title: Spinophilin regulates central angiotensin II-mediated effect on blood pressure.
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.
authors.affiliation: Leibniz Institute for Molecular Pharmacology, Berlin, Germany. goncalvs@fmp-berlin.de
authors.forename: Andrey C
authors.initials: AC
authors.lastname: da Costa Goncalves
authors.forename: Marco Antonio Peliky
authors.initials: MA
authors.lastname: Fontes
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Jürgen
authors.initials: J
authors.lastname: Janke
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleifenbaum
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
authors.forename: Jens
authors.initials: J
authors.lastname: Tank
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001794:Blood Pressure / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D005786:Gene Expression Regulation; D006339:Heart Rate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D014667:Vasopressins / Q000235:genetics / Q000378:metabolism; D000099273:Neurabins
chemical_list: D000804:Angiotensin II; D065092:Antidiuretic Hormone Receptor Antagonists; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017483:Receptors, Vasopressin; D014667:Vasopressins; D000099273:Neurabins; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse