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Spinophilin regulates central angiotensin II-mediated effect on blood pressure

Item Type:Article
Title:Spinophilin regulates central angiotensin II-mediated effect on blood pressure
Creators Name:da Costa Goncalves, A.C. and Fontes, M.A. and Klussmann, E. and Qadri, F. and Janke, J. and Gollasch, M. and Schleifenbaum, J. and Mueller, D. and Jordan, J. and Tank, J. and Luft, F.C. and Gross, V.
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.
Keywords:Angiotensin II, Spinophilin, Blood Pressure Regulation, Autonomic Nervous System, Telemetry, Animals, Mice
Source:Journal of Molecular Medicine
Page Range:1219-1229
Date:December 2011
Official Publication:https://doi.org/10.1007/s00109-011-0793-8
PubMed:View item in PubMed

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