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Nitric Oxide Signalling.jpgHigh cardiac vagal tone is a positive prognostic indicator against sudden cardiac death (1). Emerging evidence suggests that endogenous nitric oxide (NO) is a fundamental signalling molecule in the regulation of peripheral cardiac cholinergic function, although some aspects of NO signalling remain controversial(2-6). Pharmacological evidence suggests that NO generated from neuronal nitric oxide synthase (NOS-1) enhances the negative chronotropic effect of vagal nerve stimulation eg. (7,8) by activating the guanylate cyclase / cGMP pathway (8,9) to facilitate the release of acetylcholine (ACh) (9). However, the vagal heart rate response to modulators of the NO-cGMP pathway is not mimicked when the stable analogue of acetylcholine is applied, suggesting that the dominant functional role of this pathway is isoform and site specific residing at the level of the intra-cardiac ganglia (8,10). 

1. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. (1999) N Engl J Med 341:1351-1357.

2. Chowdhary S, Ng GA, Nuttall SL, Coote JH, Ross HF, Townend JN. Nitric oxide and cardiac parasympathetic control in human heart failure. (2002) Clin Sci (Lond) 102:397-402.

3. Chowdhary S, Townend JN. Role of nitric oxide in the regulation of cardiovascular autonomic control. (1999) Clin Sci (Colch) 97:5-17.

4. Balligand JL. Regulation of cardiac beta-adrenergic response by nitric oxide. (1999) Cardiovasc Res 43:607-620.

5. Vandecasteele G, Eschenhagen T, Scholz H, Stein B, Verde I, Fischmeister R. Muscarinic and beta-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. (1999) Nat Med 5:331-334.

6. Paterson DJ. Nitric oxide and the autonomic regulation of cardiac excitability. (2001) Expt Physiol 86:1-12.

7. Conlon K, Kidd C. Neuronal nitric oxide facilitates vagal chronotropic and dromotropic actions on the heart. (1999) J Auton Nerv Syst 75:136-146.

8. Herring N, Golding S, Paterson DJ. Pre-synaptic NO-cGMP pathway modulates vagal control of heart rate in isolated adult guinea pig atria. (2000) J Mol Cell Cardiol 32:1795-1804.

9. Herring N, Paterson DJ. Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the guinea-pig in vitro. (2001) J Physiol 535:507-518.

10. Sears CE, Choate JK, Paterson DJ. NO-cGMP pathway accentuates the decrease in heart rate caused by cardiac vagal nerve stimulation [In Process Citation]. (1999) J Appl Physiol 86:510-516.

11. Mohan, R.M., Golding, S. & Paterson, D.J. (2001). Intermittent hypoxia reduces nNOS expression and increases the heart rate response to cardiac sympathetic nerve stimulation in-vitroAm. J. Physiol. 281(1): H132-H138. [Abstract] [Full Text]

12. Herring, N., Rigg, L., Terrar, D.A. & Paterson D.J. (2001). NO-cGMP pathway increases the hyperpolarisation activated current, If, and heart rate during adrenergic stimulation. Cardiovas. Res. 52(3):446-453. [Abstract]

13. Mohan R.M., Heaton D.A., Danson E.J.F., Krishnan S.P.R., Cai S., Channon K.M. & Paterson D.J. (2002) Neuronal Nitric Oxide Synthase Gene Transfer Promotes Cardiac Vagal Gain of Function. Circulation Research 91(12):1089-1091. [Abstract] [Full Text] [PDF Reprint 252KB]

14. Danson, E.J.F. & Paterson, D.J. (2003) Enhanced neuronal nitric oxide synthase expression is central to cardiac vagal phenotype in exercise-trained mice J. Physiol. 546(1):225-232.  [Full Text]

15. Mohan, R.M.M., Golding, S., Heaton, D.A., Danson, E.J.F. & Paterson, D.J. (2004). Targeting neuronal nitric oxide synthase with gene transfer to modulate cardiac autonomic function. Prog. Biophys. Mol. Biol. 84:321-344 [Full text]

16. Danson, E.J., Mankia, K.S., Golding, S., Dawson,T., Everatt, L., Cai, S.J., Channon, K.M. & Paterson, D.J. (2004) Impaired regulation of neuronal NOS and heart rate during exercise in mice lacking one nNOS allele. J Physiol.558(3):963-974  [ Full Text]

17. Danson, E.J.F., Zhang, Y.H., Sears, C.E., Edwards, A.R., Casadei, B., & Paterson, D.J. (2005) Disruption of inhibitory G-proteins mediates a reduction in atrial beta-adrenergic signaling by enhancing eNOS expression. Cardiovas Res.67(4):613-23 [Abstract/Full Text].

18. Heaton, D.A., Golding, S., Bradley, C.P., Dawson, T.A., Cai, S., Channon, K.M. & Paterson, D.J. (2005) Targeted nNOS gene transfer into the cardiac vagus rapidly increases parasympathetic function in the pig. J. Mol. Cell. Cardiol.39(1):159-64 [Abstract/Full Text]

19. Wang, L., Li, D., Plested, C.P., Dawson, T.D., Teschemacher, A. and Paterson, D.J. (2006) Noradrenrgic neuron-specific overexpression of nNOS in cardiac sympathetic nerves decreases neurotransmission. J Mol Cell Cardiol.Aug;41(2):364-70 [Abstract/Full Text]

20. Heaton, D.A., Lei, M., Li, D., Golding, S., Dawson, T.A., Mohan, R.M., and Paterson, D.J. (2006) Remodelling of Cardiac Pacemaker I_CaL and Beta-adrenergic Responsiveness in Hypertension following nNOS Gene Transfer. Hypertension 48:443-452 [Abstract/Full Text]

21. Heaton, D.A., Li, D., Almond, S.C., Dawson, T.A., Wang, L., Channon, K.M., and Paterson, D.J. (2007) Gene Transfer of nNOS into Intracardiac Ganglia Reverses Vagal Impairment in Hypertensive Rats Hypertension 49:380-388[Abstract/Full Text]

22. Li, D., Wang, L., Chee-Wan, L., Dawson, T.A., and Paterson, D.J. (2007) Noradrenergic Cell Specific Gene Transfer With Neuronal Nitric Oxide Synthase Reduces Cardiac Sympathetic Neurotransmission in Hypertensive Rats. Hypertension 50(1):69-74 [Abstract/Full Text]

23. Wang, L., Henrich, M., Buckler, K., McMenamin, M., Mee, C.J., Sattelle, D.B., and Paterson, D.J. (2007) Neuronal nitric oxide synthase gene transfer decreases [Ca2+]i in cardiac sympathetic neurons J Mol Cell Cardiol. 43(6):717-25[Abstract/Full Text]

24. Dawson, T.A., Li, D., Woodward, T.D., Barber, Z.E., Wang, L. and Paterson, D.J. (2008) Cardiac Cholinergic NO-cGMP Signalling Following Acute Myocardial Infarction and nNOS Gene Transfer Am. J. Physiol. Heart Circ. Physiol.295(3):H990-H998 [Abstract/Full Text]

25. Wang, L., Li, D., Dawson, T.A. and Paterson, D.J. (2009) Long term effect of nNOS overexpression on cardiac neurotransmission mediated by a lentiviral vector. J. Physiol. 587.14:3629-3637 [Abstract / Full text].

26. Li D, Nikiforova, N., Lu, C-J. Wannop, K., McMenamin, M., Lee CW, Buckler K, Paterson DJ. (2013). Targeted neuronal nitric oxide synthase transgene delivery into stellate neurons reverses impaired intracellular calcium transients in prehypertensive rats. Hypertension Jan;61(1):202-207 [Abstract/Full Text].