Elevated blood pressure, heart rate and body temperature in mice lacking the XLαs protein of the <i>Gnas</i> locus is due to increased sympathetic tone

Nunn, Nicolas, Feetham, Claire H, Martin, Jennifer, Barrett-Jolley, Richard ORCID: 0000-0003-0449-9972 and Plagge, Antonius ORCID: 0000-0001-6592-1343
(2013) Elevated blood pressure, heart rate and body temperature in mice lacking the XLαs protein of the <i>Gnas</i> locus is due to increased sympathetic tone. EXPERIMENTAL PHYSIOLOGY, 98 (10). pp. 1432-1445.

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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.

Item Type: Article
Additional Information: ## TULIP Type: Articles/Papers (Journal) ##
Uncontrolled Keywords: Venoms, Animals, Mice, Knockout, Mice, Reserpine, Atropine, GTP-Binding Protein alpha Subunits, Gs, Peptides, Proto-Oncogene Proteins c-fos, Chromogranins, Receptors, Glucagon, Body Temperature, Stress, Psychological, Blood Pressure, Heart Rate, Male, Glucagon-Like Peptide-1 Receptor, Exenatide
Depositing User: Symplectic Admin
Date Deposited: 04 May 2016 08:40
Last Modified: 13 Oct 2023 09:10
DOI: 10.1113/expphysiol.2013.073064
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3001036