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Spinophilin regulates central angiotensin II-mediated effect on blood pressure

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Abstract

Central angiotensin II (AngII) plays an important role in the regulation of the sympathetic nervous system. The underlining molecular mechanisms are largely unknown. Spinophilin (SPL) is a regulator of G protein-coupled receptor signaling. Deletion of SPL induces sympathetically mediated arterial hypertension in mice. We tested the hypothesis that SPL restrains blood pressure (BP) by regulating AngII activity. We equipped SPL−/− and SPL+/+ mice with telemetric devices and applied AngII (1.0 mg kg−1 day−1, minipumps) or the AngII subtype 1 receptor (AT1-R) blocker valsartan (50 mg kg−1 day−1, gavage). We assessed autonomic nervous system activity through intraperitoneal application of trimethaphan, metoprolol, and atropine. We also tested the effect of intracerebroventricular (icv) AngII on blood pressure in SPL−/− and in SPL+/+ mice. Chronic infusion of AngII upregulates SPL expression in the hypothalamus of SPL+/+ mice. Compared with SPL+/+ mice, SPL−/− mice showed a greater increase in daytime BP with AngII (19.2 ± 0.8 vs. 13.5 ± 1.6 mmHg, p < 0.05). SPL−/− showed a greater depressor response to valsartan. BP and heart rate decreased more with trimethaphan and metoprolol in AngII-treated SPL−/− than in AngII-treated SPL+/+ mice. SPL−/− mice responded more to icv AngII. Furthermore, brainstem AT1-R and AngII type 2 receptor (AT2-R) expression was reduced in SPL−/− mice. AngII treatment normalized AT1-R and AT2-R expression levels. In summary, our findings suggest that SPL restrains AngII-mediated sympathetic nervous system activation. SPL is a hitherto unrecognized molecule with regard to central blood pressure control and may pave the way to novel strategies for the treatment of hypertension.

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Acknowledgments

We thank Ilona Kamer, Lisa Zocher, and Yoland Marie Anistan (Max Delbrück Center for Molecular Medicine, Berlin, Germany; Experimental and Clinical Research Center, Medical Faculty of the Charité) for technical assistance. EK (KL1415/4-2) and MK (GO766/12-1, GO766/15-1) were supported by DFG. The authors are not aware of interest conflicts.

Sponsorship

The Deutsche Forschungsgemeinschaft supported VG (Gr 1112/13-1) and ACCG (Kl1415/3-2). MAPF was supported by CNPq/CAPES-Probral, Brazil.

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Authors and Affiliations

  1. Leibniz Institute for Molecular Pharmacology, Robert-Rössle-Strasse 10, 13125, Berlin, Germany

    Andrey C. da Costa Goncalves

  2. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Andrey C. da Costa Goncalves, Enno Klussmann & Volkmar Gross

  3. Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Marco Antonio Peliky Fontes

  4. Experimental and Clinical Research Center, Medical Faculty of the Charité and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany

    Fatimunnisa Qadri, Jürgen Janke, Maik Gollasch, Johanna Schleifenbaum, Dominik Müller & Friedrich C. Luft

  5. Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany

    Jens Jordan & Jens Tank

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  1. Andrey C. da Costa Goncalves
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  2. Marco Antonio Peliky Fontes
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Correspondence to Andrey C. da Costa Goncalves.

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da Costa Goncalves, A.C., Fontes, M.A.P., Klussmann, E. et al. Spinophilin regulates central angiotensin II-mediated effect on blood pressure. J Mol Med 89, 1219–1229 (2011). https://doi.org/10.1007/s00109-011-0793-8

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  • DOI: https://doi.org/10.1007/s00109-011-0793-8

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