Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC27

Poster Communications

Investigation of cardiovascular parameters as indicators of sympathetic activity in lean and hypermetabolic Gnasxl knock-out mice.

N. Nunn1,2, C. Feetham2, A. Plagge1, R. Barrett-Jolley2

1. Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom. 2. Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.

Obesity is a growing problem worldwide; anti-obesity drugs are being developed through the use of genetically modified mouse models. We are investigating the role of the autonomic nervous system in a lean knock-out (KO) mouse model, the Gnasxl KO. Gnasxl encodes XLαs, which is an extra-large variant of the G-protein subunit, Gsα, a signalling protein involved in cAMP production. Adult mice lacking XLαs are lean and hypermetabolic, showing increased energy expenditure and lipolysis (1). They also exhibit increased urinary catecholamine excretion, suggesting the phenotype may be caused by increased sympathetic tone (1). Our aim is to analyse cardiovascular parameters to determine the extent of sympathetic nervous system (SNS) involvement in the KO phenotype. Other data from our lab suggest a central cause, due to the restricted expression pattern of XLαs (2), which includes regions of the hypothalamus and medulla that are critical for sympathetic control. We investigated three indicators of SNS activity in adult male Gnasxl KO mice: blood pressure, body temperature and heart rate. Results are given as mean ±SEM. Blood pressure was measured by non-invasive tail plethysmography in urethane-anaesthetised mice (1.3-2.1 mg/g ip), and by arterial cannulation in dose-matched urethane-chloralose anaesthetised mice (urethane 1.4-2.2 mg/g ip; chloralose 7.0-11.0 µg/g ip). Using tail plethysmography, mean blood pressure was increased in Gnasxl knock-outs (KO) (79.4 ±6.6 mmHg, n=9) compared to wild-types (WT) (66.1 ±3.2 mmHg, n=8), p<0.05 by ANOVA. This was also seen using arterial cannulation, with increased blood pressure in KO (64.6 ±4.9 mmHg, n = 10) compared to WT (48.5 ±4.5 mmHg, n=9), p<0.05 by t-test. In urethane-chloralose anaesthetised mice (urethane 1.2-2.4 mg/g ip; chloralose 6.0-12.0 µg/g ip) core body temperature, measured by rectal probe, was elevated in KO (38.0 ±0.16 °C, n=13) compared to WT (36.6 ±0.30 °C, n=12), p<0.001 by t-test. ECG was recorded in conscious, freely moving mice by telemetry; transmitters were implanted under inhalation anaesthesia (isoflurane), and ECG was recorded after a recovery period. Continuous ECG data were digitised (DSI, UK) and processed with custom and PhysioNet software (3). Mean heart rate measured over a 24 hour period was elevated in KO (626 ±40 bpm, n=3) compared to WT (561 ±28 bpm, n=3), p<0.05 by paired t-test. Together, these results suggest that Gnasxl KO mice have increased sympathetic stimulation of the cardiovascular system, consistent with a basal increase in sympathetic tone. In future experiments, we will investigate the activity of neuropeptides and antagonists on the SNS in the Gnasxl KO.

Where applicable, experiments conform with Society ethical requirements