Noradrenergic neuron-specific overexpression of nNOS in cardiac sympathetic nerves decreases neurotransmission.
Gene transfer of neuronal nitric oxide synthase (nNOS) with nonspecific adenoviral vectors can cause promiscuous transduction. We provide direct evidence that nNOS targeted only to cardiac sympathetic neurons inhibits sympathetic neurotransmission. An adenovirus constructed with a noradrenergic neuron-specific promoter (PRSx8), driving nNOS or enhanced green fluorescence protein (eGFP) gene expression caused exclusive expression in tyrosine hydroxylase (TH) positive rat cardiac sympathetic neurons. There was no detectable leakage of transgene expression in other cell types in the preparation nor did the transgene express in choline acetyltransferase (CHAT)-positive intracardiac cholinergic ganglia. Functionally, Ad.PRS-nNOS gene transfer increased nNOS activity and significantly reduced norephinephrine release evoked by field stimulation of isolated right atria. These effects were reversed by the NOS inhibitor N(omega)-Nitro-L-arginine. Our results demonstrate that noradrenergic cell-specific gene transfer with nNOS can inhibit cardiac sympathetic neurotransmission. This targeted technique may provide a novel method for reducing presynaptic sympathetic hyperactivity.
Wang
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Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, UK.
Li
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D
Plested
C P
CP
Dawson
T
T
Teschemacher
A G
AG
Paterson
D J
DJ
D000256:Adenoviridae; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015870:Gene Expression / Q000187:drug effects; D006325:Heart Atria / Q000166:cytology / Q000201:enzymology; D006329:Heart Conduction System / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology*; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis* / Q000235:genetics; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000201:enzymology*; D013566:Sympathomimetics / Q000494:pharmacology*; D014161:Transduction, Genetic
D013566:Sympathomimetics; D052248:Nitric Oxide Synthase Type I; D009638:Norepinephrine