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16 Imaging Regional Differences in Beta-2 Adrenergic Receptor Function at The Cellular Level
  1. PT Wright1,
  2. LMK Pannell1,
  3. VO Nikolaev1,2,
  4. AR Lyon3,
  5. SE Harding1,
  6. J Gorelik1
  1. 1Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College, London, UK
  2. 2Emmy Noether Group of the DFG, Department of Cardiology and Pneumology, Heart Research Center Göttingen, Georg August University, Göttingen, Germany
  3. 3Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK

Abstract

A common feature of stress cardiomyopathy is contractile impairment of the left ventricular (LV) apical myocardium, although sympathetic effectors are elevated. We investigated the responsiveness of murine cardiomyocytes (CMs) from different LV regions to beta-2 adrenergic (beta2AR) stimulation. Although, initially positively inotropic, beta2AR may become negatively inotropic via biassed-agonism. The apical myocardium may express more beta2ARs as it’s relatively reliant on inotropic support from circulating adrenaline. High initial beta2AR-cAMP activation may initiate stimulus trafficking to beta2AR-Gi signalling. Contractile response to beta2AR stimulation (1µM Isoprenaline with 300nM CGP20712A) was measured by video microscopy. Whole-cell cAMP production after beta2AR stimulation was measured by FRET-based cAMP sensors. Apical CMs (ApCMs) significantly increased their initial contractility following beta2AR stimulation compared to Basal CMs (BCMs) from rats (ApCM 2.28 fold ±0.12 n=10 vs. BCM 1.32 fold ±0.06 n=8 p<0.0001; mean ± sem) and mice (ApCM 2.38 fold ±0.2 n=6 vs. BCM 1.43 fold ±0.1 n=6 p<0.01; mean ± sem). The amplitude of the cAMP transients from ApCMs and BCMs didn’t differ for either rat (ApCM 46.7%±5.0 n=14 vs. BCM 42.4%±4.5 n=16 p=NS: values are %maximal FRET response; mean ± sem) or mouse (ApCM 9.1%±2.0 n=6 vs. BCM 7.6%±2.5 n=7 P=NS: %max FRET; mean ± sem). In rat ApCM the cAMP response persisted 250 seconds post-stimulation (ACM 2.28%±1.0 n=7 vs. BCM 0.27±0.1 n=10 p<0.05: %rawFRET; mean ± sem). ApCMs have a larger beta2AR-Gs-contractile response in two different mammalian species. A persisting cAMP response in the ApCMs may enable this by allowing cAMP greater access to PKA compartments.

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