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Disruption of inhibitory G-proteins mediates a reduction in atrial beta-adrenergic signaling by enhancing eNOS expression.

Abstract：

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 beta-adrenergic regulation of supraventricular excitability. To test this, we investigated the role of endogenous NO production on beta-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 (I(Ca)) 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 I(Ca) did not differ between groups. CONCLUSION:eNOS-derived NO inhibits beta-adrenergic responses following disruption of Gi signaling. This suggests that increased eNOS expression may be a compensatory mechanism which reduces beta-adrenergic regulation of heart rate when cardiac parasympathetic control is impaired.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Danson EJ,Zhang YH,Sears CE,Edwards AR,Casadei B,Paterson DJ

doi

10.1016/j.cardiores.2005.04.034

subject

Has Abstract

pub_date

2005-09-01 00:00:00

pages

613-23

issue

eissn

0008-6363

issn

1755-3245

pii

S0008-6363(05)00224-5

journal_volume

pub_type

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Disruption of inhibitory G-proteins mediates a reduction in atrial beta-adrenergic signaling by enhancing eNOS expression.