Copyright © 2005, European Society of Cardiology
Disruption of inhibitory G-proteins mediates a reduction in atrial β-adrenergic signaling by enhancing eNOS expression
aUniversity Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, UK
bDepartment of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK
cOxford Medical School, John Radcliffe Hospital, Oxford OX3 9DU, UK
* Corresponding author. Burdon-Sanderson Cardiac Science Centre, University of Oxford, Parks Road, Oxford OX1 3PT, UK. Tel.: +44 1865 282503; fax: +44 1865 282170. Email address: edward.danson{at}physiol.ox.ac.uk
Objective: Cardiac parasympathetic nerve activity is reduced in most cardiovascular disease states, and this may contribute to enhanced cardiac sympathetic responsiveness. Disruption of inhibitory G-proteins (Gi) ablates the cholinergic pathway and increases cardiac endothelial nitric oxide (NO) synthase (eNOS) expression, suggesting that NO may offset the impaired attenuation of β-adrenergic regulation of supraventricular excitability. To test this, we investigated the role of endogenous NO production on β-adrenergic regulation of rate (HR), contraction (CR) and calcium (Ca2+) handling in atria following blockade of Gi-coupled muscarinic receptors.
Methods: Mice were administered pertussis toxin (PTx, n = 105) or saline (C, n = 100) intraperitoneally. After 3 days, we measured CR, HR, and NOS protein levels in isolated atria. Intracellular calcium (Ca2+) transients and Ca2+ current density (ICa) were also measured in atrial myocytes.
Results: PTx treatment increased atrial myocyte eNOS protein levels compared to C (P<0.05). This did not affect basal atrial function but was associated with a significant reduction in the CR and HR response to isoprenaline (ISO) compared with C. NOS inhibition normalized responses in PTx atria with respect to responses in C atria (P<0.05), which were unaffected. Furthermore, PTx did not affect ISO-stimulated HR and CR in eNOS gene knockout mice (n = 40). In agreement with these findings, the ISO-mediated increase in Ca2+ transient was suppressed in PTx-treated myocytes (P<0.05), whereas ICa did not differ between groups.
Conclusion: eNOS-derived NO inhibits β-adrenergic responses following disruption of Gi signaling. This suggests that increased eNOS expression may be a compensatory mechanism which reduces β-adrenergic regulation of heart rate when cardiac parasympathetic control is impaired.
KEYWORDS Nitric oxide synthase; Contractility; Calcium; Catecholamines; Acetylcholine
* Presented in part at the 77th Scientific Sessions of the American Heart Association, New Orleans November 7–10th, 2004, and published in abstract form (Circulation. 2004;110[suppl III]:III-1102). Supported by the British Heart Foundation and the Wellcome Trust.
Time for primary review 24 days
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