazoxan
Journal of Pharmacology and Experimental Therapeutics, 1991Co-Authors: Eduardo Tibirica, Josiane Feldman, Claire Mermet, Francois Gonon, Pascal BousquetAbstract:Our previous in vivo electrochemical studies in the normotensive rat have shown that there was a positive correlation between the hypotensive effect of low doses of clonidine (8-40 nmol/kg i.v.) and the inhibition of the metabolic activity of catecholaminergic neurons within the nucleus reticularis region in the brain stem. Higher doses of the drug (200 nmol/kg i.v.) were required to decrease the metabolic activity in the locus ceruleus, which is involved in the sedative effect of clonidine. To investigate further the pharmacological mechanism involved in the hypotensive effect of Imidazolines, low doses of antagonists were injected centrally in the cisterna magna (5 nmol/kg intracisternal): idazoxan, an Imidazoline that labels nonadrenergic Imidazoline-preferring sites and yohimbine, which is a classical alpha-2 adrenergic antagonist. Our results show that idazoxan very potently antagonizes both the hypotensive effect of clonidine and neuronal inhibition on the nucleus reticularis lateralis region but not in the locus ceruleus. The opposite effect is observed with yohimbine, i.e., neither the hypotensive effect nor the neuronal inhibition produced by clonidine on the nucleus reticularis lateralis region were affected but it prevented the inhibitory effect of clonidine on locus ceruleus neuronal metabolic activity. In conclusion, we confirm the hypothesis that the hypotensive action of Imidazoline is due to an interaction of these substances with Imidazoline-preferring receptors in the ventrolateral medulla oblongata whereas its sedative effect is related to an action on alpha-2 adrenoceptors.
Shaikh A Ali - One of the best experts on this subject based on the ideXlab platform.
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the effects of n pendants and electron rich amidine motifs in 2 p alkoxyphenyl 2 Imidazolines on mild steel corrosion in co2 saturated 0 5 m nacl
Corrosion Science, 2015Co-Authors: Mohammad Jafar A Mazumder, Hasan A Almuallem, Shaikh A AliAbstract:Abstract A novel series of diethylenetetramine-( I ), and tetraethylenepentamine-derived Imidazolines ( II ) having p-octyloxy-, dodecyloxy and octadecyloxy-phenyl pendants as hydrophobes, have imparted very good inhibition of mild steel corrosion in CO 2 –0.5 M NaCl (40 °C, 1 atm; 120 °C, 10 bar). Pendants to the ring-nitrogen of I and II showed no change in inhibition efficiencies, while the presence of electron-rich aromatic ring in conjugation with the amidine motifs and increasing hydrophobe chain lengths imparted increasing corrosion inhibition. The formation of an Imidazoline film covering the metal surface is corroborated by an XPS study. The Imidazolines cover the metal surface before reaching their critical molar concentrations.
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heptadecyl tailed mono and bis Imidazolines a study of the newly synthesized compounds on the inhibition of mild steel corrosion in a carbon dioxide saturated saline medium
Corrosion Science, 2012Co-Authors: Mohammed W S Jawich, G A Oweimreen, Shaikh A AliAbstract:Abstract The study compares, for the first time, the corrosion inhibition properties of a diethylenetetramine-derived Imidazoline ( I ), and tetraethylenepentamine-derived Imidazoline ( II ) and bis-Imidazoline ( III ), all having heptadecyl pendants as hydrophobes. The newly synthesized Imidazolines show excellent inhibition efficiencies against the corrosion of mild steel in 0.5 M sodium chloride solutions saturated with carbon dioxide. The inhibition efficiencies increased with the increasing temperature. At a concentration of 100 ppm at 40 °C, Imidazolines I , II , and III imparted inhibition efficiencies of 84, 95 and 96%, respectively. The Imidazolines cover most of the steel surface before their critical molar concentrations are reached.
Geoffrey A. Head - One of the best experts on this subject based on the ideXlab platform.
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i1 Imidazoline receptors in cardiovascular regulation the place of rilmenidine
American Journal of Hypertension, 2000Co-Authors: Geoffrey A. Head, Sandra L. BurkeAbstract:From the very earliest suggestion of a distinction between Imidazoline receptors and a2adrenoceptors, there has been much debate as to their contribution to the antihypertensive actions of clonidine-like agents. However, with the development of drugs such as rilmenidine that are more selective for I1 Imidazoline receptors, their role and also their close relationship with a2adrenoceptors has become clearer. We have examined this question using a range of Imidazoline and a2-adrenoceptor antagonists given centrally and peripherally to conscious rabbits. We found that second-generation agents such as rilmenidine preferentially act via Imidazoline receptors but that a2-adrenoceptors are important for the hypotension produced by the firstgeneration agents clonidine and a-methyldopa. In addition to the hypotension, rilmenidine facilitates cardiac vagal baroreflexes and inhibits cardiac sympathetic baroreflexes and diminishes the increase in renal sympathetic activity produced by environmental stress. In other studies using anesthetized rabbits and direct measures of sympathetic nerve activity, we confirmed that the major site of sympathoinhibitory actions and sympathetic baroreflex effects of rilmenidine is the rostral ventrolateral medulla. Our results also suggest that a2-adrenoceptors are activated as a consequence of Imidazoline receptor activation by rilmenidine. Thus, though Imidazoline receptors appear to be the primary target of rilmenidine, “downstream” a2-adrenoceptors within the brainstem are also involved and need to be considered in developing pharmacologic strategies for antihypertensive treatment involving Imidazoline agents. Am J Hypertens 2000; 13:89S‐98S © 2000 American Journal of Hypertension, Ltd.
