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Insulin downregulates M2-muscarinic receptors in adult rat atrial cardiomyocytes: a link between obesity and cardiovascular complications

International Journal of Obesity volume 29, pages 176–182 (2005)Cite this article

Abstract

OBJECTIVE:

To determine whether decreased cardiac parasympathetic activity observed in obesity is due to insulin-induced alterations in cardiac M2-muscarinic receptors and/or adenylyl cyclase activity.

DESIGN AND METHODS:

After incubation with increasing concentrations of insulin, adult rat atrial cardiomyocytes were assayed for M2-muscarinic receptor binding density and affinity, and for M2R mRNA expression using RT-PCR analysis. Forskolin-stimulated adenylyl cyclase activity and its inhibition by carbachol were also assayed, as was endothelial nitric oxide synthase mRNA expression. The effects of insulin on M2-muscarinic receptor density and mRNA expression levels were analyzed using the insulin signaling inhibitors rapamycin, wortmanin and PD 098059.

RESULTS:

Insulin induces a concentration- and time-dependent decrease in expression of the M2R mRNA, and in [3H]N-methylscopolamine binding by the receptor. These effects on the M2R mRNA levels and on [3H]N-methylscopolamine binding were prevented by PD 98059, but not by wortmanin or rapamycin. Basal and forskolin-induced cAMP production did not differ, but the inhibition of forskolin-simulated enzyme activity by carbachol was blunted by insulin. No change in the mRNA levels for endothelial nitric oxide synthase was observed.

CONCLUSION:

In rat atrial cardiomyocytes, insulin markedly alters both the M2-muscarinc receptor density, and its mRNA expression through transcriptional regulation and adenylyl cyclase activity. These data suggest that the obesity-associated decrease in cardiac parasympathetic tone may be related to hyperinsulinemia, which could directly contribute to cardiovascular morbidity in obese patients.

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Authors and Affiliations

  1. Unité de Recherche sur les Obésités -Unité INSERM 586, Institut Louis Bugnard, Université Paul Sabatier, CHU Rangueil, Toulouse Cedex, 4, France

    A Pathak, F Smih, M Galinier, P Verwaerde, P Rouet, P Philip-Couderc & J M Senard

  2. Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 37 allées Jules Guesde, Toulouse Cedex, 07, France

    A Pathak, J L Montastruc & J M Senard

  3. Department of Cardiology, Rangueil University Hospital, 1 avenue Jean Poulhes, Toulouse, France

    A Pathak & M Galinier

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  1. A Pathak
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Correspondence to A Pathak.

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Pathak, A., Smih, F., Galinier, M. et al. Insulin downregulates M2-muscarinic receptors in adult rat atrial cardiomyocytes: a link between obesity and cardiovascular complications. Int J Obes 29, 176–182 (2005). https://doi.org/10.1038/sj.ijo.0802751

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