Neuronal nitric oxide synthase gene transfer promotes cardiac vagal gain of function.
Nitric oxide (NO) generated from neuronal nitric oxide synthase (NOS-1) in intrinsic cardiac ganglia has been implicated in parasympathetic-induced bradycardia. We provide direct evidence that NOS-1 acts in a site-specific manner to promote cardiac vagal neurotransmission and bradycardia. NOS-1 gene transfer to the guinea pig right atrium increased protein expression and NOS-1 immunolocalization in cholinergic ganglia. It also increased the release of acetylcholine and enhanced the heart rate (HR) response to vagal nerve stimulation (VNS) in vitro and in vivo. NOS inhibition normalized the HR response to VNS in the NOS-1-treated group compared with the control groups (enhanced green fluorescent protein and sham) in vitro. In contrast, an acetylcholine analogue reduced HR to the same extent in all groups before and during NOS inhibition. These results demonstrate that NOS-1-derived NO acts presynaptically to facilitate vagally induced bradycardia and that upregulation of NOS-1 via gene transfer may provide a novel method for increasing cardiac vagal function.
Mohan
R M
RM
University Laboratory of Physiology, Oxford, UK.
Heaton
D A
DA
Danson
E J F
EJ
Krishnan
S P R
SP
Cai
S
S
Channon
K M
KM
Paterson
D J
DJ
D000109:Acetylcholine / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D000109:Acetylcholine