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Research ArticleCardiovascular

A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Lyne Fellmann, Véronique Regnault, Hugues Greney, Vincent Gasparik, Adeline Muscat, Jean-Pierre Max, Luc Gigou, Valérie Oréa, Gérard Chetrite, Anne Pizard, Nathalie Niederhoffer, Claude Julien, Patrick Lacolley, Bruno Fève and Pascal Bousquet
Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 370-380; DOI: https://doi.org/10.1124/jpet.113.205328
Lyne Fellmann
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Véronique Regnault
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Hugues Greney
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Vincent Gasparik
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Adeline Muscat
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Jean-Pierre Max
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Luc Gigou
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Valérie Oréa
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Gérard Chetrite
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Anne Pizard
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Nathalie Niederhoffer
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Claude Julien
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Patrick Lacolley
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Bruno Fève
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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Pascal Bousquet
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg. France (L.F., H.G., V.G., L.G., N.N., P.B.); INSERM UMR S_961, Université de Lorraine, Vandoeuvre-les-Nancy, France (V.R., J.-P.M., A.P., P.L.); Laboratoire de Physiologie, Faculté de Pharmacie, Lyon, France (V.O., C.J.); and the INSERM S_938, Faculté de Médecine, Université Paris 6, Paris, France (A.M., G.C., B.F.)
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This article has a correction. Please see:

  • Correction to “A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats” - October 01, 2013

Abstract

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [125I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.

Footnotes

    • Received April 3, 2013.
    • Accepted June 26, 2013.
  • L.F., V.R., and H.G. contributed equally to this work.

  • P.L., B.F., and P.B. contributed equally to this work.

  • This work was supported by the French National Institute for Medical Research (INSERM), the French Ministry of Health (a grant of the National Program for Research on Diabetes), and the Universities of Strasbourg, Paris, and Nancy.

  • dx.doi.org/10.1124/jpet113.205328.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 3
1 Sep 2013
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Research ArticleCardiovascular

Sympathetic System, Adiponectin, and Syndrome X

Lyne Fellmann, Véronique Regnault, Hugues Greney, Vincent Gasparik, Adeline Muscat, Jean-Pierre Max, Luc Gigou, Valérie Oréa, Gérard Chetrite, Anne Pizard, Nathalie Niederhoffer, Claude Julien, Patrick Lacolley, Bruno Fève and Pascal Bousquet
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 370-380; DOI: https://doi.org/10.1124/jpet.113.205328

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Research ArticleCardiovascular

Sympathetic System, Adiponectin, and Syndrome X

Lyne Fellmann, Véronique Regnault, Hugues Greney, Vincent Gasparik, Adeline Muscat, Jean-Pierre Max, Luc Gigou, Valérie Oréa, Gérard Chetrite, Anne Pizard, Nathalie Niederhoffer, Claude Julien, Patrick Lacolley, Bruno Fève and Pascal Bousquet
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 370-380; DOI: https://doi.org/10.1124/jpet.113.205328
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