Peripheral vagal control of heart rate is impaired in neuronal NOS knockout mice.
The role of nitric oxide (NO) in the vagal control of heart rate (HR) is controversial. We investigated the cholinergic regulation of HR in isolated atrial preparations with an intact right vagus nerve from wild-type (nNOS+/+, n = 81) and neuronal NO synthase (nNOS) knockout (nNOS-/-, n = 43) mice. nNOS was immunofluorescently colocalized within choline-acetyltransferase-positive neurons in nNOS+/+ atria. The rate of decline in HR during vagal nerve stimulation (VNS, 3 and 5 Hz) was slower in nNOS-/- compared with nNOS+/+ atria in vitro (P < 0.01). There was no difference between the HR responses to carbamylcholine in nNOS+/+ and nNOS-/- atria. Selective nNOS inhibitors, vinyl-L-niohydrochloride or 1-2-trifluoromethylphenyl imidazole, or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one significantly (P < 0.05) attenuated the decrease in HR with VNS at 3 Hz in nNOS+/+ atria. NOS inhibition had no effect in nNOS-/- atria during VNS. In all atria, the NO donor sodium nitroprusside significantly enhanced the magnitude of the vagal-induced bradycardia, showing the downstream intracellular pathways activated by NO were intact. These results suggest that neuronal NO facilitates vagally induced bradycardia via a presynaptic modulation of neurotransmission.
Choate
J K
JK
Department of Physiology, Monash University, Victoria 3800, Australia.
Danson
E J
EJ
Morris
J F
JF
Paterson
D J
DJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006325:Heart Atria / Q000201:enzymology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007031:Hypothalamus / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D052248:Nitric Oxide Synthase Type I; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000502:physiology; D010276:Parasympatholytics / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012849:Sinoatrial Node / Q000294:innervation / Q000502:physiology; D013268:Stimulation, Chemical; D014630:Vagus Nerve / Q000166:cytology / Q000502:physiology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C111862:N(5)-(1-imino-3-butenyl)ornithine; D010069:Oxadiazoles; D010276:Parasympatholytics; D011810:Quinoxalines; D002586:Cesium; C098186:1-(2-trifluoromethylphenyl)imidazole; D009569:Nitric Oxide; D001285:Atropine; D002217:Carbachol; D011433:Propranolol; D009952:Ornithine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D006162:Guanylate Cyclase