title: Elevated blood pressure, heart rate and body temperature in mice lacking the XLαs protein of the Gnas locus is due to increased sympathetic tone.
abstract: Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl-deficient mice have a lean and hypermetabolic phenotype, with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS-related phenotypes, we have now investigated the cardiovascular system. The Gnasxl KO mice were ∼20 mmHg hypertensive in comparison to wild-type (WT) littermates (P ≤ 0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate in conscious KOs (630 ± 10 versus 584 ± 12 beats min(-1), KO versus WT, P ≤ 0.05). Body temperature was also elevated (38.1 ± 0.3 versus 36.9 ± 0.4°C, KO versus WT, P ≤ 0.05). To investigate autonomic nervous system influences, we used heart rate variability analyses. We empirically defined frequency power bands using atropine and reserpine and verified high-frequency (HF) power and low-frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. The LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. In contrast, atropine and exendin-4, a centrally acting agonist of the glucagon-like peptide-1 receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a greater increase in heart rate in KOs. Mild stress had a blunted effect on the LF/HF ratio in KOs consistent with elevated basal sympathetic activity. We conclude that XLαs is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues.
authors.affiliation: A. Plagge: Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK. a.plagge@liv.ac.uk. R. Barrett-Jolley: Institute of Ageing and Chronic Disease, 4th floor UCD Building, University of Liverpool, Daulby Str., Liverpool, L69 3GA, UK. Email: rbj@liv.ac.uk.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nunn
authors.forename: Claire H
authors.initials: CH
authors.lastname: Feetham
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martin
authors.forename: Richard
authors.initials: R
authors.lastname: Barrett-Jolley
authors.forename: Antonius
authors.initials: A
authors.lastname: Plagge
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001831:Body Temperature / Q000187:drug effects; D002864:Chromogranins; D000077270:Exenatide; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency* / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D013315:Stress, Psychological; D014688:Venoms / Q000494:pharmacology
chemical_list: D002864:Chromogranins; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D018027:Receptors, Glucagon; D014688:Venoms; D001285:Atropine; D012110:Reserpine; D000077270:Exenatide; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs