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Short-term over-expression of neuronal nitric oxide synthase (nNOS) with adenoviral gene transfer into peripheral cardiac autonomic neurons can facilitate cholinergic neurotransmission, and inhibit sympathetic transmission, by regulating cyclic nucleotide-dependent pathways coupled to neuronal calcium entry. We tested the idea whether cardiac neuromodulation by nNOS could be sustained by long-term over-expression of the enzyme following lentiviral gene transfer. We developed a lentiviral vector with an elongation factor 1 (EF1alpha) promoter to drive nNOS or enhanced green fluorescent protein (eGFP) expression. Lenti.EF1alpha-nNOS or Lenti.EF1alpha-eGFP was transferred to the right atrium of Spague-Dawley (SD) rats and acetylcholine (ACh) or noradrenaline (NA) release to field stimulation was measured 4 months after gene transfer. Atria transduced with Lenti.EF1alpha-nNOS had higher nNOS expression compared to the atria treated with Lenti.EF1alpha-eGFP (P < 0.05). We also detected significant increases (P < 0.05) in atrial cGMP and cAMP levels in the same tissue. Immunohistochemistry revealed co-localisation of eGFP in intrinsic cholinergic neurons (choline acetyltransferase positive) and intrinsic adrenergic neurons (tyrosine hydroxylase positive) following gene transfer. nNOS-transduced animals displayed enhanced ACh release (P < 0.05) and reduced NA release (P < 0.05) compared to the eGFP-treated group. nNOS-specific inhibition reversed the enhanced ACh release. Persistent nNOS over-expression mediated by a lentiviral vector can modulate sympatho-vagal control of cardiac excitability. This approach may provide a new tool to target impaired cardiac autonomic phenotypes that are disrupted by several cardiovascular pathologies.

Original publication

DOI

10.1113/jphysiol.2009.172866

Type

Journal article

Journal

J Physiol

Publication Date

15/07/2009

Volume

587

Pages

3629 - 3637

Keywords

Action Potentials, Animals, Genetic Vectors, Heart, Lentivirus, Long-Term Potentiation, Neurons, Nitric Oxide Synthase Type I, Rats, Rats, Sprague-Dawley, Rats, Transgenic, Synaptic Transmission, Up-Regulation