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- Title
Disruption of inhibitory G-proteins mediates a reduction in atrial β-adrenergic signaling by enhancing eNOS expression
- Authors
Danson, E.J.F.; Zhang, Y.H.; Sears, C.E.; Edwards, A.R.; Casadei, B.; Paterson, D.J.
- Abstract
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 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 (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 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.
- Subjects
CARDIOVASCULAR diseases; PROTEINS; BIOMOLECULES; ORGANIC compounds
- Publication
Cardiovascular Research, 2005, Vol 67, Issue 4, p613
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1016/j.cardiores.2005.04.034